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Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this work and share the first authorship.
Cancers 2019, 11(12), 2015;
Submission received: 19 November 2019 / Revised: 5 December 2019 / Accepted: 9 December 2019 / Published: 13 December 2019
(This article belongs to the Special Issue Latest Development in Multiple Myeloma)


Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients’ serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of “operational cure”, although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment.

1. Introduction

Multiple Myeloma (MM) is a hematologic malignancy caused by the outgrowth of monoclonal plasma cells that leads to end-organ damage [1]. In 2018, MM accounted for 1.2% of all cancer diagnoses and 1.6% of all cancer deaths in Europe [2]. The median overall survival (OS) of newly diagnosed (ND) MM patients improved from 3.9 years for patients diagnosed between 2004 and 2007 to 6.3 years for those diagnosed between 2008 and 2012 to a median OS that is not yet reached in patients diagnosed after 2012 [3]. The introduction of new drug classes like proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and, more recently, monoclonal antibodies (mAbs) has been the main determinant of the observed OS improvement, together with an improved supportive care. Nevertheless, the main cause of death in MM patients is still the development of drug-resistant disease [4]. Although obtaining deep responses is a universally recognized predictive factor of good outcome [5], long-term disease control, rather than disease eradication, is still the aim of MM treatment in current clinical practice, since the available data show that even patients achieving minimal residual disease (MRD) negativity relapse. This confirms the so-far incurable nature of MM. Recent data, comparing the survival of young MM patients treated between 2005 and 2015 to that of young patients affected by curable hematologic diseases (e.g., diffuse large B cell lymphoma (DLBCL) and Hodgkin Lymphoma (HL)) [6] and to that of the general population showed that MM patients have a 20-fold excess mortality compared to the general population, while DLBCL and HL have a non-significant excess mortality [6].
However, more recent results from clinical trials exploring novel three-drug and four-drug combinations showed unprecedented rates of prolonged and deep responses [7,8,9,10,11], with acceptable safety profiles even in elderly patients, thus increasing the likelihood not only to achieve disease control, but potentially cure, at least in a subset of patients. To design a potentially curative strategy, we have to focus on the first stages of the disease (smoldering MM (SMM), newly diagnosed MM (NDMM)), when the patient is treatment-naïve and disease genomic complexity is lower, as compared to the advanced relapsed/refractory setting.
In this review, we provide a summary of the new techniques used to detect residual disease at high sensitivity and of the results obtained in SMM and NDMM with new-generation combinations. We also explore how we can exploit these data in the future, towards a potential cure of MM.

2. Evolution of Response Criteria and MRD Techniques

To enable disease eradication strategies, it is mandatory to have sensitive methods to detect small amounts of residual disease after treatment. MM response criteria evolved together with therapies. While before the introduction of novel agents, the rates of complete remission (CR) were very low (2% after 3 cycles of vincristine–doxorubicin–dexamethasone [12]), with novel combinations CR can now be obtained in >60% of patients [9]. Conventionally, MM response is evaluated measuring M-protein levels in the blood and urine, but it is now clear that even when M-protein disappears, residual disease can still be present [13]. The Spanish group showed that, among patients with a conventionally defined CR, there was a significant difference in outcome between MRD-negative and MRD-positive patients (median progression-free survival (PFS) 63 vs. 27 months, p < 0.001; median OS not reached vs. 59 months, p < 0.001). Interestingly, the outcome of patients with MRD-positive CR was similar to the outcome of those achieving only a partial response (PR), thus suggesting that the advantage of reaching CR over PR relies on the MRD-negative status. Recently, response criteria have been updated, introducing a universal definition of MRD beyond CR (for a detailed definition of the updated response criteria, please refer to Kumar et al., 2016) [14,15,16,17].
Two techniques have been developed and validated to detect MRD into the bone marrow: multiparameter flow cytometry (MFC) and next-generation sequencing (NGS).
MFC detects and quantifies tumor plasma cells using cell surface and cytoplasmic markers. Neoplastic plasma cells are characterized by the aberrant expression of molecules like CD19, CD20, CD27, CD28, CD33, CD38, CD45, CD56, CD117, and surface membrane immunoglobulin [18]. The first attempts to detect MRD by MFC had a maximum sensitivity of 10−4–10−5. The optimization of the MFC assay using two 8-color tubes, a bulk-lysis procedure, the acquisition of ≥107 cells/sample, and the automatic plasma cell gating through a software tool led to reproducible results and enhanced the maximum sensitivity to 10−5–10−6 (next-generation flow, NGF) [19,20]. Using NGF, Flores-Montero and colleagues demonstrated that 25% of patients who were classified as MRD-negative by second-generation MFC were indeed MRD-positive by NGF [20]. Moreover, NGF negativity predicted a significantly longer PFS than second-generation MFC negativity among CR patients (p = 0.02) [20].
NGS technique was mainly developed by Adaptive Biotechnologies (Seattle, WA, USA) by producing and validating ClonoSEQ® Assay, which has recently obtained, by the Food and Drug Administration (FDA), the authorization as standardized technique for the disease evaluation in MM patients [21]. In this test, DNA from the immunoglobulin genes is amplified and sequenced using baseline bone marrow sample and identical sequences detected in more than 5% of the reads are identified as clonal gene rearrangements. These rearrangements are then searched in follow-up samples to identify MRD [22,23]. NGS reaches maximum sensitivity up to 10−6 [21].
Ongoing clinical trials are evaluating NGS vs. NGF/MFC and their correlation [24], and will help understand if the two techniques can be considered equivalent in identifying MRD negativity at a specific cut-off. Each technique has its own advantages and drawbacks (Table 1).
The maximum sensitivity reached is a key point, especially in a curative perspective. Each log depletion in MRD levels predicts a 1-year median OS advantage (5.9 years at 10−2–10−3, 6.8 years at 10−3–10−4, and ≥7.5 years at 10−4), suggesting that MRD levels at the highest sensitivity should be pursued [25]. Several reports suggested that once MRD-negative statuses are reached with a high sensitivity technique, patient prognoses are similar independently from the treatment that induced MRD negativity [26,27]. This observation also seems to apply to patients with adverse baseline prognostic factors (e.g., high-risk cytogenetics or elevated Revised International Staging System (R-ISS) stage), among whom MRD-negative patients at a sensitivity of 10−5–10−6 [26,28], but not at a sensitivity of 10−4 [29], showed similar clinical outcomes compared to standard-risk patients. Nevertheless, reaching MRD negativity in high-risk patients may be harder [30], and intensive regimens are likely needed in this patient population [8,9].
Even when evaluating MRD at a sensitivity of 10−6, there are still patients that can relapse. Relapses can also be caused by extramedullary disease [31]. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is currently considered the standard of care to assess residual disease outside the bone marrow [32,33]. The predictive role of post-treatment PET/CT has been demonstrated by different studies [34,35,36] and, in a head-to-head comparison [34], the normalization of PET/CT outperformed that of conventional magnetic resonance imaging after therapy for the prediction of PFS and OS. Recently, Zamagni et al. presented data on the standardization of PET/CT to define criteria for MRD negativity using the 5-point Deauville score. PET/CT imaging was a reliable predictor of outcomes regardless of treatment. The achievement of a Deauville score ≤3 was the predictor of a longer time to disease progression and overall survival (OS) and, consequently, a potential standardized definition of PET/CT negativity [37].
MRD assessed by PET/CT and bone marrow techniques synergistically predict patient outcome, with the best PFS detected in patients who were MRD-negative both within and outside the bone marrow [38]; hence the definition of Imaging MRD negativity.
Both the NGS and the NGF-plus-Imaging approaches are needed for the response evaluation in the setting of a curative strategy. Nevertheless, from a practical perspective, it should be determined if all these techniques are necessary for all patients, or if it is possible to develop an algorithm to define how to proceed. To do this, we need to answer open questions such as: In which patients should we perform MRD (CR, stringent CR (sCR) very good partial response (VGPR))? What is the proportion of patients who are still PET-positive despite being MRD-negative in the bone marrow with a high cut-off level (e.g., 10−6)? Vice versa, how many PET-positive patients are MRD-negative? Who are the patients that show discrepancies between the two evaluations? Ongoing studies including both BM and PET/CT evaluation at specific time points will help in drawing conclusions [37].
In the future, liquid biopsy approaches that use peripheral blood samples could potentially overcome the need to assess MRD both in the bone marrow and by imaging. However, these techniques are still at early developmental stages [39].
Besides achieving MRD negativity, a more important factor is maintaining it [40]: here comes the definition of “sustained MRD negativity” by the International Myeloma Working Group (IMWG), which uses the 1-year cut-off. An effort should be made to define the optimal duration of MRD negativity to reach an “operational cure”; this still remains an unanswered question, with a potentially great clinical relevance. For instance, in the chronic myeloid leukemia field, a sustained major molecular response lasting at least 2 years is usually required to be a candidate for treatment discontinuation [41], and longer deep molecular response durations prior to discontinuation are associated with the increasing probability of maintaining a major molecular response after discontinuation [42]. Little data are available in MM. Using MFC to monitor MM patients after induction and at different time points post-autologous stem-cell transplantation (ASCT), Gu and colleagues showed that, among patients achieving MRD negativity after the post-induction time point, MRD reappearance can happen 18–24 months after ASCT, thus suggesting that long-term confirmation of sustained MRD negativity may be necessary [43].

3. Treatment of High-Risk SMM

SMM [44] is an asymptomatic plasma cell neoplasm harboring a variable risk of progression to MM. Several scores have been proposed to assess SMM risk of progression to symptomatic MM (Table 2) [45,46].
The 2/20/20 model was the most recently proposed; its name comes from the resulting cut-offs of M-protein, bone marrow plasma cells (BMPC), and free light chains (FLC). M-protein >2g/dL (hazard ratio (HR) 1.56, p = 0.01; BMPC % >20% (HR 2.28, p < 0.0001), and FLC ratio (FLCr) >20 (HR 2.13, p < 0.0001)) independently predicted shorter time to progression (TTP) in multivariate analysis. Three risk groups were identified: Low risk (none of the risk factors), intermediate risk (1 risk factor), and high risk (≥2 risk factors), with a median TTP of 110, 68, and 29 months, respectively (p < 0.0001) [45]. The high-risk group consisted of 36% of the analyzed cohort of SMM.
A retrospective multicenter study by the IMWG validated the 2/20/20 model; furthermore, incorporating the cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH; presence vs. absence of t(4,14), t(14,16), 1q gain, and/or del13), they identified four risk categories with a 2-year progression risk of 3.7% (low risk), 25% (low–intermediate), 49% (intermediate–high), and 72% (high) [49].
The current standard of care for SMM is periodical monitoring, with a suggested frequency based on patient risk to identify the possible evolution to symptomatic MM in due time and avoid severe organ damage. While this strategy suits well low-risk SMM patients who are unlikely to progress to MM, it may be questionable in high-risk SMM. In this setting, open questions are: (1) Can these patients benefit from an early therapy aiming at delaying the very likely evolution to MM? (2) Is there a possibility that early treatment may actually cure the disease? The latter hypothesis is based upon the very good outcome observed in patients with symptomatic MM and good prognosis [50], as well as upon a lower genomic complexity during the early phases of the disease that, together with a lower tumor burden, might suggest a higher possibility of cure [51]. Moreover, better treatment feasibility is expected in asymptomatic patients in good conditions. This rationale led to the design of clinical trials for the treatment of high-risk SMM (Table 3).
In the phase III randomized QuiRedex study, 119 high-risk SMM patients [52] received lenalidomide–dexamethasone (Rd) vs. observation. After a median follow-up of 75 months, the median TTP was not reached in the Rd group (n = 57) vs. 23 months in the observation group (n = 62, HR 0.24, p < 0.0001). An advantage in OS in the Rd arm was also detected (HR 0.43, p = 0.024). Interestingly, survival was similar in the two groups for patients who had previously received subsequent lines of therapy at the progression to active disease (HR 1.34, p = 0.50). The Rd combination showed acceptable levels of toxicity: Grade ≥3 adverse events (AEs) were infection (6%), asthenia (6%), neutropenia (5%), and skin rash (3%). During treatment, two patients treated with lenalidomide died of infection. A higher rate of second primary malignancies (SPMs) was detected in the Rd group (10%) vs. the observation group (2%). Of note, progression was defined by classical CRAB criteria (hyperCalcemia, Renal failure, Anemia, and Bone lesions) and advanced imaging techniques at screening were not performed, thus suggesting that the study also included patients who would currently be classified as having symptomatic MM.
The efficacy of lenalidomide was also shown in the phase II/III E3A06 study, in which lenalidomide was compared to observation in SMM [62]. After a median follow-up of 35 months in phase III of the trial, the overall response rate (ORR) was 50% in the R group and 0% in the observational group. One-year, 2-year, and 3-year PFS were respectively 98%, 93%, and 91% in the R group, favorably comparing with respectively 89%, 76%, and 66% in the observational arm (HR 0.28, p = 0.002). Among lenalidomide-treated patients, grade 3/4 non-hematologic toxicities occurred in 28% of the phase III patients, with hypertension and infections being most common toxicities. However, no difference in scores regarding the quality of life was noted between the lenalidomide and the observational groups. In this trial, SPMs were detected in 11.4% of lenalidomide-treated patients vs. 3.4% of patients in the observational group.
In this setting, another attractive drug is the second-generation PI ixazomib, which is characterized by a convenient oral administration and shows good safety results. In a phase I study, ixazomib associated with dexamethasone showed good tolerability and high response rate (ORR 64%, PR 57%, and VGPR 14%) [55]. A phase II study exploring the entirely oral triplet ixazomib–lenalidomide–dexamethasone confirmed the good tolerability profile and efficacy of this combination, with a 58% of ≥VGPR (CR 19%, VGPR 34%) [58].
MAbs were also evaluated for the treatment of SMM. The anti-SLAMF7 elotuzumab as single agent showed a low response rate (ORR 10%, minimal response (MR) 29%), with a 2-year PFS of 69%, while first data of the combination with Rd showed a ≥VGPR rate of 43% [56,57].
The phase II CENTAURUS trial evaluated daratumumab alone in 123 patients with three different dose schedules and durations (long intense, intermediate, short intense; Table 3) [60]. At a median follow-up of 25.9 months, ≥VGPR rates were higher in the long intense and intermediate arms compared to the short intense arm (29%, 25%, and 18%, respectively). The 24-month PFS rates were 90%, 82%, and 75% in the three arms. Grade ≥3 AEs occurred in 44% (long intense), 27% (intermediate), and 15% (short intense) of patients. The most frequent grade 3–4 AEs were hypertension and hyperglycemia. The subcutaneous formulation of daratumumab is also being explored in a randomized phase III trial against active monitoring in this setting (NCT03301220). Another anti-CD38 mAb, isatuximab, is under evaluation (NCT02960555).
More intense regimens using three- or four-drug combinations ±ASCT were used in the high-risk SMM setting, aiming at the eradication of MM.
In a small cohort of 12 high-risk SMM patients, Korde and colleagues demonstrated that carfilzomib–lenalidomide–dexamethasone (KRd) induced deep responses (≥CR 100%) and MRD negativity (92% by MFC); after a median follow-up of 15.9 months, none of the patients progressed to MM [53]. Interestingly, the same regimen administered in the NDMM setting produced a lower rate of deep responses (≥CR 56%), suggesting that high-risk SMM patients can be more sensitive to treatment [53].
In the single-arm, phase II GEM-CESAR trial, patients received KRd as induction, ASCT, KRd as consolidation and maintenance therapy with Rd. After a median follow-up of 32 months (8–128), the 30-month PFS was 93% and each phase of therapy was associated with increasing rates of MRD negativity evaluated by NGF (sensitivity 3 × 10−6; 31% after induction, 56% after ASCT, 63% after consolidation). During induction, the most common G≥3 AEs were infections (18%), skin rash (9%), neutropenia (6%), and thrombocytopenia (11%). Cardiac AEs were rare: 1 grade 1 atrial fibrillation, 1 cardiac failure secondary to respiratory infection, and 3 cases of hypertension during consolidation [54].
Another ongoing randomized phase II study (HO147SMM) is comparing KRd to Rd, but no data are available yet.
The addition of the anti-CD38 mAb daratumumab to KRd induction and consolidation is being evaluated in the ASCENT study (NCT03289299), which is now recruiting patients. A randomized comparison of daratumumab–Rd vs. Rd in the context of high-risk SMM is also ongoing (NCT03937635).

