Advances in Amyloidosis: A Theme Issue in Honor of Prof. Dr. Giampaolo Merlini

A special issue of Hemato (ISSN 2673-6357). This special issue belongs to the section "Plasma Cell Disorders".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 46845

Special Issue Editors


E-Mail Website
Guest Editor
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy
Interests: amyloidosis; monoclonal gammopathies of clinical significance; biomarkers

E-Mail Website
Guest Editor
Amyloidosis Center and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Interests: local and systemic amyloidosis; genetic of plasma cell dyscrasias; monoclonal gammopathies of clinical significance; auto and allo transplantation

E-Mail Website
Guest Editor
Service d'Hématologie, Hôpital Pitié Salpêtrière, 47‐83 boulevard de l'hôpital, F‐75013 Paris, France
Interests: myeloma; AL amyloidosis; monoclonal gammopathy of clinical significance; POEMS; transplantation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Theme Issue aims to honor Prof. Giampaolo Merlini’s outstanding scientific and clinical achievements in the field of systemic amyloidosis. Prof. Merlini was introduced to the concept of “sick molecules and diseases” and to the then neglected and enigmatic condition of amyloidosis by his two mentors, Jan Waldenström and Elliott Osserman at the brink of his career. Since then, he has been devoting his life to elucidating the mechanism of this disease and translating his observations in better care for patients. Patients, in turn, are the constant source of inspiration for his research. Prof. Merlini demonstrated that amyloidogenic light chain exert a direct organ toxicity, discovered the first small molecule, iodo-deoxy-doxorubicin, which could interfere with the amyloidogenic process, set up innovative methods for the diagnosis of amyloidosis, introduced biomarkers in the staging and monitoring of this disease, and contributed to the development of most of the currently available therapeutic regimens. In the last forty years, our understanding of the mechanisms of amyloidosis has advanced greatly, providing novel therapeutic targets and reliable tools for diagnosis. In addition, prognostic stratification and monitoring of the disease became available, and we can now choose between an increasing number of effective therapeutic agents. Thanks to these developments, we are witnessing a constant improvement of the outcome of patients with amyloidosis.
This Special Issue will cover a diverse range of topics, from the classification and differential diagnosis of the various types of amyloidosis to the pathogenesis of clonal and organ disease in light chain amyloidosis. The placing of old and novel therapeutic strategies according to patients’ risk level will be discussed, as well as established and promising tools for disease monitoring.

Prof. Dr. Giovanni Palladini
Prof. Dr. Stefan Schönland
Dr. Laurent Garderet
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Hemato is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Amyloidosis
  • Biology of amyloid plasma cell clone and light chains
  • Amyloid typing
  • Biomarkers (staging and response assessment)
  • Stem cell transplant in AL amyloidosis
  • Non-transplant chemo-immuno-therapy in AL amyloidosis
  • MRD in AL amyloidosis