4. Treatment of Symptomatic NDMM

The first efforts aiming at a curative approach in NDMM were done by the University of Arkansas group in the 1990s, developing a program called Total Therapy (TT) using a series of non-cross-resistant induction regimens, 2 cycles of high-dose chemotherapy, followed by ASCT and maintenance treatment [63]. Toxicity concerns and the unavailability of novel agents hindered the success of this approach, although the long-term follow-up of treated patients (median 21 years) showed a plateau in the survival curves with an estimated cure rate of 9% based on PFS data and of 18% based on the duration of CR [64].
Currently, general treatment approaches in NDMM patients are tailored upon their eligibility for high-dose therapy (HDT) and ASCT [65].

4.1. ASCT-Eligible Patients

The current therapeutic approach includes sequential induction therapy and ASCT ± consolidation, followed by maintenance. Induction is typically administered for 4–6 cycles prior to ASCT [66]. The introduction of the PI bortezomib increased the response rate compared to classical chemotherapy [67], and is now a backbone of treatment. The addition of a third drug to the bortezomib–dexamethasone (Vd) combination (i.e., thalidomide [VTd], cyclophosphamide [VCd], lenalidomide [VRd], doxorubicin [PAD]) increased the depth of response [68]. In a head-to-head comparison, VTd was superior to VCd as induction prior to HDT–ASCT in terms of ORR (92% vs. 83%) and ≥VGPR rate (66% vs. 56%) [69], demonstrating that even with first-generation novel agents, the combination of a PI and an IMiD was beneficial.
In phase III trials, VRd induction was tested in the PETHEMA and Intergroupe Francophone du Myélome (IFM) 2009 studies (Table 4).
No randomized trial directly compared VRd vs. VTd induction, although a recent integrated analysis of French and Spanish trials was performed (VRd: PETHEMA, GEM 2012, and IFM 2009; VTd: GEM2005 and IFM 2013-04) [79]. In the Spanish studies, after 6 cycles of induction, the ≥VGPR rate was 66.3% vs. 51.2% (p = 0.003) in VRd vs. VTd groups. In the French studies, after 4 cycles of induction, the ≥VGPR rate was similar between VRd vs. VTd groups (57.1% vs. 56.5%). The safety profile of VRd was better than that of VTd in both Spanish and French studies, with a lower rate of polyneuropathy (PNP).
High-dose melphalan (200 mg/m2, MEL200) followed by ASCT is currently a standard approach in transplant-eligible patients, due to the longer PFS showed in randomized clinical studies comparing ASCT vs. novel agent-based therapy [50,74,80,81], but the role of double vs. single ASCT is still an open issue. The EMN02/HO95 phase III trial showed a benefit in the double ASCT arm in terms of PFS (3-year PFS 73% vs. 64% in double vs. single ASCT); this effect was particularly evident in the high cytogenetic risk group, where an OS benefit was also noticed [82]. Similarly, in a meta-analysis including three phase III trials, after a median follow-up of 10 years, double ASCT was significantly better than single ASCT in terms of PFS and OS. Consistent with the EMN02/HO95 data, the benefit was particularly evident in the high-risk group [82], suggesting that, in this patient population, a double ASCT is advisable. Nevertheless, the STAMINA trial did not show any difference in PFS or OS of patients receiving double vs. single ASCT. It is always difficult to perform comparisons between different trials, but the better and prolonged induction (VRD) used in the majority of the patients enrolled in the STAMINA study (whereas 3-4 cycles of VCD were used in the EMN02 study) and the lower compliance to the second ASCT procedure reported in the same study can partially explain the different results [83].
Many trials explored consolidation regimens with the rationale to deepen patient response. In the most recently published PETHEMA study, VRd induction, ASCT, and VRd consolidation produced a ≥CR rate of 58% (46% sCR, 12% CR) [75]. These data are consistent with the IFM phase II and phase III studies using VRd consolidation. In the IFM2009 study, VRd consolidation after VRd induction and ASCT showed a similar trend, with the ≥CR rate increasing from 27% during the induction phase, to 47% after ASCT to 50% after consolidation (sCR 40%, CR 10%) (Table 4) [70]. Response deepened over time, as well as MRD negativity. In the PETHEMA study, MRD by NGF with a cut-off sensitivity of 3 × 10−6 progressively increased from 34.5% post-induction to 53.4 % post-ASCT, to 58% after consolidation [75]. The phase III STAMINA and EMN02/HO95 trials were designed to evaluate the role of consolidation vs. no consolidation in a randomized fashion. In the STAMINA trial, the 38-month probability for PFS was respectively 58% with single ASCT + VRd consolidation, 58% with tandem ASCT and no consolidation, and 53% with single ASCT and no consolidation, with no statistical differences [83]. In the EMN02/HO95 study, VRd consolidation after ASCT/bortezomib–melphalan–prednisone (VMP) showed a PFS advantage, with a 5-year PFS of 48% in the VRd consolidation arm and 41% in the no consolidation arm [83,84].
In transplant-eligible patients, maintenance therapy is the standard approach after ASCT ± consolidation. A meta-analysis of three phase III trials randomizing patients to lenalidomide vs. observation/placebo showed a significant benefit in the lenalidomide arm in terms of PFS (median, 53 months vs. 24 months, HR 0.48; p = 0.001) and OS (not reached (NR) vs. 86 months, HR 0.75; p = 0.001) [85]. More recently, the Myeloma XI study confirmed the advantage of lenalidomide maintenance vs. observation after ASCT (median PFS 57 vs. 30 months, HR 0.48, p < 0.0001; 3-year OS 87.5% vs. 80.2%, HR 0.69, p = 0.01) [86]. Maintenance with lenalidomide can also further deepen the response, with 27–30% of MRD-positive patients becoming MRD-negative during treatment [87]. Besides its efficacy, the tolerability of continuous lenalidomide maintenance is an important issue. In the meta-analysis, about 30% of subjects receiving lenalidomide experienced a treatment-related AE that led to discontinuation. Moreover, a higher incidence of SPMs in the lenalidomide arm was reported, although it was outweighed by the advantage of a better disease control [85]. Although the optimal duration is currently considered to be until progressive disease, the median actual duration is generally around 2–3 years [85], with retrospective data showing a benefit in patients continuing the drug for at least 2 years [88,89]. However, there are currently no randomized prospective data showing evidence that lenalidomide until progressive disease is better than its administration for a prolonged but fixed duration [74].
Maintenance with lenalidomide alone showed conflicting results in high-risk patients [85,86], and the addition of PIs was suggested to be beneficial [90]. In a phase III trial [91], long-term treatment with bortezomib showed to abrogate the negative effect of deletion 17p [92,93,94]. Moreover, in a randomized study, the administration of the second-generation PI ixazomib as post-ASCT maintenance improved PFS compared to placebo and showed a similar effectiveness for both standard- and high-risk patients [95].
The high rate of deep responses (CR and MRD negativity) obtained after this sequential first-line treatment could further be improved by incorporating the second-generation irreversible PI carfilzomib or adding a fourth drug class, such as the anti-CD38 mAbs.
The incorporation of carfilzomib into first-line treatment was tested in several trials (Table 4) [53,96,97,98]. In the randomized phase II FORTE trial, carfilzomib was combined either with lenalidomide (KRd) or cyclophosphamide (KCd) with or without ASCT (arm A KCd–ASCT–KCd; arm B KRd–ASCT–KRd; arm C KRd-12 cycles), followed by maintenance with KR or R. After a median follow-up of 26 months, the post-consolidation response rates and MRD negativity were significantly higher in the two KRd arms (B and C) than in the KCd arm (A): ≥VGPR rate was 74% (arm A), 87% (arm B), and 87% (arm C), and the ≥CR rate 38% (arm A), 50% (arm B), and 52% (arm C). The MRD negativity rate by MFC 10−5 after consolidation was respectively 41% (arm A), 58% (arm B), and 54% (arm C) [99]. The main non-hematologic grade ≥3 AEs were hypertension (8% KRd-12 vs. 3% KRd–ASCT and KCd–ASCT), cardiac AEs (2% KRd-12 vs. 3% KRd–ASCT vs. 3% KCd–ASCT), infections (13% KRd-12 vs. 10% KRd–ASCT vs. 9% KCd–ASCT), and hepatic AEs (10% KRd-12 vs. 8% KRd–ASCT vs. 1% KCd–ASCT) [99].
Despite similar MRD negativity rates, a lower number of early relapsing patients was noted in the KRd–ASCT arm than in the KRd-12 arm. This was observed in intermediate + high-risk patients, but not in standard-risk patients, suggesting that, despite the use of second-generation PIs upfront, ASCT could still play a role in this patient population [9].
The addition of an anti-CD38 antibody to triplet regimens has been explored in several trials as well. In the phase III trial CASSIOPEIA, daratumumab–VTd (Dara–VTd) induction-ASCT–Dara–VTd was superior to VTd-ASCT-VTd in terms of response rate after consolidation, with ≥VGPR rate of 83% vs. 78%, CR rate of 10% vs. 6%, and sCR rate of 28.9% vs. 20.3%. MRD negativity (10−5) after consolidation was reached in 64% vs. 44% of patients in the Dara–VTd vs. VTd arms; PFS was significantly improved in the Dara–VTd group, as compared with the control group (HR 0.47, 95% confidence interval (CI) 0.33–0.67, p < 0.0001) [77].
The phase II GRIFFIN study compared Dara–VRd to VRd alone (Table 4). Dara–VRd improved the sCR rate by end of consolidation (42.4% vs. 32.0%). Overall, post-consolidation response was better in the Dara–VRd arm (≥VGPR 91%, ≥CR 52%, of which 59% MRD-negative) compared to the VRd arm (≥VGPR 73%, ≥CR 42%, of which 24% MRD-negative); MRD negativity was achieved in 44% of patients in the Dara–VRd arm after consolidation (10−5 threshold by NGS) [76].
A phase Ib study evaluated the addition of daratumumab to carfilzomib-based induction (Dara–KRd). Serious AEs occurred in 46% of patients. The most common grade 3–4 AEs were lymphopenia (50%) and neutropenia (23%); 1 cardiac grade 3 AE was observed (congestive heart failure). In 22 treated patients, ORR was 100% (CR 5%, ≥VGPR 86) [11].
Similarly, the addition of isatuximab to KRd is being investigated in the phase II GMMG-CONCEPT study. In the safety run-in phase (10 patients), the overall safety profile was consistent with those previously reported with KRd and isatuximab. Non-hematologic grade ≥3 AEs were treatment-unrelated cerebral vascular disorder (2 patients), self-limiting ventricular tachycardia (1), and diarrhea (1). Three patients experienced a grade 2 infusion-related reaction (IRR) during the first infusion of isatuximab [100].
Quadruplet regimens not including mAbs may allow to achieve deep responses in the majority of patients, preserving the opportunity to use mAbs after induction ± ASCT in patients not achieving MRD negativity. Bortezomib–lenalidomide–cyclophosphamide–dexamethasone (VRCd) produced a ≥VGPR rate of 33% after 4 induction cycles [71], while carfilzomib–lenalidomide–cyclophosphamide–dexamethasone (KRCd) produced a ≥VGPR rate of 82% (MRD negativity 55% at 10−4–10−5 sensitivity by flow cytometry) after a median of 4 induction cycles (range 1–12) in transplant-eligible patients [72].
In a small group of patients, the addition of the second-generation oral PI ixazomib to Rd (Ixa–Rd) during induction followed by ASCT or by ixazomib maintenance induced a good response, with 63% of patients achieving ≥VGPR and 12% MRD negativity. However, responses were not as deep as those reached in patients treated with upfront daratumumab or carfilzomib, making Ixa–Rd less appealing from a curative perspective [78].

4.2. ASCT-Ineligible Patients

ASCT-ineligible patients are a heterogeneous population. Scores predicting mortality and the risk of treatment toxicity in elderly patients have been assessed. Evidence from clinical trials [101] suggested that frailty-adapted therapies should be applied and that mainly fit patients can benefit from strategies aiming at the deepest possible response, due to higher toxicities with similar therapies in intermediate–fit/frail patients that in the end hamper the effectiveness of treatment itself [102,103].
The standard first-line treatment schemes for elderly patients are VMP, Rd, and VRd. In the phase III VISTA trial, VMP was superior to melphalan-prednisone (MP) in terms of CR rate, PFS, and OS (median 56 months vs. 43 months) [104,105].
Continuous Rd significantly increased PFS and OS compared to MPT and also prolonged PFS (but not OS) compared to Rd18 (median PFS 26 months for Rd vs. 21 months for Rd18 and 21.9 months for MPT; 4-year estimated OS 59% for Rd vs. 56% for Rd18 and 51% for MPT). Rd was also generally better tolerated than MPT [106]. In a phase III clinical trial specifically designed for intermediate–fit patients, according to the IMWG frailty score, continuous Rd was compared to Rd induction for 9 cycles followed by R maintenance alone at lower doses: PFS was superimposable, with a better tolerability with Rd–R [107].
VRd was also prospectively compared to Rd in the SWOGS0777 trial (Table 5), which, however, was not restricted to elderly patients (median age 63 years) [108]. The addition of bortezomib to Rd resulted in significantly improved PFS (43 months vs. 30 months in the Rd group; p = 0.0018) and OS (75 months vs. 64 months in the Rd group; p = 0.025). Regarding safety, the VRd combination showed higher rates of grade ≥3 AEs (82 vs. 75%), neurological toxicities (33% vs. 11%), and discontinuation (23% vs. 10%). The high neurological toxicity could be due to the two-weekly intravenous infusion of bortezomib used in this trial. In a small phase II study [109], a modified VRd, including lower lenalidomide doses (15 mg) and weekly subcutaneous bortezomib (“VRd lite”), produced a median PFS of 35.1 months and fewer toxic effects.
Studies exploring the upfront use of anti-CD38 mAbs in transplant-ineligible patients showed deep responses also in this setting. In the ALCYONE trial, the quadruplet daratumumab–VMP (Dara–VMP) was compared to VMP showing a clear advantage in PFS (HR 0.50, 95% CI 0.38–0.65, p < 0.001) [27]. At least CR rates were 42 vs. 24% and MRD negativity rates by NGS were 22.3% vs. 6.2%, respectively. Safety issues mostly consisted of IRRs (overall 27%, grade ≥3 5%) and a high incidence of infections (grade ≥3 pneumonia 11% vs. 4% in the Dara–VMP vs. VMP arms).
Similarly, in the phase III randomized MAIA study, Dara–Rd significantly prolonged PFS as compared to Rd (HR 0.56, 95% CI 0.43–0.73, p < 0.001), with ≥CR rates of 47% vs. 24% and MRD negativity in 24% vs. 7% patients, respectively. The safety profile was similar in the two arms, but the daratumumab group experienced a higher incidence of neutropenia and infections (including pneumonia) than the Rd group. As in the ALCYONE study, IRRs were reported in the daratumumab arm (overall 40%, mostly of grades 1–2 with an incidence of grade ≥3 IRRs of 2.7%) [110].
An ongoing phase I study is investigating isatuximab, in combination with VRd (Isa–VRd): the first report on 22 patients showed good tolerability, with 46% of grade ≥3 AEs, mostly hematologic. Besides, response rates are promising, with MRD negativity rates (10−6) by NGS of 33% and by NGF 18% [111].
The good results from the upfront use of second-generation PIs in the transplant-eligible setting encouraged its exploration in several clinical trials for the treatment of elderly patients. Carfilzomib associated with melphalan and prednisone (KMP) showed promising results in a phase I/II study, with 90% ORR and 58% ≥VGPR rates and about 8% of grade ≥3 cardiovascular AEs [112]. However, in the phase III CLARION study, KMP failed to outperform VMP in terms of PFS, OS and MRD negativity rates [113]. The safety profile was different between the two arms, with KMP inducing more acute renal failure (any grade 13.9% vs. 6.2%), more cardiac failure (any grade 10.8% vs. 4.3%), and less peripheral neuropathy (grade ≥2 2.5% vs. 35.1%) than VMP.
The association of carfilzomib with cyclophosphamide dexamethasone (KCd) was evaluated in two phase I/II studies, the first adopting the once-weekly carfilzomib schedule and the second the twice-weekly schedule [114,115]. Both trials demonstrated a high efficacy profile (median PFS 35.7 and 35.5 months, respectively; 3-year OS: 72% and 75%) with acceptable toxicity. Overall toxicities mainly occurred during the induction phase and the incidence of non-hematologic AEs was similar to that observed with the KMP combination. KCd showed a lower myelotoxicity than KMP and VMP. Of note, few AEs emerged during maintenance. The once- and twice-weekly schedules were compared in a meta-analysis, with no significant differences in terms of efficacy and toxicities, and with a benefit also observed in high-risk patients [116].

5. Future Perspectives

Patient fitness is one of the first factors to consider when planning the treatment strategy. Despite the manageable profile of some effective combinations, frail patients can unlikely tolerate full-dose combinations that may induce high MRD negativity. In these patients, disease control rather than cure may be the more realistically achievable goal. Nevertheless, disease control lasting for a few years, even without achieving CR or MRD negativity, could allow very elderly patients to have the same survival of age-matched healthy subjects, considering their actual life expectancy. On the other hand, in fit patients, the outcome-limiting factor is usually disease progression, and a curative approach aiming at sustained MRD negativity could be pursued. This approach should incorporate baseline risk evaluation and dynamic risk evaluation (MRD achievement and duration) during treatment (Figure 1).
Baseline risk factors such as International Staging System (ISS), cytogenetics, lactate dehydrogenase (LDH) levels [117], extramedullary disease [118], circulating plasma cells [119], TP53 mutations [94], and many others can help define our therapeutic strategy. For instance, the use of double ASCT and long-term treatment with a PI plus IMiDs maintenance could be beneficial in the presence of high-risk cytogenetics [92]. The dynamic evaluation of patient risk after the start of treatment can also help tune treatment intensity. Many MRD-driven therapeutic choices are under investigation in clinical trials. One possibility is to evaluate treatment escalation in patients who do not achieve MRD negativity at a pre-specified time point. In particular, this could be the approach for high-risk aggressive MM, mirroring a strategy such as the one used for acute leukemia, where achieving MRD is the goal to achieve cure. Another possibility is to evaluate treatment withholding in patients with sustained MRD negativity. This could be the option with standard-risk disease, where the disease behavior is more similar to that of chronic leukemias. In MRD-negative patients, if a reappearance of MRD is detected, restarting prior therapy if previously interrupted, or starting a different second-line therapy before the development of an overt relapse, can also be explored. Of note, the deferral of treatment is currently recommended, even at the reappearance of a monoclonal component (biochemical relapse), if the increase of the monoclonal component is slow [120]. Treating the reappearance of MRD might be a further step for prolonged disease control but its usefulness should be demonstrated in well-designed trials.
Before using MRD in the treatment of MM, several questions need to be answered. The first question is in which patients we should test MRD (in CR or sCR patients only, or in VGPR patients). The rationale to test MRD in VGPR patients is that, due to the long half-life of serum immunoglobulin (~1 month), the complete clearance of monoclonal component could take months until all the cells producing it have been eradicated, especially in IgG cases [121]. In these cases, VGPR patients who are MRD-negative in the bone marrow achieve CR in the months following MRD testing. However, MM is a spatially heterogeneous disease and residual plasma cells in extramedullary sites can produce the monoclonal component in VGPR cases in the presence of MRD negativity in the bone marrow. If this is the case, MRD should probably be measured at sCR and the confirmation of bone marrow MRD negativity with imaging techniques should be performed. In the context of a MRD-driven therapy, it is also tricky to evaluate (a) the impact and the likelihood of “false negative” or “false positive” MRD results; (b) the right time point; (c) the reasonably achievable cut-off at a specific time point. For instance, in the transplant-eligible setting, the post-induction time point could be used to investigate different durations and/or intensifications of induction regimens, and to understand whether or not intensification with transplant is necessary. It is possible that, after different treatments, different cut-offs can be achievable. As an example, a 10−5 negativity can be the reasonable goal after induction, but with prolonged intensification (transplant or further consolidation), a deepest MRD negativity should likely be the goal. This means that different MRD cut-offs at different time points should be considered in planning MRD-driven treatment strategies. Moreover, the question is if treatment decision can rely on a single MRD evaluation, or if, as for all the other response categories, MRD needs to be confirmed. This also affects the choice of the best time point (for instance, can we reasonably use a post-induction time point to make decisions on treatment intensification if we consider an induction with 4 cycles only?). Secondly, we should also consider the importance of MRD duration, particularly in the context of continuous therapy.
In the transplant-eligible setting, a further issue is the role of checking and the feasibility of pursuing MRD negativity in the peripheral blood stem-cell collection. Autografts contaminated with MM cells (MRD-positive autografts at a sensitivity of 10−7 by NGS) predicted a worse PFS than MRD-negative autografts [122]. However, this effect was mitigated in patients receiving further treatment after ASCT. Indeed, it should be noted that ASCT, consolidation and maintenance, especially with drugs not used during induction, still have the potential to eradicate MRD in a substantial number of patients who are MRD-positive at post-induction time point [7,8,43,70,123].
While the achievement of MRD negativity is clearly predictive of good outcomes, some NDMM patients are characterized by an MGUS-like plasma cell compartment [124]. In these patients, long-term disease control can be accomplished without achieving deep responses, probably due to an immune control of the residual disease. Further research is needed to reliably identify this patient population.
Moreover, the restoration of a physiological immune system at the time of MRD assessment could also play a role in predicting the patients that will possibly not relapse [28].

6. Conclusions

In conclusion, we are living exciting times in the field of MM, with many new regimens and strategies in the pipeline and an increasing knowledge of the complexity of the disease. Even if we currently do not have any evidence that we are able to cure MM in the great majority of treated patients, the longer follow-ups of the recent studies will determine the percentage of subjects able to actually maintain a disease-free status for a very long time. New well-designed MRD-driven trials will help us determine if it will be worth aiming at the cure of the disease and what will be the best therapeutic approach to achieve it.

Author Contributions

Substantial contributions to the conception or design: All the authors. Acquisition, analysis, or interpretation of data: All the authors. First draft: M.D., L.B., S.O., and F.G. Supervision: M.B. and F.G. Critical revision for important intellectual content: All the authors. Final approval of the version to be published: All the authors. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: All the authors.


No funding was provided for this contribution.

Conflicts of Interest

S.O. has received honoraria from Amgen, Celgene, and Janssen; and has served on the advisory boards for Adaptive Biotechnologies, Janssen, Amgen, and Takeda. M.B. has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie; and has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma. F.G. has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and served on the advisory boards for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Roche, Takeda, and AbbVie. The other authors declare no competing financial interests.


IMWGInternational Myeloma Working Group
MRDminimal residual disease
NGFnext-generation flow
NGSnext-generation sequencing
FLCfree light chain
M-proteinmyeloma protein
FCMflow cytometry
SUVmax maximum standardized uptake value
MFCmultiparameter flow cytometry
PET/CT Positron emission tomography/computed tomography
TTP time to progression
NRnot reached
CA chromosomal abnormalities
PCs plasma cells
BMPCsbone marrow PCs
HRhazard ratio
FLCrfree light chain ratio
FISHfluorescence in situ hybridization
R, Lenlenalidomide
d, dex dexamethasone
PFSprogression-free survival
OSoverall survival
MMmultiple myeloma
CRABhypercalcemia, renal failure, anemia, and bone lesions
SMMsmoldering MM
ORRoverall response rate
ASCTautologous stem-cell transplantation
NAnot available
AEadverse event
G-CSFgranulocyte colony-stimulating factor
NDMMnewly diagnosed multiple myeloma
PDprogressive disease
MRminimal response
PRpartial response
VGPRvery good PR
CR complete response
nCR near CR
sCRstringent CR
CHFcongestive heart failure
SPMssecond primary malignancies
MRD negMRD negative/negativity
M, Mel melphalan
Mel200melphalan at 200 mg/m2
SAEs serious AEs
TEAEstreatment-emergent AEs
GIT gastrointestinal toxicity
QWgiven every week
Q2Wgiven every two weeks
Q4Wgiven every 4 weeks
CIconfidence interval
ISS International Staging System
R-ISSRevised ISS
LDHlactate dehydrogenase
EMD extramedullary disease
CPC circulating plasma cells
mAb monoclonal antibody
PI proteasome inhibitor
IMiDsimmunomodulatory drugs