Published Papers (13 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

6 pages, 225 KiB  
Article
Histological Kidney Re-Evaluation after Daratumumab Monotherapy for AL Amyloidosis
by Roberta Fenoglio, Gianluca Rabajoli, Antonella Barreca, Emanuele De Simone, Savino Sciascia and Dario Roccatello
Hemato 2022, 3(2), 367-372; https://doi.org/10.3390/hemato3020025 - 13 Jun 2022
Viewed by 1684
Abstract
Background: AL amyloidosis is a systemic disorder characterized by extracellular deposition of characteristic fibrils that results in progressive multi-organ failure and premature death. Recently daratumumab has been demonstrating higher hematological and organ response rates when compared to the standard of care. We hereby [...] Read more.
Background: AL amyloidosis is a systemic disorder characterized by extracellular deposition of characteristic fibrils that results in progressive multi-organ failure and premature death. Recently daratumumab has been demonstrating higher hematological and organ response rates when compared to the standard of care. We hereby report our long-term experience on the effects of daratumumab given alone on the deposition of amyloid as evaluated in repeat renal biopsy. Results: Six patients were enrolled. All patients had proteinuria that was associated with renal function impairment in four. After therapy with daratumumab, four patients achieved complete hematological response and two had partial hematological response at the end of treatment. With regard to renal response, four out of six patients achieved an organ response; one patient had fluctuating proteinuria levels and did not meet the needed criteria at the end of the treatment and the last patient, who was already in dialysis at the time of therapy initiation, remained on dialysis despite complete hematological and cardiac responses. A significant decrease in 24-h proteinuria from 7.9 g/24 h to 1.1 (p < 0.005) with stabilization or improvement of sCr (from 1.5 mg/dL to 1.2 mg/dL; p = 0.34) were observed. All patients underwent a repeat biopsy after 24 administrations of daratumumab. In five patients, the repeat biopsy showed unchanged features; while in one it showed an improvement. Conclusions: Our data, based on real life experience, show that daratumumab monotherapy can be an effective therapeutic option. It is capable not only of achieving a substantial rate of renal improvement in pre-treated and naïve patients, but also of limiting renal deposition Full article
9 pages, 480 KiB  
Communication
Beyond Survival in AL amyloidosis: Identifying and Satisfying Patients’ Needs
by Hamza Hassan and Vaishali Sanchorawala
Hemato 2022, 3(1), 38-46; https://doi.org/10.3390/hemato3010004 - 04 Jan 2022
Viewed by 3145
Abstract
The survivorship needs of patients with light-chain (AL) amyloidosis are complex, as is the diagnosis and treatment itself. Early diagnosis is critical in improving patient outcomes; however, given the nonspecific nature of the symptoms, most patients with AL amyloidosis require evaluation by multiple [...] Read more.
The survivorship needs of patients with light-chain (AL) amyloidosis are complex, as is the diagnosis and treatment itself. Early diagnosis is critical in improving patient outcomes; however, given the nonspecific nature of the symptoms, most patients with AL amyloidosis require evaluation by multiple specialists, resulting in significant delays in diagnosis of up to 3 years. An early and accurate diagnosis can help reduce the psychological toll of the patient’s journey to diagnosis. Given the high symptom burden and complex process of diagnosis, it is not surprising that patients with AL amyloidosis report worse health-related quality of life than the general population. Organ dysfunction associated with AL amyloidosis also may make the treatment directed towards plasma cell clone difficult to tolerate, leading to morbidity and mortality. Furthermore, supportive care requires an integrated, multidimensional and patient-centered approach to improve survival and feelings of well-being, as organ responses lag behind hematologic responses. The impact of AL amyloidosis is often devastating for the patient and may last beyond the effects of treatment. Future research is needed to study and assess the needs of survivors of AL amyloidosis utilizing valid, reliable and standardized measures. Full article
Show Figures

Figure 1

Review

Jump to: Research

20 pages, 1662 KiB  
Review
Laboratory-Based Rationale for Targeting the Protein Homeostasis Network in AL Amyloidosis
by Giada Bianchi, Maria Moscvin and Raymond L. Comenzo
Hemato 2022, 3(2), 298-317; https://doi.org/10.3390/hemato3020022 - 25 Apr 2022
Viewed by 2316
Abstract
AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is [...] Read more.
AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is the prototypic, protein-toxicity hematologic disorder. Based on laboratory evidence of increased, constitutive proteotoxic stress, PCs are intrinsically vulnerable to agents that target proteins whose function is to guarantee that nascent polypeptides either reach a functional conformation or are disposed of (proteostasis network). The clinical efficacy of proteasome inhibitors (PIs), such as bortezomib, in the treatment of plasma cell (PC) disorders has provided proof of concept that disrupting protein homeostasis is an effective and generally safe therapeutic approach. Therefore, the intrinsic biology of PC offers us the opportunity to rationally develop therapies that target this distinct proteostasis vulnerability of PC dyscrasias. In this manuscript, we will review the laboratory rationale for the effectiveness of FDA-approved and investigational agents targeting protein homeostasis in AL amyloidosis and related PC disorders. Full article
Show Figures