  1. Palumbo, A.; Anderson, K. Multiple myeloma. N. Engl. J. Med. 2011, 364, 1046–1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Dyba, T.; Randi, G.; Bettio, M.; Gavin, A.; Visser, O.; Bray, F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur. J. Cancer 2018, 103, 356–387. [Google Scholar] [CrossRef] [PubMed]
  3. Nandakumar, B.; Binder, M.; Dispenzieri, A.; Kapoor, P.; Buadi, F.; Gertz, M.A.; Lacy, M.; Dingli, D.; Hwa, L.; Leung, N.; et al. Continued improvement in survival in multiple myeloma (MM) including high-risk patients. J. Clin. Oncol. 2019, 37. Abstract #8039 [ASCO 2019 Meeting]. [Google Scholar] [CrossRef]
  4. Castañeda-Avila, M.A.; Ortiz-Ortiz, K.J.; Torres-Cintrón, C.R.; Birmann, B.M.; Epstein, M.M. Trends in cause of death among patients with multiple myeloma in Puerto Rico and the United States SEER population, 1987–2013. Int. J. Cancer 2019, 146, 35–43. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, M.; Delasalle, K.; Feng, L.; Thomas, S.; Giralt, S.; Qazilbash, M.; Handy, B.; Lee, J.J.; Alexanian, R. CR represents an early index of potential long survival in multiple myeloma. Bone Marrow Transplant. 2010, 45, 498–504. [Google Scholar] [CrossRef]
  6. Ravi, P.; Kumar, S.K.; Cerhan, J.R.; Maurer, M.J.; Dingli, D.; Ansell, S.M.; Rajkumar, S.V. Defining cure in multiple myeloma: A comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J. 2018, 8, 26. [Google Scholar] [CrossRef]
  7. Avet-Loiseau, H.; Moreau, P.; Attal, M.; Hulin, C.; Arnulf, B.; Corre, J.; Garderet, L.; Karlin, L.; Lambert, J.; Macro, M.; et al. Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial. J. Clin. Oncol. 2019, 37. Abstract #8017 [ASCO 2019 International Meeting]. [Google Scholar] [CrossRef]
  8. Zimmerman, T.; Raje, N.S.; Vij, R.; Reece, D.; Berdeja, J.G.; Stephens, L.A.; McDonnell, K.; Rosenbaum, C.A.; Jasielec, J.; Richardson, P.G.; et al. Final Results of a Phase 2 Trial of Extended Treatment (tx) with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (KRd) Plus Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM). Blood 2016, 128. Abstract #675 [ASH 2016 58th Meeting]. [Google Scholar] [CrossRef]
  9. Gay, F.; Cerrato, C.; Petrucci, M.T.; Zambello, R.; Gamberi, B.; Ballanti, S.; Omedè, P.; Palmieri, S.; Troia, R.; Spada, S.; et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the forte trial. J. Clin. Oncol. 2019, 37. Abstract #8002 [ASCO 2019 Annual Meeting]. [Google Scholar] [CrossRef]
  10. Voorhees, P.M.; Rodriguez, C.; Reeves, B.; Nathwani, N.; Costa, L.J.; Lutska, Y.; Hoehn, D.; Pei, H.; Ukropec, J.; Qi, M.; et al. Efficacy and Updated Safety Analysis of a Safety Run-in Cohort from Griffin, a Phase 2 Randomized Study of Daratumumab (Dara), Bortezomib (V), Lenalidomide (R), and Dexamethasone (D.; Dara-Vrd) Vs. Vrd in Patients (Pts) with Newly Diagnosed (ND) Multiple, M. Blood 2018, 132. Abstract #151 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  11. Jakubowiak, A.J.; Chari, A.; Lonial, S.; Weiss, B.M.; Comenzo, R.L.; Wu, K.; Khokhar, N.Z.; Wang, J.; Doshi, P.; Usmani, S.Z. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. J. Clin. Oncol. 2017, 35. Abstract #8000 [ASCO 2017 Annual Meeting]. [Google Scholar] [CrossRef]
  12. Lokhorst, H.M.; Schmidt-Wolf, I.; Sonneveld, P.; van der Holt, B.; Martin, H.; Barge, R.; Bertsch, U.; Schlenzka, J.; Bos, G.M.J.; Croockewit, S.; et al. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 2008, 93, 124–127. [Google Scholar] [CrossRef] [PubMed]
  13. Lahuerta, J.-J.; Paiva, B.; Vidriales, M.-B.; Cordón, L.; Cedena, M.-T.; Puig, N.; Martinez-Lopez, J.; Rosiñol, L.; Gutierrez, N.C.; Martín-Ramos, M.-L.; et al. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials. J. Clin. Oncol. 2017, 35, 2900–2910. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Rajkumar, S.V.; Harousseau, J.-L.; Durie, B.; Anderson, K.C.; Dimopoulos, M.; Kyle, R.; Blade, J.; Richardson, P.; Orlowski, R.; Siegel, D.; et al. Consensus recommendations for the uniform reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 1. Blood 2011, 117, 4691–4695. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Kumar, S.; Paiva, B.; Anderson, K.C.; Durie, B.; Landgren, O.; Moreau, P.; Munshi, N.; Lonial, S.; Bladé, J.; Mateos, M.-V.; et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016, 17, e328–e346. [Google Scholar] [CrossRef]
  16. Paiva, B.; Gutiérrez, N.C.; Rosiñol, L.; Vídriales, M.-B.; Montalbán, M.-Á.; Martínez-López, J.; Mateos, M.-V.; Cibeira, M.-T.; Cordón, L.; Oriol, A.; et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood 2012, 119, 687–691. [Google Scholar] [CrossRef]
  17. Nanni, C.; Zamagni, E.; Versari, A.; Chauvie, S.; Bianchi, A.; Rensi, M.; Bellò, M.; Rambaldi, I.; Gallamini, A.; Patriarca, F.; et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: A new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur. J. Nucl. Med. Mol. Imaging 2016, 43, 414–421. [Google Scholar] [CrossRef]
  18. Flores-Montero, J.; de Tute, R.; Paiva, B.; Perez, J.J.; Böttcher, S.; Wind, H.; Sanoja, L.; Puig, N.; Lecrevisse, Q.; Vidriales, M.B.; et al. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry Part B Clin. Cytom. 2016, 90, 61–72. [Google Scholar] [CrossRef]
  19. Stetler-Stevenson, M.; Paiva, B.; Stoolman, L.; Lin, P.; Jorgensen, J.L.; Orfao, A.; Van Dongen, J.; Rawstron, A.C. Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. Cytometry Part B Clin. Cytom. 2016, 90, 26–30. [Google Scholar] [CrossRef]
  20. Flores-Montero, J.; Sanoja-Flores, L.; Paiva, B.; Puig, N.; García-Sánchez, O.; Böttcher, S.; Van Der Velden, V.H.J.; Pérez-Morán, J.J.; Vidriales, M.B.; García-Sanz, R.; et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia 2017, 31, 2094–2103. [Google Scholar] [CrossRef] [Green Version]
  21. FDA. Authorizes First Next Generation Sequencing-Based Test to Detect Very Low Levels of Remaining Cancer Cells in Patients with Acute Lymphoblastic Leukemia or Multiple Myeloma. Available online: (accessed on 23 October 2019).
  22. Faham, M.; Zheng, J.; Moorhead, M.; Carlton, V.E.H.; Stow, P.; Coustan-Smith, E.; Pui, C.H.; Campana, D. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2012, 120, 5173–5180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Ladetto, M.; Brüggemann, M.; Monitillo, L.; Ferrero, S.; Pepin, F.; Drandi, D.; Barbero, D.; Palumbo, A.; Passera, R.; Boccadoro, M.; et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia 2014, 28, 1299–1307. [Google Scholar] [CrossRef] [PubMed]
  24. Avet-Loiseau, H.; Bene, M.C.; Wuilleme, S.; Corre, J.; Attal, M.; Arnulf, B.; Garderet, L.; Macro, M.; Stoppa, A.-M.; Delforge, M.; et al. Concordance of Post-consolidation Minimal Residual Disease Rates by Multiparametric Flow Cytometry and Next-generation Sequencing in CASSIOPEIA. In Proceedings of the 17th International Myeloma Workshop, Boston, MA, USA, 12–15 September 2019; Volume 8. [Abstract #OAB–004]. [Google Scholar]
  25. Rawstron, A.C.; Gregory, W.M.; de Tute, R.M.; Davies, F.E.; Bell, S.E.; Drayson, M.T.; Cook, G.; Jackson, G.H.; Morgan, G.J.; Child, J.A.; et al. Minimal residual disease in myeloma by flow cytometry: Independent prediction of survival benefit per log reduction. Blood 2015, 125, 1932–1935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Perrot, A.; Lauwers-Cances, V.; Corre, J.; Robillard, N.; Hulin, C.; Chretien, M.L.; Dejoie, T.; Maheo, S.; Stoppa, A.M.; Pegourie, B.; et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood 2018, 132, 2456–2464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Mateos, M.-V.; Dimopoulos, M.A.; Cavo, M.; Suzuki, K.; Jakubowiak, A.; Knop, S.; Doyen, C.; Lucio, P.; Nagy, Z.; Kaplan, P.; et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N. Engl. J. Med. 2018, 378, 518–528. [Google Scholar] [CrossRef] [PubMed]
  28. Paiva, B.; Cedena, M.T.; Puig, N.; Arana, P.; Vidriales, M.B.; Cordon, L.; Flores-Montero, J.; Gutierrez, N.C.; Martín-Ramos, M.L.; Martinez-Lopez, J.; et al. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood 2016, 127, 3165–3174. [Google Scholar] [CrossRef] [PubMed]
  29. Rawstron, A.C.; Child, J.A.; de Tute, R.M.; Davies, F.E.; Gregory, W.M.; Bell, S.E.; Szubert, A.J.; Navarro-Coy, N.; Drayson, M.T.; Feyler, S.; et al. Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study. J. Clin. Oncol. 2013, 31, 2540–2547. [Google Scholar] [CrossRef]
  30. Oliva, S.; op Bruinink, D.H.; ŘÍhová, L.; Spada, S.; van der Holt, B.; Troia, R.; Gambella, M.; Pantani, L.; Grammatico, S.; Gilestro, M.; et al. Minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) in newly diagnosed transplant eligible multiple myeloma (MM) patients: Results from the EMN02/HO95 phase 3 trial. J. Clin. Oncol. 2017, 35. [Google Scholar] [CrossRef]
  31. Paiva, B.; Puig, N.; Cedena, M.T.; Cordon, L.; Vidriales, M.-B.; Burgos, L.; Flores-Montero, J.; Lopez-Anglada, L.; Gutierrez, N.; Calasanz, M.J.; et al. Impact of Next-Generation Flow (NGF) Minimal Residual Disease (MRD) Monitoring in Multiple Myeloma (MM): Results from the Pethema/GEM2012 Trial. Blood 2017, 130. Abstract #905 [ASH 2017 58th Meeting]. [Google Scholar] [CrossRef]
  32. Bladé, J.; Fernández De Larrea, C.; Rosiñol, L.; Cibeira, M.T.; Jiménez, R.; Powles, R. Soft-tissue plasmacytomas in multiple myeloma: Incidence, mechanisms of extramedullary spread, and treatment approach. J. Clin. Oncol. 2011, 29, 3805–3812. [Google Scholar] [CrossRef]
  33. Moreau, P. PET-CT in MM: A new definition of CR. Blood 2011, 118, 5984–5985. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Moreau, P.; Attal, M.; Caillot, D.; Macro, M.; Karlin, L.; Garderet, L.; Facon, T.; Benboubker, L.; Escoffre-Barbe, M.; Stoppa, A.-M.; et al. Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial. J. Clin. Oncol. 2017, 35, 2911–2918. [Google Scholar] [CrossRef] [PubMed]
  35. Zamagni, E.; Patriarca, F.; Nanni, C.; Zannetti, B.; Englaro, E.; Pezzi, A.; Tacchetti, P.; Buttignol, S.; Perrone, G.; Brioli, A.; et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood 2011, 118, 5989–5995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Bartel, T.B.; Haessler, J.; Brown, T.L.Y.; Shaughnessy, J.D.; van Rhee, F.; Anaissie, E.; Alpe, T.; Angtuaco, E.; Walker, R.; Epstein, J.; et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood 2009, 114, 2068–2076. [Google Scholar] [CrossRef] [Green Version]
  37. Zamagni, E.; Nanni, C.; Dozza, L.; Carlier, T.; Tacchetti, P.; Versari, A.; Chauvie, S.; Gallamini, A.; Attal, M.; Gamberi, B.; et al. Standardization of 18F-FDG PET/CT According to Deauville Criteria for MRD Evaluation in Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Joined Analysis of Two Prospective Randomized Phase III Trials. Blood 2018, 132. Abstract #257 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef] [Green Version]
  38. Rasche, L.; Alapat, D.; Kumar, M.; Gershner, G.; McDonald, J.; Wardell, C.P.; Samant, R.; Van Hemert, R.; Epstein, J.; Williams, A.F.; et al. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia 2019, 33, 1713–1722. [Google Scholar] [CrossRef]
  39. Mazzotti, C.; Buisson, L.; Maheo, S.; Perrot, A.; Chretien, M.-L.; Leleu, X.; Hulin, C.; Manier, S.; Hébraud, B.; Roussel, M.; et al. Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv. 2018, 2, 2811–2813. [Google Scholar] [CrossRef] [Green Version]
  40. Avet-Loiseau, H.; San-Miguel, J.F.; Casneuf, T.; Iida, S.; Lonial, S.; Usmani, S.Z.; Spencer, A.; Moreau, P.; Plesner, T.; Weisel, K.; et al. Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): An. Blood 2018, 132. Abstract #3272 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  41. Radich, J.P.; Deininger, M.; Abboud, C.N.; Altman, J.K.; Berman, E.; Bhatia, R.; Bhatnagar, B.; Curtin, P.; DeAngelo, D.J.; Gotlib, J.; et al. Chronic myeloid leukemia, version 1.2019. JNCCN J. Natl. Compr. Cancer Netw. 2018, 16, 1108–1135. [Google Scholar] [CrossRef]
  42. Saussele, S.; Richter, J.; Guilhot, J.; Gruber, F.X.; Hjorth-Hansen, H.; Almeida, A.; Janssen, J.J.W.M.; Mayer, J.; Koskenvesa, P.; Panayiotidis, P.; et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): A prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018, 19, 747–757. [Google Scholar] [CrossRef] [Green Version]
  43. Gu, J.; Liu, J.; Chen, M.; Huang, B.; Li, J. Longitudinal Flow Cytometry Identified “Minimal Residual Disease” (MRD) Evolution Patterns for Predicting the Prognosis of Patients with Transplant-Eligible Multiple Myeloma. Biol. Blood Marrow Transplant. 2018, 24, 2568–2574. [Google Scholar] [CrossRef] [Green Version]