Figure 1

36 pages, 4497 KiB  
Review
From the Light Chain Sequence to the Tissue Microenvironment: Contribution of the Mesangial Cells to Glomerular Amyloidosis
by Luis Del Pozo-Yauner, Elba A. Turbat-Herrera, Julio I. Pérez-Carreón and Guillermo A. Herrera
Hemato 2022, 3(1), 232-267; https://doi.org/10.3390/hemato3010019 - 17 Mar 2022
Cited by 4 | Viewed by 2793
Abstract
Studies carried out in the last three decades have significantly advanced our knowledge about the structural factors that drive the amyloid aggregation of the immunoglobulin light chains. Solid-state nuclear magnetic resonance and cryo-electron microscopy studies have resulted in huge progress in our knowledge [...] Read more.
Studies carried out in the last three decades have significantly advanced our knowledge about the structural factors that drive the amyloid aggregation of the immunoglobulin light chains. Solid-state nuclear magnetic resonance and cryo-electron microscopy studies have resulted in huge progress in our knowledge about the AL fibril structure. Now, it is known that the assembly of the light chain into AL fibrils implies an extensive conformational rearrangement that converts the beta-sandwich fold of the protein into a near flat structure. On the other hand, there has also been significant progress made in understanding the role that some cell types play as facilitators of AL formation. Such a role has been studied in glomerular amyloidosis, where mesangial cells play an important role in the mechanism of AL deposition, as well as for the pathogenic mechanisms that result in glomerular/renal damage. This review addresses what we currently know about why and how certain light chains are prone to forming amyloid. It also summarizes the most recent publications on the structure of AL fibrils and analyzes the structural bases of this type of aggregate, including the origin of its structural diversity. Finally, the most relevant findings on the role of mesangial cells in the amyloid deposition of light chains in the glomerular space are summarized. Full article
Show Figures

Figure 1

22 pages, 1016 KiB  
Review
Future Developments in the Treatment of AL Amyloidosis
by Foteini Theodorakakou, Despina Fotiou, Meletios A. Dimopoulos and Efstathios Kastritis
Hemato 2022, 3(1), 131-152; https://doi.org/10.3390/hemato3010012 - 07 Feb 2022
Cited by 3 | Viewed by 6206
Abstract
The treatment of AL amyloidosis has evolved, and outcomes have improved, but primarily for patients with low or intermediate-risk disease. Recent advances have been limited to improvements in anti-clonal therapies, which, alone, cannot change the poor prognosis of patients with high-risk disease. Thus, [...] Read more.
The treatment of AL amyloidosis has evolved, and outcomes have improved, but primarily for patients with low or intermediate-risk disease. Recent advances have been limited to improvements in anti-clonal therapies, which, alone, cannot change the poor prognosis of patients with high-risk disease. Thus, new strategies are needed that combine different approaches to the treatment of the disease. Targeted therapies against plasma/B-cell clones that avoid chemotherapy or potentially cardiotoxic drugs may improve the depth of hematologic responses and reduce complications. Amyloid fibril and light-chain oligomer targeting may reduce direct toxicity and enhance tissue clearance. Future combinations should be tailored to clone characteristics and specific amyloid properties, but early identification of those at high risk to develop AL amyloidosis will also be integrated into management algorithms. Full article
Show Figures