  44. Rajkumar, S.V.; Dimopoulos, M.A.; Palumbo, A.; Blade, J.; Merlini, G.; Mateos, M.-V.; Kumar, S.; Hillengass, J.; Kastritis, E.; Richardson, P.; et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014, 15, e538–e548. [Google Scholar] [CrossRef]
  45. Lakshman, A.; Vincent Rajkumar, S.; Buadi, F.K.; Binder, M.; Gertz, M.A.; Lacy, M.Q.; Dispenzieri, A.; Dingli, D.; Fonder, A.L.; Hayman, S.R.; et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018, 8. [Google Scholar] [CrossRef] [PubMed]
  46. Cherry, B.M.; Korde, N.; Kwok, M.; Manasanch, E.E.; Bhutani, M.; Mulquin, M.; Zuchlinski, D.; Yancey, M.A.; Maric, I.; Calvo, K.R.; et al. Modeling progression risk for smoldering multiple myeloma: Results from a prospective clinical study. Proc. Leuk. Lymphoma 2013, 54, 2215–2218. [Google Scholar] [CrossRef] [PubMed]
  47. Kyle, R.A.; Remstein, E.D.; Therneau, T.M.; Dispenzieri, A.; Kurtin, P.J.; Hodnefield, J.M.; Larson, D.R.; Plevak, M.F.; Jelinek, D.F.; Fonseca, R.; et al. Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma. N. Engl. J. Med. 2007, 356, 2582–2590. [Google Scholar] [CrossRef]
  48. Pérez-Persona, E.; Vidriales, M.B.; Mateo, G.; García-Sanz, R.; Mateos, M.V.; De Coca, A.G.; Galende, J.; Martín-Nuñez, G.; Alonso, J.M.; De Heras, N.L.; et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007, 110, 2586–2592. [Google Scholar] [CrossRef]
  49. San Miguel, J.; Mateos, M.-V.; Gonzalez, V.; Dimopoulos, M.A.; Kastritis, E.; Hajek, R.; de Larrea Rodríguez, C.; Morgan, G.J.; Merlini, G.; Mangiacavalli, S.; et al. Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria. J. Clin. Oncol. 2019, 37. Abstract #8000 [ASCO 2019 Annual Meeting] Updated data presented at the meeting. [Google Scholar] [CrossRef]
  50. Gay, F.; Oliva, S.; Petrucci, M.T.; Conticello, C.; Catalano, L.; Corradini, P.; Siniscalchi, A.; Magarotto, V.; Pour, L.; Carella, A.; et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomised, multicentre, phase 3 trial. Lancet Oncol. 2015, 16, 1617–1629. [Google Scholar] [CrossRef]
  51. López-Corral, L.; Gutiérrez, N.C.; Vidriales, M.B.; Mateos, M.V.; Rasillo, A.; García-Sanz, R.; Paiva, B.; San Miguel, J.F. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin. Cancer Res. 2011, 17, 1692–1700. [Google Scholar] [CrossRef] [Green Version]
  52. Mateos, M.V.; Hernández, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; Corral, L.L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): Long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016, 17, 1127–1136. [Google Scholar] [CrossRef]
  53. Korde, N.; Roschewski, M.; Zingone, A.; Kwok, M.; Manasanch, E.E.; Bhutani, M.; Tageja, N.; Kazandjian, D.; Mailankody, S.; Wu, P.; et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015, 1, 746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Mateos, M.-V.; Martínez-López, J.; Rodríguez-Otero, P.; de la Calle, G.V.; González, M.-S.; Oriol, A.; Gutiérrez, N.-C.; Paiva, B.; Rios, R.; Rosiñol, L.; et al. Curative strategy (gem-cesar) for high-risk smoldering myeloma: Carfilzomib, lenalidomide and dexamethasone (krd) as induction followed by hdt-asct, consolidation with krd and maintenance with rd. HemaSphere 2019, 3, 390. [Google Scholar] [CrossRef]
  55. Mailankody, S.; Salcedo, M.; Tavitian, E.; Korde, N.; Lendvai, N.; Hassoun, H.; Lesokhin, A.M.; Lahoud, O.B.; Smith, E.L.; Hultcrantz, M.; et al. Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study. J. Clin. Oncol. 2019, 37. Abstract #8051 [ASCO 2019 Annual Meeting]. [Google Scholar] [CrossRef]
  56. Jagannath, S.; Laubach, J.; Wong, E.; Stockerl-Goldstein, K.; Rosenbaum, C.; Dhodapkar, M.; Jou, Y.-M.; Lynch, M.; Robbins, M.; Shelat, S.; et al. Elotuzumab monotherapy in patients with smouldering multiple myeloma: A phase 2 study. Br. J. Haematol. 2018, 182, 495–503. [Google Scholar] [CrossRef] [PubMed]
  57. Liu, C.; Ghobrial, I.M.; Bustoros, M.; Reyes, K.; Hornburg, K.; Badros, A.Z.; Vredenburgh, J.J.; Boruchov, A.; Matous, J.V.; Caola, A.; et al. Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. Blood 2018, 132. Abstract #154 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  58. Bustoros, M.; Liu, C.; Reyes, K.; Hornburg, K.; Guimond, K.; Styles, R.; Savell, A.; Berrios, B.; Warren, D.; Dumke, H.; et al. Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. Blood 2018, 132. Abstract #804 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  59. Brighton, T.A.; Khot, A.; Harrison, S.J.; Ghez, D.; Weiss, B.M.; Kirsch, A.; Magen, H.; Gironella, M.; Oriol, A.; Streetly, M.; et al. Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clin. Cancer Res. 2019, 25, 3772–3775. [Google Scholar] [CrossRef] [Green Version]
  60. Landgren, O.; Cavo, M.; Chari, A.; Cohen, Y.C.; Spencer, A.; Voorhees, P.M.; Estell, J.; Sandhu, I.; Jenner, M.; Williams, C.; et al. Updated Results from the Phase 2 Centaurus Study of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM). Blood 2018, 132. Abstract #1994 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  61. Rajkumar, S.V.; Voorhees, P.M.; Goldschmidt, H.; Baker, R.I.; Bandekar, R.; Kuppens, S.; Neff, T.; Qi, M.; Dimopoulos, M.A. Randomized, open-label, phase 3 study of subcutaneous daratumumab (DARA SC) versus active monitoring in patients (Pts) with high-risk smoldering multiple myeloma (SMM): AQUILA. J. Clin. Oncol. 2018, 36. Abstract #TPS8062 (ASCO 2018 Annual Meeting]. [Google Scholar] [CrossRef]
  62. Lonial, S.; Jacobus, S.; Fonseca, R.; Weiss, M.; Kumar, S.; Orlowski, R.Z.; Kaufman, J.L.; Yacoub, A.M.; Buadi, F.K.; O’Brien, T.; et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J. Clin. Oncol. 2019, 37. Abstract #8001 [ASCO 2019 Annual Meeting]. [Google Scholar] [CrossRef]
  63. Barlogie, B.; Jagannath, S.; Desikan, K.R.; Mattox, S.; Vesole, D.; Siegel, D.; Tricot, G.; Munshi, N.; Fassas, A.; Singhal, S.; et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999, 93, 55–65. [Google Scholar] [CrossRef] [PubMed]
  64. Barlogie, B.; Mitchell, A.; van Rhee, F.; Epstein, J.; Yaccoby, S.; Zangari, M.; Heuck, C.; Hoering, A.; Morgan, G.J.; Crowley, J. Curing Multiple Myeloma (MM) with Total Therapy (TT). Blood 2014, 124. Abstract #195 [ASH 2014 56th Meeting]. [Google Scholar] [CrossRef]
  65. Mateos, M.V.; San Miguel, J.F. Management of multiple myeloma in the newly diagnosed patient. Hematology 2017, 2017, 498–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Moreau, P.; Attal, M.; Facon, T. Frontline therapy of multiple myeloma. Blood 2015, 125, 3076–3084. [Google Scholar] [CrossRef]
  67. Harousseau, J.-L.; Attal, M.; Avet-Loiseau, H.; Marit, G.; Caillot, D.; Mohty, M.; Lenain, P.; Hulin, C.; Facon, T.; Casassus, P.; et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: Results of the IFM 2005-01 phase III trial. J. Clin. Oncol. 2010, 28, 4621–4629. [Google Scholar] [CrossRef]
  68. Gay, F.; Engelhardt, M.; Terpos, E.; Wäsch, R.; Giaccone, L.; Auner, H.W.; Caers, J.; Gramatzki, M.; van de Donk, N.; Oliva, S.; et al. From transplant to novel cellular therapies in multiple myeloma: EMN guidelines and future perspectives. Haematologica 2018, 103, 197–211. [Google Scholar] [CrossRef]
  69. Moreau, P.; Hulin, C.; Macro, M.; Caillot, D.; Chaleteix, C.; Roussel, M.; Garderet, L.; Royer, B.; Brechignac, S.; Tiab, M.; et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: Results of the prospective IFM2013-04 trial. Blood 2016, 127, 2569–2574. [Google Scholar] [CrossRef]
  70. Roussel, M.; Lauwers-Cances, V.; Robillard, N.; Hulin, C.; Leleu, X.; Benboubker, L.; Marit, G.; Moreau, P.; Pegourie, B.; Caillot, D.; et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: A phase II study by the Intergroupe Francophone du Myélome. J. Clin. Oncol. 2014, 32, 2712–2717. [Google Scholar]
  71. Kumar, S.; Flinn, I.; Richardson, P.G.; Hari, P.; Callander, N.; Noga, S.J.; Stewart, A.K.; Turturro, F.; Rifkin, R.; Wolf, J.; et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012, 119, 4375–4382. [Google Scholar] [CrossRef]
  72. Pawlyn, C.; Davies, F.; Cairns, D.; Striha, A.; Hockaday, A.; Kishore, B.; Garg, M.; Williams, C.; Karunanithi7, K.; Lindsay, J.; et al. Quadruplet KCRD (Carfilzomib, Cyclophosphamide, Lenalidomide and Dexamethasone) Induction for Newly Diagnosed Myeloma Patients. In Proceedings of the International Myeloma Workshop, Boston, MA, USA, 12–15 September 2019; p. e2, [Abstract #OAB–002]. Updated data presented at the meeting. [Google Scholar]
  73. Jackson, G.H.; Davies, F.E.; Pawlyn, C.; Cairns, D.; Striha, A.; Hockaday, A.; Collett, C.; Jones, J.R.; Kishore, B.; Garg, M.; et al. A Quadruplet Regimen Comprising Carfilzomib, Cyclophosphamide, Lenalidomide, Dexamethasone (KCRD) Vs an Immunomodulatory Agent Containing Triplet (CTD/CRD) Induction Therapy Prior to Autologous Stem Cell Transplant: Results of the Myeloma XI Study. Blood 2018, 132. Abstract #302 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  74. Attal, M.; Lauwers-Cances, V.; Hulin, C.; Leleu, X.; Caillot, D.; Escoffre, M.; Arnulf, B.; Macro, M.; Belhadj, K.; Garderet, L.; et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N. Engl. J. Med. 2017, 376, 1311–1320. [Google Scholar] [CrossRef] [PubMed]
  75. Rosinol, L.; Oriol, A.; Rios, R.; Sureda, A.; Blanchard, M.J.; Hernández, M.T.; Martínez-Martínez, R.; Moraleda, J.M.; Jarque, I.; Bargay, J.; et al. Bortezomib, Lenalidomide and Dexamethasone (VRD-GEM) As Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): Results of a Prospective Phase III Pethema/GEM Trial. Blood 2017, 130. Abstract #2017 [ASH 2017 59th Annual Meeting]. [Google Scholar] [CrossRef]
  76. Voorhees, P.; Kaufman, J.L.; Laubach, J.; Sborov, D.; Reeves, B.; Rodriguez, C.; Chari, A.; Silbermann, R.; Costa, L.; Anderson, L.; et al. Daratumumab + Lenalidomide, Bortezomib & Dexamethasone Improves Depth of Response in Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN. In Proceedings of the 17th International Myeloma Workshop, Boston, MA, USA, 12–15 Septemebr 2019; pp. 546–547, [Abstract #OAB–87]. [Google Scholar]
  77. Moreau, P.; Attal, M.; Hulin, C.; Arnulf, B.; Belhadj, K.; Benboubker, L.; Béné, M.C.; Broijl, A.; Caillon, H.; Caillot, D.; et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 2019, 394, 29–38. [Google Scholar] [CrossRef]
  78. Kumar, S.K.; Berdeja, J.G.; Niesvizky, R.; Lonial, S.; Laubach, J.P.; Hamadani, M.; Stewart, A.K.; Hari, P.; Roy, V.; Vescio, R.; et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: Long-term follow-up including ixazomib maintenance. Leukemia 2019, 33, 1736–1746. [Google Scholar] [CrossRef] [PubMed]
  79. Rosiñol Dachs, L.; Hebraud, B.; Oriol, A.; Colin, A.-L.; Rios, R.; Hulin, C.; Blanchard, M.J.; Caillot, D.; Sureda, A.; Hernández, M.T.; et al. Integrated Analysis of Randomized Controlled Trials Evaluating Bortezomib + Lenalidomide + Dexamethasone or Bortezomib + Thalidomide + Dexamethasone Induction in Transplant-Eligible Newly Diagnosed Multiple Myeloma. Blood 2018, 132. Abstract #3245 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  80. Palumbo, A.; Cavallo, F.; Gay, F.; Di Raimondo, F.; Ben Yehuda, D.; Petrucci, M.T.; Pezzatti, S.; Caravita, T.; Cerrato, C.; Ribakovsky, E.; et al. Autologous Transplantation and Maintenance Therapy in Multiple Myeloma. N. Engl. J. Med. 2014, 371, 895–905. [Google Scholar] [CrossRef]
  81. Cavo, M.; Hájek, R.; Pantani, L.; Beksac, M.; Oliva, S.; Dozza, L.; Johnsen, H.E.; Petrucci, M.T.; Mellqvist, U.-H.; Conticello, C.; et al. Autologous Stem Cell Transplantation Versus Bortezomib-Melphalan-Prednisone for Newly Diagnosed Multiple Myeloma: Second Interim Analysis of the Phase 3 EMN02/HO95 Study. Blood 2017, 130. Abstract #397 [ASH 2017 59th Meeting]. [Google Scholar] [CrossRef]
  82. Cavo, M.; Goldschmidt, H.; Rosinol, L.; Pantani, L.; Zweegman, S.; Salwender, H.J.; Lahuerta, J.J.; Lokhorst, H.M.; Petrucci, M.T.; Blau, I.; et al. Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies. Blood 2018, 132. Abstract #124 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  83. Stadtmauer, E.A.; Pasquini, M.C.; Blackwell, B.; Hari, P.; Bashey, A.; Devine, S.; Efebera, Y.; Ganguly, S.; Gasparetto, C.; Geller, N.; et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J. Clin. Oncol. 2019, 37, 589–597. [Google Scholar] [CrossRef]
  84. Sonneveld, P.; Beksac, M.; Van der Holt, B.; Dimopoulos, M.; Carella, A.; Ludwig, H.; Driessen, C.; Wester, R.; Hajek, R.; Cornelisse, P.; et al. Consolidation followed by maintenance vs maintenance alone in newly diagnosed, transplant eligible multiple myeloma: A randomized phase 3 study of the european myeloma network (emn02/ho95 mm trial). HemaSphere 2018, 2, 5–6. [Google Scholar]
  85. McCarthy, P.L.; Holstein, S.A.; Petrucci, M.T.; Richardson, P.G.; Hulin, C.; Tosi, P.; Bringhen, S.; Musto, P.; Anderson, K.C.; Caillot, D.; et al. Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J. Clin. Oncol. 2017, 35, 3279–3289. [Google Scholar] [CrossRef] [PubMed]
  86. Jackson, G.H.; Davies, F.E.; Pawlyn, C.; Cairns, D.A.; Striha, A.; Collett, C.; Hockaday, A.; Jones, J.R.; Kishore, B.; Garg, M.; et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019, 20, 57–73. [Google Scholar] [CrossRef] [Green Version]
  87. Oliva, S.; Gambella, M.; Larocca, A.; Spada, S.; Marzanati, E.; Mantoan, B.; Grammatico, S.; Conticello, C.; Gamberi, B.; Offidani, M.; et al. Prognostic Impact of Minimal Residual Disease By ASO-RQ-PCR in Multiple Myeloma: A Pooled Analysis of 2 Phase III Studies in Patients Treated with Lenalidomide after Front-Line Therapy. Blood 2016, 128. Abstract #4409 [ASH 2016 58th Meeting]. [Google Scholar] [CrossRef]
  88. Bonello, F.; Pulini, S.; Ballanti, S.; Gentile, M.; Spada, S.; Annibali, O.; Omedé, P.; Ronconi, S.; Cangialosi, C.; Podda, L.; et al. Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis. Cancers 2019, 11, 1735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Mian, I.; Milton, D.R.; Shah, N.; Nieto, Y.; Popat, U.R.; Kebriaei, P.; Parmar, S.; Oran, B.; Shah, J.J.; Manasanch, E.E.; et al. Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma. Cancer 2016, 122, 3831–3837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Sonneveld, P.; Avet-Loiseau, H.; Lonial, S.; Usmani, S.; Siegel, D.; Anderson, K.C.; Chng, W.-J.; Moreau, P.; Attal, M.; Kyle, R.A.; et al. Treatment of multiple myeloma with high-risk cytogenetics: A consensus of the International Myeloma Working Group. Blood 2016, 127, 2955–2962. [Google Scholar] [CrossRef]
  91. Goldschmidt, H.; Lokhorst, H.M.; Mai, E.K.; van der Holt, B.; Blau, I.W.; Zweegman, S.; Weisel, K.C.; Vellenga, E.; Pfreundschuh, M.; Kersten, M.J.; et al. Bortezomib before and after high-dose therapy in myeloma: Long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 2018, 32, 383–390. [Google Scholar] [CrossRef]
  92. D’Agostino, M.; De Paoli, L.; Conticello, C.; Offidani, M.; Ria, R.; Petrucci, M.T.; Spada, S.; Marcatti, M.; Catalano, L.; Gilestro, M.; et al. Continuous therapy in standard- and high-risk newly-diagnosed multiple myeloma: A pooled analysis of 2 phase III trials. Crit. Rev. Oncol. Hematol. 2018, 132, 9–16. [Google Scholar] [CrossRef]
  93. Gay, F.; Jackson, G.; Rosiñol, L.; Holstein, S.A.; Moreau, P.; Spada, S.; Davies, F.; Lahuerta, J.J.; Leleu, X.; Bringhen, S.; et al. Maintenance Treatment and Survival in Patients With Myeloma. JAMA Oncol. 2018, 4, 1389. [Google Scholar] [CrossRef]
  94. D’Agostino, M.; Zaccaria, G.M.; Ziccheddu, B.; Genuardi, E.; Maura, F.; Oliva, S.; Auclair, D.; Yesil, J.; Capra, A.; Colucci, P.; et al. Clinical and Biological Early Relapse Predictors in Multiple Myeloma: An Analysis from the MMRF CoMMpass Study. In Proceedings of the 17 th International Myeloma Workshop, Boston, MA, USA, 12–15 September 2019; pp. 20–21, [Abstract #OAB–018]. [Google Scholar]
  95. Dimopoulos, M.A.; Gay, F.; Schjesvold, F.; Beksac, M.; Hajek, R.; Weisel, K.C.; Goldschmidt, H.; Maisnar, V.; Moreau, P.; Min, C.K.; et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): A double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019, 393, 253–264. [Google Scholar] [CrossRef] [Green Version]
  96. Jakubowiak, A.J.; Dytfeld, D.; Griffith, K.A.; Lebovic, D.; Vesole, D.H.; Jagannath, S.; Al-Zoubi, A.; Anderson, T.; Nordgren, B.; Detweiler-Short, K.; et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012, 120, 1801–1809. [Google Scholar] [CrossRef] [PubMed]
  97. Jakubowiak, A.; Raje, N.; Vij, R.; Reece, D.; Berdeja, J.; Vesole, D.; Jagannath, S.; Cole, C.; Faham, M.; Nam, J.; et al. Improved Efficacy After Incorporating Autologous Stem Cell Transplant (Asct) Into Krd Treatment With Carfilzomib (Cfz), Lenalidomide (Len), And Dexamethasone (Dex) In Newly Diagnosed Multiple Myeloma. Haematologica 2016, 101, 1–2. [Google Scholar]
  98. Roussel, M.; Lauwers-Cances, V.; Robillard, N.; Belhadj, K.; Facon, T.; Garderet, L.; Escoffre, M.; Pegourie, B.; Benboubker, L.; Caillot, D.; et al. Frontline Therapy with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Induction Followed By Autologous Stem Cell Transplantation, Krd Consolidation and Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Primary Results of th. Blood 2016, 128. Abstract #1142 [ASH 2017 59th Meeting]. [Google Scholar] [CrossRef]
  99. Gay, F.; Cerrato, C.; Scalabrini, D.R.; Galli, M.; Belotti, A.; Zamagni, E.; Ledda, A.; Grasso, M.; Angelucci, E.; Liberati, A.M.; et al. Carfilzomib-Lenalidomide-Dexamethasone (KRd) Induction-Autologous Transplant (ASCT)-Krd Consolidation Vs KRd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Induction-ASCT-KCd Consolidation: Analysis of the Randomized FORTE Trial in Newly Di. Blood 2018, 132. Abstract #121 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  100. Weisel, K.; Asemissen, A.M.; Schieferdecker, A.; Besemer, B.; Zago, M.; Mann, C.; Lutz, R.; Benner, A.; Tichy, D.; Bokemeyer, C.; et al. Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (I-KRd) in front-line treatment of high-risk Multiple Myeloma: Results of the Safety Run-In cohort in the phase II, multicenter GMMG-CONCEPT trial. In Proceedings of the International Myeloma Workshop, Boston, MA, USA, 12–15 September 2019; pp. 25–26, [Abstract #OAB–023]. [Google Scholar]
  101. Bringhen, S.; D’Agostino, M.; Paris, L.; Ballanti, S.; Pescosta, N.; Spada, S.; Pezzatti, S.; Grasso, M.; Rota-Scalabrini, D.; De Rosa, L.; et al. Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: Updated results of the EMN01 randomized trial. Haematologica 2019. [ahead of print]. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Salvini, M.; D’Agostino, M.; Bonello, F.; Boccadoro, M.; Bringhen, S. Determining treatment intensity in elderly patients with multiple myeloma. Expert Rev. Anticancer Ther. 2018, 18, 917–930. [Google Scholar] [CrossRef] [PubMed]
  103. Palumbo, A.; Bringhen, S.; Mateos, M.-V.; Larocca, A.; Facon, T.; Kumar, S.; Offidani, M.; McCarthy, P.; Evangelista, A.; Lonial, S.; et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 2015, 125, 2068–2074. [Google Scholar] [CrossRef]
  104. San Miguel, J.F.; Schlag, R.; Khuageva, N.K.; Dimopoulos, M.A.; Shpilberg, O.; Kropff, M.; Spicka, I.; Petrucci, M.T.; Palumbo, A.; Samoilova, O.S.; et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N. Engl. J. Med. 2008, 359, 906–917. [Google Scholar] [CrossRef] [Green Version]
  105. San Miguel, J.F.; Schlag, R.; Khuageva, N.K.; Dimopoulos, M.A.; Shpilberg, O.; Kropff, M.; Spicka, I.; Petrucci, M.T.; Palumbo, A.; Samoilova, O.S.; et al. Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma. J. Clin. Oncol. 2013, 31, 448–455. [Google Scholar] [CrossRef] [Green Version]
  106. Facon, T.; Dimopoulos, M.A.; Dispenzieri, A.; Catalano, J.V.; Belch, A.; Cavo, M.; Pinto, A.; Weisel, K.; Ludwig, H.; Bahlis, N.J.; et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood 2018, 131, 301–310. [Google Scholar] [CrossRef] [Green Version]
  107. Larocca, A.; Salvini, M.; De Paoli, L.; Cascavilla, N.; Benevolo, G.; Galli, M.; Montefusco, V.; di Toritto, T.C.; Baraldi, A.; Spada, S.; et al. Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study. Blood 2018, 132. Abstract #305 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  108. Durie, B.G.M.; Hoering, A.; Abidi, M.H.; Rajkumar, S.V.; Epstein, J.; Kahanic, S.P.; Thakuri, M.; Reu, F.; Reynolds, C.M.; Sexton, R.; et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet 2017, 389, 519–527. [Google Scholar] [CrossRef] [Green Version]
  109. O’Donnell, E.K.; Laubach, J.P.; Yee, A.J.; Chen, T.; Huff, C.A.; Basile, F.G.; Wade, P.M.; Paba-Prada, C.E.; Ghobrial, I.M.; Schlossman, R.L.; et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br. J. Haematol. 2018, 182, 222–230. [Google Scholar] [CrossRef] [PubMed]
  110. Facon, T.; Kumar, S.; Plesner, T.; Orlowski, R.Z.; Moreau, P.; Bahlis, N.; Basu, S.; Nahi, H.; Hulin, C.; Quach, H.; et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N. Engl. J. Med. 2019, 380, 2104–2115. [Google Scholar] [CrossRef] [PubMed]
  111. Ocio, E.M.; Otero, P.R.; Bringhen, S.; Oliva, S.; Nogai, A.; Attal, M.; Moreau, P.; Kanagavel, D.; Fitzmaurice, T.; Wu, J.; et al. Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant. Blood 2018, 132. Abstract #595 [ASH 2018 60th Meeting]. [Google Scholar] [CrossRef]
  112. Moreau, P.; Kolb, B.; Attal, M.; Caillot, D.; Benboubker, L.; Tiab, M.; Touzeau, C.; Leleu, X.; Roussel, M.; Chaleteix, C.; et al. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood 2015, 125, 3100–3104. [Google Scholar] [CrossRef] [Green Version]
  113. Facon, T.; Lee, J.H.; Moreau, P.; Niesvizky, R.; Dimopoulos, M.; Hajek, R.; Pour, L.; Jurczyszyn, A.; Qiu, L.; Klippel, Z.; et al. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood 2019, 133, 1953–1963. [Google Scholar] [CrossRef]
  114. Bringhen, S.; Petrucci, M.T.; Larocca, A.; Conticello, C.; Rossi, D.; Magarotto, V.; Musto, P.; Boccadifuoco, L.; Offidani, M.; Omede, P.; et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: A multicenter, phase 2 study. Blood 2014, 124, 63–69. [Google Scholar] [CrossRef] [Green Version]
  115. Bringhen, S.; D’Agostino, M.; De Paoli, L.; Montefusco, V.; Liberati, A.M.; Galieni, P.; Grammatico, S.; Muccio, V.E.; Esma, F.; De Angelis, C.; et al. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia 2018, 32, 979–985. [Google Scholar] [CrossRef]
  116. Bringhen, S.; Mina, R.; Petrucci, M.T.; Gaidano, G.; Ballanti, S.; Musto, P.; Offidani, M.; Spada, S.; Benevolo, G.; Ponticelli, E.; et al. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: A pooled analysis of two phase I/II studies. Haematologica 2019, 104, 1640–1647. [Google Scholar] [CrossRef] [Green Version]
  117. Palumbo, A.; Avet-Loiseau, H.; Oliva, S.; Lokhorst, H.M.; Goldschmidt, H.; Rosinol, L.; Richardson, P.; Caltagirone, S.; Lahuerta, J.J.; Facon, T.; et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J. Clin. Oncol. 2015, 33, 2863–2869. [Google Scholar] [CrossRef] [PubMed]
  118. Usmani, S.Z.; Heuck, C.; Mitchell, A.; Szymonifka, J.; Nair, B.; Hoering, A.; Alsayed, Y.; Waheed, S.; Haider, S.; Restrepo, A.; et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica 2012, 97, 1761–1767. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Granell, M.; Calvo, X.; Garcia-Guiñón, A.; Escoda, L.; Abella, E.; Martínez, C.M.; Teixidó, M.; Gimenez, M.T.; Senín, A.; Sanz, P.; et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: Implications for plasma cell leukemia definition. Haematologica 2017, 102, 1099–1104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Sonneveld, P. Management of multiple myeloma in the relapsed/refractory patient. Hematology 2017, 2017, 508–517. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Landgren, O.; Rustad, E.H. Meeting report: Advances in minimal residual disease testing in multiple myeloma 2018. Adv. Cell Gene Ther. 2019, 2, e26. [Google Scholar] [CrossRef] [Green Version]
  122. Takamatsu, H.; Takezako, N.; Zheng, J.; Moorhead, M.; Carlton, V.E.H.; Kong, K.A.; Murata, R.; Ito, S.; Miyamoto, T.; Yokoyama, K.; et al. Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation. Ann. Oncol. 2017, 28, 2503–2510. [Google Scholar] [CrossRef]
  123. Hahn, T.E.; Wallace, P.K.; Fraser, R.; Fei, M.; Tario, J.D.; Howard, A.; Zhang, Y.; Blackwell, B.; Brunstein, C.G.; Efebera, Y.A.; et al. Minimal Residual Disease (MRD) Assessment before and after Autologous Hematopoietic Cell Transplantation (AutoHCT) and Maintenance for Multiple Myeloma (MM): Results of the Prognostic Immunophenotyping for Myeloma Response (PRIMeR) Study. Biol. Blood Marrow Transplant. 2019, 25, S4–S6. [Google Scholar] [CrossRef]