Figure 1

11 pages, 255 KiB  
Review
Monitoring Patients with Light Chain (AL) Amyloidosis during and after Therapy: Response Assessment and Identification of Relapse
by Paolo Milani and M. Teresa Cibeira
Hemato 2022, 3(1), 98-108; https://doi.org/10.3390/hemato3010008 - 21 Jan 2022
Cited by 1 | Viewed by 4798
Abstract
Light chain amyloidosis is a complex disease where a small B-cell clone produces a monoclonal immunoglobulin light chain that causes deposits and specific organ dysfunction. The available treatment strategies aim to reduce or eliminate amyloidogenic light chain production in order to avoid amyloid [...] Read more.
Light chain amyloidosis is a complex disease where a small B-cell clone produces a monoclonal immunoglobulin light chain that causes deposits and specific organ dysfunction. The available treatment strategies aim to reduce or eliminate amyloidogenic light chain production in order to avoid amyloid deposition and allow the repair of organ damage. An international effort allowed the definition of validated hematologic and organ response criteria based on biomarkers. Recently, new methods for the assessment of minimal residual disease were also proposed but still need international validation. Lastly, a joint effort is also required to accurately define relapse/progression criteria in order to apply timely therapeutic interventions. In this review, we describe the validated response criteria and report on the future direction for the definition of progression criteria in this disease. Full article
16 pages, 690 KiB  
Review
Mechanisms of Organ Damage and Novel Treatment Targets in AL Amyloidosis
by Francesca Lavatelli
Hemato 2022, 3(1), 47-62; https://doi.org/10.3390/hemato3010005 - 12 Jan 2022
Cited by 6 | Viewed by 4443
Abstract
The deposition of amyloid light chains (LCs) in target sites translates into tissue damage and organ dysfunction. Clinical and experimental advances have cast new light on the pathophysiology of damage in AL amyloidosis. The currently accepted view is that, besides the alterations caused [...] Read more.
The deposition of amyloid light chains (LCs) in target sites translates into tissue damage and organ dysfunction. Clinical and experimental advances have cast new light on the pathophysiology of damage in AL amyloidosis. The currently accepted view is that, besides the alterations caused by fibrillar deposits in the extracellular space, direct proteotoxicity exerted by prefibrillar LC species is an important pathogenic factor. As our knowledge on the pathological species and altered cellular pathways grows, novel potential therapeutic strategies to prevent or reduce damage can be rationally explored. Complementing chemotherapy with approaches aimed at disrupting the deposited fibrils and stabilizing prefibrillar amyloidogenic LC may allow halting or even reverting damage in target sites. This review recapitulates the current knowledge and the most recent acquisitions regarding the mechanisms of organ damage in AL amyloidosis, with special emphasis on the heart, and will provide a critical discussion on possible novel treatment targets. Full article
Show Figures

Figure 1

14 pages, 626 KiB  
Review
Learning from Patients: The Interplay between Clinical and Laboratory Research in AL Amyloidosis
by Moshe E. Gatt and Marjorie Pick
Hemato 2022, 3(1), 3-16; https://doi.org/10.3390/hemato3010002 - 22 Dec 2021
Cited by 1 | Viewed by 2413
Abstract
Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone, and also patient-related factors, influence the mechanism and rate [...] Read more.
Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone, and also patient-related factors, influence the mechanism and rate of the process. The lessons learnt from patient care definitely imply that this is not solely due to the deposition of material in the tissues that cause organ injury but amyloid light chain precursors are likely to mediate cellular toxicity. The disease rarity, combined with the lack of in vitro tools, and that multi-organ failure has a wide clinical spectrum, result in investigative challenges and treatment limitations (due to AL patient frailty). All these characteristics make the disease difficult to diagnose and indicate the need to further study its origins and treatments. This review will focus on the various aspects of the amyloidogenic plasma cell clone, as learnt from the patient care and clinics, and its implications on basic as well as clinical trials of AL research. Details regarding the etiology of the plasma cell clone, understanding the diagnosis of AL, and improvement of patient care with specific consideration of the future perspectives of individualized patient therapy will be described. Full article
Show Figures

Figure 1

9 pages, 528 KiB  
Review
Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy
by Ute Hegenbart, Marc S. Raab and Stefan O. Schönland
Hemato 2021, 2(4), 739-747; https://doi.org/10.3390/hemato2040050 - 07 Dec 2021
Cited by 1 | Viewed by 2378
Abstract
Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell [...] Read more.
Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future. Full article
Show Figures

Figure 1

12 pages, 272 KiB  
Review
Differences and Similarities in Treatment Paradigms and Goals between AL Amyloidosis and Multiple Myeloma
by Monique C. Minnema, Rimke Oostvogels, Reinier Raymakers and Margot Jak
Hemato 2021, 2(4), 680-691; https://doi.org/10.3390/hemato2040045 - 18 Nov 2021
Cited by 1 | Viewed by 2820
Abstract
Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is [...] Read more.
Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with >10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases. Full article
15 pages, 1942 KiB  
Review
Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis
by Gareth J. Morgan, Joel N. Buxbaum and Jeffery W. Kelly
Hemato 2021, 2(4), 645-659; https://doi.org/10.3390/hemato2040042 - 05 Oct 2021
Cited by 11 | Viewed by 6348
Abstract
Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to [...] Read more.
Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the natively folded state of full-length light chains could act as pharmacological kinetic stabilizers, protecting light chains against unfolding, proteolysis and aggregation. Although the sequence of the pathological light chain is unique to each patient, fortunately light chains have highly conserved residues that form binding sites for small molecule kinetic stabilizers. We envision that such stabilizers could complement existing and emerging therapies to benefit light chain amyloidosis patients. Full article
Show Figures

Figure 1

10 pages, 9736 KiB  
Review
The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure
by Christian Haupt
Hemato 2021, 2(3), 505-514; https://doi.org/10.3390/hemato2030032 - 06 Aug 2021
Cited by 2 | Viewed by 2447
Abstract
The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, [...] Read more.
The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis. Full article
Show Figures

Figure 1

12 pages, 1628 KiB  
Review
Epidemiology of Amyloidosis and Genetic Pathways to Diagnosis and Typing
by Kari Hemminki and Asta Försti
Hemato 2021, 2(3), 429-440; https://doi.org/10.3390/hemato2030027 - 13 Jul 2021
Viewed by 2667
Abstract
We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which [...] Read more.
We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which Sweden is a global endemic area, at 2/million. Surprisingly, the disease was also endemic within Sweden; the incidence in the province with the highest incidence was 100 times higher than in the rest of Sweden. Risk of non-Hodgkin lymphoma increased five-fold in the affected individuals. Among non-hereditary amyloidosis, the incidence for AL amyloidosis (abbreviated as AL) was estimated at 3.2/million, with a median survival time of 3 years. Secondary systemic amyloidosis (most likely AA amyloidosis) showed an incidence of 1.15/million for combined sexes. The female rate was two times higher than the male rate, probably relating to the higher female prevalence of rheumatoid arthritis. The median survival time was 4 years. We also identified patients who likely had familial autoinflammatory disease, characterized by early onset and immigrant background from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500 times higher than that in individuals with Swedish parents. Germline genetics focused on AL on which we carried out a genome-wide association study (GWAS) in three AL cohorts (N = 1129) from Germany, UK, and Italy. Single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at p < 10−5; some of these were previously documented to influence multiple myeloma (MM) risk, including the SNP at the IRF4 binding site. In AL, SNP rs9344 at the splice site of cyclin D1, influencing translocation (11;14), reached the highest significance, p = 7.80 × 10−11; the SNP was only marginally significant in MM. The locus close to gene SMARCD3, involved in chromatin remodeling, was also significant. These data provide evidence for common genetic susceptibility to AL and MM. We continued by analyzing genetic associations in nine clinical profiles, characterized by organ involvement or Ig profiles. The light chain only (LCO) profile associated with the SNP at the splice site of cyclin D1 with p = 1.99 × 10−12. Even for the other profiles, distinct genetic associations were found. It was concluded that the strong association of rs9344 with LCO and t(11;14) amyloidosis offer attractive mechanistic clues to AL causation. Mendelian randomization analysis identified associations of AL with increased blood monocyte counts and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17 alias BCMA) protein. Two other associations with the TNFRSF members were found. We discuss the corollaries of the findings with the recent success of treating t(11;14) AL with a novel drug venetoclax, and the application of BCMA as the common target of plasma cell immunotherapies. Full article
Show Figures

Figure 1

Back to TopTop