  124. Paiva, B.; Vídriales, M.B.; Rosiñol, L.; Martínez-López, J.; Mateos, M.V.; Ocio, E.M.; Montalbán, M.A.; Cordón, L.; Gutiérrez, N.C.; Corchete, L.; et al. A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. Leukemia 2013, 27, 2056–2061. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Proposed algorithm to set treatment goal in NDMM patients. ISS, international staging system; FISH, fluorescence in-situ hybridization; LDH, lactate dehydrogenase; R-ISS, revised ISS; EMD, extramedullary disease; CPC, circulating plasma cells; mAb, monoclonal antibody; PI, proteasome inhibitor; IMiDs, immunomodulatory drugs; ASCT, autologous stem cell transplantation; TE, transplant eligible; MRD, minimal residual disease.
Figure 1. Proposed algorithm to set treatment goal in NDMM patients. ISS, international staging system; FISH, fluorescence in-situ hybridization; LDH, lactate dehydrogenase; R-ISS, revised ISS; EMD, extramedullary disease; CPC, circulating plasma cells; mAb, monoclonal antibody; PI, proteasome inhibitor; IMiDs, immunomodulatory drugs; ASCT, autologous stem cell transplantation; TE, transplant eligible; MRD, minimal residual disease.
Cancers 11 02015 g001
Table 1. Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for the detection of minimal residual disease (MRD) in multiple myeloma.
Table 1. Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for the detection of minimal residual disease (MRD) in multiple myeloma.
Baseline sampleRequired for molecular marker identificationNot required
Number of cells1–2 million cells/20 µg DNA10 million cells/tube
StandardizationCommercial companies (e.g., Adaptive Biotechnologies) Euro Flow consortium
Sample processingFresh and/or stored samplesFresh sample required; processing within ≤48 h
Sample quality controlNot feasiblePossible to check by global bone marrow cell analysis
Sensitivity1 in 10−5–10−61 in 10−5–10−6
Clonal evolutionEvaluableNot evaluable
Time required1 week3–4 h
Support requiredBioinformatics supportExpert flow cytometrist;
Automated software
MRD, minimal residual disease; NGS, next-generation sequencing; NGF, next-generation flow.
Table 2. Smoldering multiple myeloma: risk stratification systems.
Table 2. Smoldering multiple myeloma: risk stratification systems.
Stratification SystemNLow RiskIntermediate RiskHigh Risk
CriteriaTTP (Median)CriteriaTTP (Median)CriteriaTTP (Median)
Mayo Clinic [47]273- M-protein <3 g/dL
- BMPCs <10%
19 years- M-protein <3 g/dL
- BMPCs ≥10%
8 years- M-protein ≥3 g/dL
- BMPCs ≥10%
2 years
PETHEMA [48]89- Aberrant PCs by MFC <95%
- Immunoparesis
NR- Aberrant PCs by MFC ≥95%
- Immunoparesis
6 years- Aberrant PCs by MFC ≥95%
- Immunoparesis
1.9 years
Mayo 2/20/20 [45]421None of the risk factors:
- M-protein >2g/dL
- BMPCs >20%
- FLCr >20
9.1 yearsOne risk factor:
- M-protein >2g/dL
- BMPCs >20%
- FLCr >20
5.6 years≥2 risk factors:
- M-protein >2g/dL
- BMPCs >20%
- FLCr >20
2.4 years
Low RiskIntermediate LowIntermediate HighHigh Risk
NCriteria2-year progression riskCriteria2-year progression riskCriteria2-year progression riskCriteria2-year progression risk
2/20/20 + CA by FISH * [49]2004None of the risk factors:
- M-protein >2g/dL
- FLCr >20
- BMPCs >20%
Presence of any of the CA *
8%1 risk factor:
- M-protein >2g/dL
- FLCr >20
- BMPCs >20%
Presence of any of the CA *
21%2 risk factors:
- M-protein >2g/dL
- FLCr >20
- BMPCs >20%
Presence of any of the CA *
37%≥3 risk factors:
- M-protein >2g/dL
- FLCr >20
- BMPCs >20%
Presence of any of the CA *
* High-risk chromosomal abnormalities: t(4,14), t(14,16), 1q gain, or del13. N, number; M-protein, myeloma protein; BMPCs, bone marrow plasma cells; CA, chromosomal abnormalities; FLCr, free light chain ratio; MFC, multiparameter flow cytometry; NR, not reached; PCs, plasma cells; TTP, time to progression; FISH, fluorescence in situ hybridization.
Table 3. Smoldering multiple myeloma: Selected clinical trials.
Table 3. Smoldering multiple myeloma: Selected clinical trials.
ProtocolPhaseTreatmentPtsResponseTTP/PFS/OSToxicity (≥G3)
QuiRedex [52]
Phase IIIRd vs. observation Induction: 28-day cycle (cycles 1–9) lenalidomide 25 mg p.o. days (D) 1–21 + dex 20 mg p.o. D1–4, 12–15
Maintenance: (cycles 1–24) 28-day cycle
Lenalidomide 10 mg D1–21
119FU 73 months
Best response 26% CR after maintenance
Median TTP NR (HR 0.24)
3-year PFS 77%
3-, 5-year OS 94%, 88% (HR 0.43)
median TTP 23 months (p < 0.001)
3-year PFS 30% (p < 0.001)
3-, 5-year OS 80%, 71%, (p = 0.03)
Neutropenia 5%
Thrombocytopenia 2%
Anemia 2%
Infection 6%
Asthenia 6%
Skin rash 3%
120107 [53]
Phase II KRd induction
Rd maintenance
Induction: 28-day cycle
(cycles 1–8) carfilzomib 20/36 mg/m2 iv D1, 2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. D 1–21 + dex 20 mg (cycles 1–4) and 10 (cycles 5–8) p.o. or iv D1, 2, 8, 9, 15, 16
Maintenance (cycles 1–24): 28-day cycle
lenalidomide 25 mg D1–21
12CR 100%. MRD neg (MFC 10−5 ) 92%No progression to MM
3-, 4-year PFS 94%, 70.6%
3-, 4- year OS: 100%
Lymphopenia 39%
Neutropenia 28%
Anemia 22%
Thrombocytopenia 11%
Diarrhea 17%
Lung infection 17%
Hypophosphatemia 11%
1 case of CHF
Phase IIKRd induction
KRd consolidation
Rd maintenance
Induction: 28-day cycle
(cycles 1–6): carfilzomib 20/36 mg/m2 iv D1, 2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. D1–21 + dex 40 mg D1, 8, 15, 22
ASCT melphalan 200 mg/m2
Consolidation: KRd 2 cycles
Maintenance: 28-day cycle lenalidomide 10 mg days 1–21 + 20 mg days 1, 8, 15, 22 for 2 years
90ORR: 100%. ≥CR: 70%
MRD (NGF) 57%
30 months PFS 98%Induction (G3-4):
Neutropenia 6% Thrombocytopenia 11% Infections 18%
Consolidation: Ongoing
NCT03673826 HO147SMMPhase IIKRd vs. Rd
Rd maintenance
(cycles 1–9) carfilzomib 20/36 mg/m2 iv D1, 2, 8, 9, 15, 16, lenalidomide 25 mg p.o. D1–21, dexamethasone 20 mg p.o. (cycles 1–4) and 10 mg p.o. (cycles 5–9) D1, 8, 15, 22
(cycles 1–9) lenalidomide 25 mg p.o D1–21, dexamethasone 20 mg p.o. (cycles 1–4) and 10 mg p.o. (cycles 5–9) D1, 8, 15, 22
Maintenance: (cycles 1–24) lenalidomide 10 mg p.o. days 1–21 of a 28-day cycle
NCT03289299 ASCENTPhase IIDara KRd + Rd maintenanceInduction: 28-day cycle (cycles 1–6) carfilzomib 20/36 mg/m2 iv D1, 2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. D1–21 + dex 40 mg D1, 8, 15, 22, daratumumab 16 mg/kg iv D1, 8, 15, and 22 of cycles 1–2; D1 and 15 of cycles 3–6;
6 cycles, KR as in induction + dex 20 mg p.o. D1, 8, 15, 22 Daratumumab 16 mg/kg iv D1 of cycles 7–12
Maintenance: 12 cycles, lenalidomide 10 mg p.o. D1–21
+ daratumumab; 16 mg/kg iv D1 of odd cycles for cycles 13–24
15-294 [55]
Phase IIxazomib dexamethasone28-day cycle
(cycles 1–12) ixazomib 4 mg on D1, 8, and 15, and dexamethasone on days 1, 8, 15, and 22 (40 mg/week the first 4 cycles, thereafter 20 mg/week)
14ORR 64%64% ORR (8 PR, and 1 VGPR) no patient progressed to MMLung infection (14%)
CA204-011 [56]
Phase IIElotuzumab (cycle 1) elotuzumab 20 mg/kg iv D1, 8 then [cycle 2—progressive disease] Elotuzumab monthly q4 week
(cycle 1) elotuzumab 10 mg/kg iv D1, 8, 15, 22
(cycle 2—progressive disease) elotuzumab monthly q2 week
31Both groups ORR 10%Both groups
2-year PFS 69%
Upper respiratory tract infection 7%
Fatigue 6%
Diarrhea 6%
Insomnia 6%
14-338 [57]
Phase IIElotuzumab Rd + stem-cell mobilization + maintenanceInduction: 28-day cycle
(cycles 1–2) elotuzumab 10 mg/kg iv D1, 8, 15, 22 + lenalidomide 25 mg p.o. D1–21 + dex 40 mg p.o. D1, 8, 15, 22 (cycles 3–8): elotuzumab 10 mg/kg iv D1, 15 + lenalidomide as in cycles 1–2 + dex 40 mg p.o. D1, 8, 15
Maintenance: 28-day cycle
(cycles 9–4) elotuzumab 10 mg/kg iv D
1 + lenalidomide as in cycles 1–2
50≥VGPR 43%NAHypophosphatemia 34% Neutropenia 26%
Lymphopenia 22%
16-313 [58]
Phase IIIxazomib-RdInduction: 28-day cycle
(cycles 1–9): ixazomib 4 mg p.o. D1, 8, 15 + lenalidomide 25 mg
p.o. D1–21 + dex 40 mg p.o. D1, 8, 15, 22
Maintenance: 28-day cycle
(cycles 10-24): ixazomib 4 mg p.o. D1, 8,
15 + lenalidomide 25 mg p.o. D1–21
26≥VGPR 53.8%NAHypophosphatemia 13% Lymphopenia 13%
Neutropenia 8.7% (G4 Neutropenia in 1 pt)
CR100755 [59]
Phase IISiltuxumab vs. placebo(cycle 1—until progressive disease): siltuximab 15 mg/kg iv every 4 weeks
87NA1-year PFS: 84%
Median PFS: NR
1-year PFS: 74.4%
Median PFS: 23.8 months
Infections (5 patients in siltuximab group and 6 patients in placebo group)
Urinary disorders (one patient in the siltuximab group and three patients in the placebo group)
Phase IIIsatuximab(cycles 1–30): 28-day cycle
isatuximab iv D1, 8, 15, and 22 of cycle 1, on D1 and 15 of cycles 2–6, and on D1 of subsequent courses
NCT02316106, CENTAURUS [60]Phase IIDaratumumab iv (3 arms, 41 patients each)Daratumumab 16 mg/kg iv in 8-week cycles
Long intensity:(cycle 1) every 1 week; (cycle 2–3) every other
week; (cycles 4–7) every 4 weeks; (cycles 8–20) every 8 weeks
Intermediate intensity: (cycle 1) every 1 week and (cycles 2–20) every 8 weeks
Short intensity: (cycle 1) every week for 8 infusions
123≥CR rate 7% in
combined Long and Int arms
Long intensity
24-month PFS 90%
intermediate intensity 24-month PFS 82%
short intensity 24-month PFS
Long intensity serious adverse events, 32%
≥G3 AE 44%
- Hypertension 7%
- Hyperglycemia 2%
intermediate intensity serious adverse events 15%
≥G3 AE 27%
- Hypertension 5%
- Hyperglycemia 5%
short intensity
serious adverse events, 10%
≥G3 AE 15%
- Hypertension 3%
- Hyperglycemia 0%
NCT03301220 AQUILA [61]Phase IIIDaratumumab sc for 3 years vs. observationDaratumumab sc injection (daratumumab 1800 mg + rHuPH20 [2000 U/mL]) once weekly for cycles 1 and 2 (D1, 8, 15, and 22 of each week), every 2 weeks for cycles 3–6 (D1 and 15), and thereafter every 4 weeks (D1) until 39 cycles or up to 36 months or PD
NCT01169337 E3A06 [62]Phase II–IIIR vs. observation
(median FU 35 months)
Lenalidomide 25 mg p.o. D1-21 in 28 days cycle until PD
180Overall response 47.7% phase II 48.9% phase IIIPFS 1 year
(98% vs. 89%),
PFS 2 years
(93% vs. 76%)
PFS 3 years
(91% vs. 66%)
G3/4 non-hematologic AEs 28%:
- Infections 10%
- Fatigue 6.8%
- Hypertension 9%
G4 hematologic AEs 4.5%, primarily neutropenia (n = 4), cumulative incidence of invasive SPMs 11.4% (Len) and 3.5% (observation).
D, day; Pts, patients; R, Len, lenalidomide; d, dex, dexamethasone; FU, follow-up; TTP, time to progression; PFS, progression-free survival; OS, overall survival; G, grade; P, p-value; MM, multiple myeloma; K, carfilzomib; ORR, overall response rate; Dara, daratumumab; ASCT, autologous stem-cell transplantation; NA, not available; NR, not reached; iv, intravenous; D, day; AE, adverse event; sc, subcutaneous; p.o., orally; HR, hazard ratio; CR, complete response; PR, partial response; VGPR, very good PR; PD, progressive disease; CHF, congestive heart failure; SPMs, second primary malignancies; MRD, minimal residual disease; neg, negative.
Table 4. Newly diagnosed multiple myeloma: selected clinical trials enrolling transplant-eligible patients.
Table 4. Newly diagnosed multiple myeloma: selected clinical trials enrolling transplant-eligible patients.
ProtocolPhaseTreatmentSubjectsResponseTTP/PFS/OSToxicity (≥G3)
IFM2008 [70]
Phase IIVRd induction
Stem-cell mobilization
VRd consolidation
R maintenance
Induction 21-day cycles (cycles 1–3)
Bortezomib iv 1.3 mg/m2 D1, 4, 8, and 11
Lenalidomide p.o. 25 mg D1–14
Dexamethasone p.o. 40 mg D1, 8, 15
Stem-cell harvest
Consolidation 21-day cycles (cycles 1–3)
Bortezomib iv 1.3 mg/m2 D1, 4, 8, and 11
Lenalidomide p.o. 25 mg D1–14 + dex p.o. 40 mg D1, 8, 15
Lenalidomide p.o. 10 mg per day for the first 3 months, a possible dose increase to 15 mg for 1 year
31After induction
58% ≥VGPR
23 % ≥CR
16% MRD neg MFC (10−4–10−5)
After ASCT
70% ≥VGPR
54% MRD neg MFC (10−4–10−5)
After consolidation
87% ≥VGPR
50 ≥CR
58% MRD neg MFC (10−4–10−5)
Best response (after maintenance)
84% ≥VGPR
58% ≥ CR
68% MRD neg MFC (10−4–10−5)
Estimated 3-year PFS 77% and OS 100% (median FU 39 months)Neutropenia 65%
Thrombocytopenia 19%
Anemia 3%
Infections 6%
NCT00507442 EVOLUTION [71]Phase II randomizedVRd (n = 42) vs.
VRCd (n = 48)
VCd (n = 33)
Induction 21-day cycles
(cycles 1–8)
Bortezomib 1.3 mg/m2, days 1, 4, 8, 11
Dexamethasone 40 mg, D1, 8, 15
Cyclophosphamide 500 mg/m2, D1, 8
Lenalidomide p.o., 15 mg in VRCd and 25 mg in VRd D1–14
Maintenance 6-week cycles (cycles 1–4) Bortezomib 1.3 mg/m2, D1, 8, 15, 22
Stem-cell mobilization any time after 2 cycles
ASCT any time after 4 cycles
140VRd best response
61% ≥VGPR
21% CR
VRCd best response
54% ≥VGPR
21% CR
VCd best response
24% ≥VGPR
10% CR
1-year PFS
83% VRd
86% VRCd
93% VCd
100% VCd-mod
1-year OS estimate
92% VRCd arm
100% for the other three arms
Neuropathy 17%
Neuropathy 13%
Neuropathy 9%
MyelomaXI [72,73]
Phase III randomizedTransplant eligible:
CTd vs. CRd vs. KCRd induction
CVd intensification vs. no intensification
Mel200 ASCT
Lenalidomide maintenance vs. observation
Transplant eligible:
CTd: 21-day cycle cyclophosphamide 500 mg p.o. D1, 8, 15
thalidomide 50 mg p.o. continuously D1–21
dexamethasone 40 mg p.o. D1–4, 12–15
CRd: 28-day cycle cyclophosphamide 500 mg p.o. D1, 8
lenalidomide 25 mg p.o. D1–21
dexamethasone 40 mg p.o. D1–4, 12–15
KCRd: 28-day cycle
carfilzomib 36 mg/m2 i.v. D1, 2, 8, 9, 15, and 16
cyclophosphamide 500 mg p.o. D1, 8
lenalidomide 25 mg p.o. D1–21 dexamethasone 40 mg p.o. D1–4, 8, 9, 15, and 16
CVd: 21-day cycles
Bortezomib i.v. 1.3 mg/m2 D1, 4, 8, and 11
cyclophosphamide 500 mg p.o. D1, 8, and 15
Dexamethasone p.o. 20 mg D1, 2, 4, 5, 8, 9, 11, and 12
Lenalidomide p.o. 10 mg D1–21
53% ≥VGPR
11% MRD neg (MFC 10−4–10−5)
65% ≥VGPR
21% MRD neg
82% ≥VGPR
55% MRD neg
3-year PFS
50.3% CTd/CRd
64.5% KCRd
- Neutropenia
12.8% CTd
22.3% CRd
16.4% KCRd
- Thrombocytopenia
1.2% CTd
2.3% CRd
8.4% KCRd
IFM2009 [74]
Phase IIIVRd induction
VRd consolidation
Induction: 21-day cycles (cycles 1–3) Bortezomib i.v. 1.3 mg/m2 D1, 4, 8, and 11
Lenalidomide p.o. 25 mg D1–14
Dexamethasone p.o. 20 mg D1, 2, 4, 5, 8, 9, 11, and 12
Stem-cell mobilization with cyclophosphamide and G-CSF
Consolidation (cycles 4–8) VRd reduced dex 10 mg (VRd-alone group)
Melphalan 200 mg/m2 ASCT + 2 cycles of
VRd reduced dex 10 mg (transplantation group)
Lenalidomide p.o. 10 mg per day for the first 3 months, a possible dose increase to 15 mg for 1 year
700VRd arm
After induction
45% ≥VGPR
After consolidation
≥69% VGPR
Best response (after maintenance)
77% ≥VGPR
48% CR
of which 65% MRD neg
After induction
47% ≥VGPR
After consolidation
78% ≥VGPR
Best response
88% ≥VGPR
59% CR
of which 79% MRD neg
Median PFS 50 vs. 36 months
OS 4years
81% vs. 82%
Neutropenia (47% vs. 92%)
Gastrointestinal disorders (7% vs. 28%)
Infections (9% vs. 20%)
GEM2012MENOS65 [75]
Phase IIIVRd 6 cycles
Stem cell mobilization after 3 induction cycles
VRd 2 cycles post-transplant consolidation
Induction (cycles 1–6)
Bortezomib 1.3 mg/m2 sc D1, 4, 8, 11 Lenalidomide 25 mg/day D1–21
Dexamethasone 40 mg on D1–4 and 9–12 at 4 weeks
Melphalan 200 mg/m2 iv D 2
Busulfan 9.6 mg/kg + Melphalan 140 mg/m2
(cycles 7–8) same schedule as induction
458After induction
29% VGPR
39% CR
28% sCR
34% MRD-neg (by NGF)
After ASCT
27% VGPR
49% CR
36% sCR
53% MRD neg
After consolidation
58% MRD neg
Neutropenia 11%
Thrombocytopenia 6%
Hepatic 4%
Skin 3%
Neuropathy 1%
UMCC 2009.056 [8]
Phase I/II
Phase II extended
Phase I
KRd without ASCT induction and KRd maintenance
Phase II
KRd induction
KRd consolidation
KRd maintenance
Phase I/II
Induction (cycles 1–8) Carfilzomib iv 20/36 mg/m2 D1, 2, 8, 9, 15, 16 (20 mg/m2 given on cycle 1, D1)
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg/week
Maintenance (cycles 9–24) Carfilzomib 36 mg/m2 D1, 2, 15, 16
Lenalidomide p.o. same dose of C8 D1–21
Dexamethasone p.o. 20 mg weekly
Phase II
Induction (cycles 1–4)
Carfilzomib iv 20/36 mg/m2 D1, 2, 8, 9, 15, 16 (20 mg/m2 given on cycle 1, D1)
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg/week
Stem-cell collection using G-CSF and plerixafor
ASCT Melphalan 200 mg/m2 conditioning
Consolidation (cycles 5–8) Carfilzomib i.v. 36 mg/m2 D1, 2, 8, 9, 15, 16
Lenalidomide p.o. 15 mg D1–21 (with option to escalate to 25 mg)
Dexamethasone p.o. 20 mg weekly
Maintenance (cycles 9–18) Carfilzomib 36 mg/m2 D1, 2, 15, 16
Lenalidomide p.o. same dose of cycle 8 D1–21
Dexamethasone p.o. 20 mg weekly
Lenalidomide as single-agent off-study after C18.
53 (phase I/II)
76 (phase II)
Phase I/II
Post-induction (C8)
55% sCR
Phase II
Post-consolidation (C8)
96% ≥VGPR, 73% CR
69% sCR.
Post-consolidation (C8)
82% MRD neg (MFC) (N = 33) 66% MRD neg (NGS) (N = 29)
Post-Maintenance (C18)
90% MRD neg (MFC) (N = 20) 71% MRD neg (NGS) (N = 16)
Phase I/II
4- year PFS 63%
4-year OS 93%
Phase II
2-year PFS 97% and 2-year OS 99%
(median FU 17 months)
Phase II
Lymphopenia 28% Neutropenia 18% Infections 8%
110221 [53]
Phase IIKRd induction
R maintenance
Induction (cycles 1–8) Carfilzomib iv 20/36 mg/m2, D1, 2, 8, 9, 15, 16
Lenalidomide 25 mg p.o. D1–21
Dexamethasone 20 mg (cycles 1–4) and 10 (cycles 5–8) p.o. or iv D1, 2, 8, 9, 15, 16 then
Maintenance (cycles 1–24) lenalidomide 25 mg D1–21
4562% MRD neg (calculated on NGS-evaluable NDMM patients)18-month PFS: 100% vs. 84%Lymphopenia 34%
Thrombocytopenia 11%
Neutropenia 15%
Anemia 12%
Infection 6%
Cardiac 5%
Vascular 6%
Phase IIKCd-ASCT-KCd (arm A),
KRd-ASCT- KRd (arm B),
KRd 12 cycles (arm C)
Induction (cycles 1–4) Carfilzomib 36 mg/m2 D1, 2, 8, 9, 15, and 16 of a 28-day cycle; lenalidomide p.o. 25 mg D1–21
Dexamethasone 20 mg D1, 2, 8, 9, 15, and 16) or
Cyclophosphamide 300 mg/m2 on D1, 8, and 15
ASCT/mel200 or 4 KRd cyles (cycles 4–8)
Consolidation (cycles 8–12)
4 cycles same as induction
KR vs. R (random)
474Pre-maintenance response rates: ≥VGPR:
76% Arm A
89% Arm B
87% Arm C
32% Arm A
44 % Arm B
43 % Arm C
Pre-maintenance MRD neg MFC
42% Arm A
58% Arm B
54% Arm C
NADermatologic 1–13%
Neutropenia 15–20%
Thrombocytopenia 8–15%
Infections 12–14%
Increased liver enzymes 1–10%
Hypertension 3–8%
Cardiac 2–3%
Phase IIDara-VRd induction
Dara-VRd consolidation
Dara-R maintenance
Induction (cycles 1–6)
Lenalidomide 25 mg p.o. D1–14
Bortezomib 1.3 mg/m2 sc D1, 4, 8, and 11
Dexamethasone 40 mg weekly
Daratumumab 16 mg/kg iv D1, 8, and 15 of cycles 1–4 and on D1 of cycles 5–6.
Maintenance (C7–32) lenalidomide 10 mg p.o. daily (15 mg beginning at cycle 10 if tolerated) on D1–21 every 28 days and Dara 16 mg/kg iv every 56 days;
Maintenance lenalidomide may be continued beyond C32
207 (safety run in 16 pts)Post-consolidation
91% ≥VGPR
52% ≥CR of which
59% MRD neg
73% ≥VGPR
42% ≥CR of which
24% MRD neg
NA (FU 13.5 months)>10%
Cytopenia similar in two arms
40% of Dara infusion-related reaction (mainly G1–2)
Phase IIIDara-VTd-ASCT-Dara-VTd vs.
Maintenance Daratumumab vs. observation
Induction (cycles 1–4) and consolidation (cycle 5–6) Bortezomib 1.3 mg/m2 D1, 4, 8, 11 Thalidomide 100 mg daily p.o. in all cycles
Dexamethasone 40 mg p.o. or iv D1, 2, 8, 9, 15, 16, 22, and 23 of induction cycles 1 and 2 and D1 and 2 of induction cycles 3 and 4 and 20 mg on D8, 9, 15, 16 of induction cycles 3–4 and D1, 2, 8, 9, 15, and 16 of both consolidation cycles.
Daratumumab iv 16 mg/kg once weekly in induction cycles 1 and 2 and once every 2 weeks during induction cycles 3 and 4 and consolidation
Stem-cell mobilization with cyclophosphamide (3 g/m2)
Mel200 mg/m2 iv conditioning
Daratumumab (16 mg/kg) every 8 weeks until disease progression or for a maximum of 2 years
83% ≥VGPR
10% CR
28.9% sCR
64% MRD neg (MFC)
39% MRD neg (NGS)
78% ≥VGPR
6% CR
20.3% sCR
44% MRD neg (MFC)
23% MRD neg (NGS)
Probability: 18 months PFS
(Dara–VTd) 93%
Neutropenia 28% vs. 15%
Thrombocytopenia 11 vs. 7%
Neuropathy 9% vs. 9%
GIT 16%
Reaction infusion 4% in Dara–VTd
MMY1001 [11]
Phase IbDara-KRdDaratumumab 16 mg/kg QW for cycles 1–2, Q2W for cycles 3-6, and Q4W (1st dose of Dara split over 2 days)
Carfilzomib 20/36 mg/m2 iv weekly D1, 8 and 15 of each 28-day cycle (20 mg/m2 on cycle 1, D1) for ≤13 cycles or elective discontinuation for ASCT
Lenalidomide p.o. 25 mg D1–21 and Dexamethasone 20–40 mg per week
22Best response
33% VGPR
14% CR
43% sCR
1-year PFS 95%Lymphopenia 50%
Neutropenia 23%
1 (5%)
cardiac grade 3 TEAE was observed (congestive heart failure)
C16005 [78]
Phase I/IIIxa-Rd induction
Ixa maintenance
Induction 28-day cycles
(cycles 1–12) Ixazomib p.o. 4 mg D1, 8, and 15
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg D1, 8, 15, and 22
Discontinuation → ASCT
Only for patients who did not proceed to ASCT:
Single-agent ixazomib, given at the last tolerated dose during induction
6563% ≥VGPR
32% CR
MRD neg 12.5% (MFC)
Median PFS 35.4 monthsNeutropenia 14%
Thrombocytopenia 9%
GIT 6%
NDMM, newly diagnosed multiple myeloma; pts, patients; V, bortezomib; R, lenalidomide; d, dex, dexamethasone; C, cyclophosphamide; K, carfilzomib; T, thalidomide; iv, intravenous; D, day; ASCT, autologous stem-cell transplantation; Mel200, melphalan at 200 mg/m2; Bu, busulfan; Ixa, ixazomib; p.o., orally; G-CSF, granulocyte colony-stimulating factor; Dara, daratumumab; Pts, patients; PR, partial response; VGPR, very good PR; CR, complete response; sCR, stringent CR; MRD, minimal residual disease; MFC; multiparameter flow cytometry NGS, next-generation sequencing; N, number; neg, negative; TTP, time to progression; PFS, progression-free survival; OS; overall survival; FU, follow-up; mod, modified; NA; not available; NR, not reached; G, grade AE, adverse event; TEAE; treatment-emergent AE; GIT, gastrointestinal toxicity. QW, given every week; Q2W, given every two weeks; Q4W, given every 4 weeks.
Table 5. Newly diagnosed multiple myeloma: selected clinical trials enrolling transplant-ineligible patients.
Table 5. Newly diagnosed multiple myeloma: selected clinical trials enrolling transplant-ineligible patients.
ProtocolPhaseTreatmentSubjectsResponseTTP/PFS/OSToxicity (≥G3)
SWOG S0777 [108]
Phase IIIVRd vs. RdVRd 21-day cycles (cycles 1–8)
Bortezomib 1.3 mg/m2 iv D1, 4, 8, and 11 +;
Lenalidomide p.o. 25 mg daily D1–14
Dexamethasone p.o. 20 mg daily D1, 2, 4, 5, 8, 9, 11, and 12
Rd 28-day cycles (cycles 1–6)
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg D1, 8, 15, and 22
43% vs. 32%
CR 15.7% vs. 8.4%
Median PFS 43 vs/ 30 months,
median OS 75 vs. 64 months
Neurological AEs 33% vs. 11%
Phase IIIDara-VMp vs. VMpInduction 42-day cycles
(cycles 1–9)
Bortezomib 1.3 mg/m2 sc twice-weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2–9)
Melphalan p.o. 9 mg/m2 once-daily on D1–4
Prednisone p.o. 60 mg/m2, once-daily on D1–4
Daratumumab iv 16 mg/kg
Dexamethasone 20 mg once-weekly in cycle 1, every 3 weeks in cycles 2–9, and every 4 weeks thereafter until disease progression
706≥VGPR 71% vs. 49%
≥CR 42% vs. 24%
MRD neg by NGS
Dara-VMp arm: 22.3%
VMp arm: 6.2%
Median PFS NRNeutropenia 40% vs. 38%
Anemia 16% vs. 19%,
Thrombocytopenia 34% vs. 37%
Pneumonia 11% vs. 4%
MAIA [110]
Phase IIIDara-Rd vs. RdDara–Rd 28-day cycles
Daratumumab iv 16 mg /kg once-weekly during cycles 1–2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg D1, 8, 15, and 22
Rd 28-day cycle
Lenalidomide p.o. 25 mg D1–21
Dexamethasone p.o. 40 mg D1, 8, 15, and 22
737≥VGPR 79% vs. 53%
≥CR 47% vs. 24%
MRD neg by NGS Dara–Rd arm: 24.2%
Rd arm: 7.3%
Median PFS NRNeutropenia 50% vs. 35%
Anemia 12% vs. 20%
Lymphopenia 15% vs. 11%
Pneumonia 14% vs. 8%
SARVRD [111]
Phase IIsa-VRd induction + Isa-Rd maintenance (16)Induction 6-week cycles
Isatuximab iv 10 mg/kg (cycles 1–4)
D1, 8, 15, 22, 29 (cycle 1),; D1, 15, 29 (cycles 2–32 (cycles 1–4)
Lenalidomide p.o. 25 mg/day D1–14 and D22–35 (cycles 1–4)
Dexamethasone 20 mg D1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33
Maintenance 4-week cycles
Isatuximab iv 10 mg/kg on D1, 15 (all cycles)
Lenalidomide p.o. 25 mg D1–21 (all cycles)
Dexamethasone p.o. 40 mg D1, 8, 15, 22 (all cycles)
22ORR 93%
MRD neg by NGS 50% (33% at 10−6)
NGF 44% (18% at 10−6)
NAG≥3 AEs were reported in 10 (46%) and SAEs in 4 (18%) pts
Lymphopenia (8/22)
Neutropenia (4/22)
Thrombocytopenia (4/22)
V, bortezomib; R, lenalidomide; d, dexamethasone; Dara, daratumumab; M, melphalan; p, prednisone; Isa, isatuximab; D, day; iv, intravenous; p.o., orally; sc, subcutaneous; PR, partial response; VGPR, very good PR; CR, complete response; MRD, minimal residual disease; neg, negative; NGS, next-generation sequencing; NGF, next-generation flow; G, grade; AEs; adverse events; SAEs, serious AEs.

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D'Agostino, M.; Bertamini, L.; Oliva, S.; Boccadoro, M.; Gay, F. Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies. Cancers 2019, 11, 2015.

AMA Style

D'Agostino M, Bertamini L, Oliva S, Boccadoro M, Gay F. Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies. Cancers. 2019; 11(12):2015.

Chicago/Turabian Style

D'Agostino, Mattia, Luca Bertamini, Stefania Oliva, Mario Boccadoro, and Francesca Gay. 2019. "Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies" Cancers 11, no. 12: 2015.

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