The Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma

Round 1

Reviewer 1 Report

Dear Authors, I found this work an interesting   work on the Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma. However, its current presentation is 3 degrees below journal standards. It needs some serious extra work. Regards. P.S.

[1] Writing:

1-1 Add list of used abbreviations and their explanations at then end right before Reference section. 

1-2 Add Study outline in line 60 at the end of Introduction section.

1-3 Add Consort Diagram for Study Data Sample and different exclusion as each stage. [Example: https://trialsjournal.biomedcentral.com/articles/10.1186/1745-6215-12-253] 

1-4 Break down Results section for better read: 3.1. Descriptive & Inferential Analysis 3.2. Survival Analysis 

1-5 Where are your multivariate CPH results ? Where are your OS Multivariate CPH Table results ? These are the important ones ! Add them in subsection "3.Results"

1-6 Break down Discussion into three subsections for easy read: 4.1. Summary and Contributions; 4.2. Strength and Limitations; 4.3 Future Work 

1-7 Add a paragraph for 4.3. Future Work.  

1-8 References: Make sure to make them in MDPI format. Example: Article years are in bold font. 

[2] Statistical: 

2-1 Did you check proportionality assumption in the CPH survival model ? Explain it in the revision.

2-2 Report final MV CPH survival model in a table. 

2-3 Important:  Predicted Multivariate CPH survival curves for the groups with 95%CI band are missing. Please add them. Please Note that the current KM curves are categorized as descriptive analysis and are insufficient.

Some moderate English editing is needed in the revision. 

Author Response

Reviewer 1:

Comments and Suggestions for Authors

Dear Authors, I found this work an interesting   work on the Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma. However, its current presentation is 3 degrees below journal standards. It needs some serious extra work. Regards. P.S.

[1] Writing:

1-1 Add list of used abbreviations and their explanations at then end right before Reference section.

Response: Added as suggested

1-2 Add Study outline in line 60 at the end of Introduction section.

Response: Current Oncology does not have any info regarding “Study outline” in their author guidelines and none of the recent articles have any such section (checked 5+ articles). In order to be able to make any changes, there is a need for further explanations regarding what the reviewer has requested. We would appreciate if the Editor could comment or advise on this matter.

1-3 Add Consort Diagram for Study Data Sample and different exclusion as each stage. [Example: https://trialsjournal.biomedcentral.com/articles/10.1186/1745-6215-12-253 ]

Response: We have re-written the study's exclusion criteria in more detail. In line with your suggestion, a Consort Diagram for Study Data Example and different exclusion stages were prepared as a Figure 1 and added to the study.

1-4 Break down Results section for better read: 3.1. Descriptive & Inferential Analysis 3.2. Survival Analysis

Response: We believe the reviewer meant “for easier comprehension”. Our correction is based on this. We have rearranged the Results section as suggested.

1-5 Where are your multivariate CPH results ? Where are your OS Multivariate CPH Table results ? These are the important ones ! Add them in subsection "3.Results"

Response: Multivariate CPH results by using forward conditional method were already given in the last paragraph of the “Results” section and in Table 5. Anyway, to avoid the apparent confusion experienced by the reviewer due to use of different terminology, the “multivariable cox regression” terms were changed to “multivariate cox proportional hazards model” and the “Exp(β)” terms were changed to “hazard ratio (HR)”, in line with the terminology preferred by the reviewer.

1-6 Break down Discussion into three subsections for easy read:

4.1. Summary and Contributions; 4.2. Strength and Limitations; 4.3 Future Work

Response: We believe the reviewer meant “for easier comprehension”. Our correction is based on this. We have rearranged the Discussion section as suggested. However, we must note that Current Oncology does not suggest any subtitles in the Discussion –other than “Conclusions”. We would like the Editor to advise on these changes, and determine whether they are necessary.

1-7 Add a paragraph for 4.3. Future Work. 

Response: We added a paragraph for 4.3. Future Work. Again, we must note that Current Oncology does not suggest any subtitles other than “Conclusions” in the Discussion section. We would like the Editor to advise on these changes, and determine whether they are necessary.

1-8 References: Make sure to make them in MDPI format. Example: Article years are in bold font.

Response: Done.

[2] Statistical:

2-1 Did you check proportionality assumption in the CPH survival model ? Explain it in the revision.

Response: Of course. Proportionality assumption was checked by using Schoenfeld residuals. Further information has been given in the “Statistical Analysis” section.

2-2 Report final MV CPH survival model in a table.

Response: The final multivariate cox proportional hazards model (forward conditional method) was given in Table 5.

2-3 Important:  Predicted Multivariate CPH survival curves for the groups with 95%CI band are missing. Please add them. Please Note that the current KM curves are categorized as descriptive analysis and are insufficient.

Response: These tables are descriptive by definition in all studies that have ever used them, and calling them “insufficient” is incorrect. Perhaps “incomplete” may be acceptable. Nonetheless, the predicted Multivariate CPH plot for SPM was added as Figure 3.

Reviewer 2 Report

The project examined potential associations of various patient characteristics on overall survival. The authors found an association between second primary malignancies and lower overall survival. The authors did not find an association between frailty and lower overall survival, in contrast to some previous reports.

Line 38, I would not say that side effects are limited, as the drugs can still confer some serious side effects.

Line 78, It seems that quite a few patients were excluded. Could you tell us how many patients were excluded. In the Discussion, please discuss how the exclusion of these patients may (or may not) have affected the lack of a detected association between frailty and overall survival.

Please disclose the median and range of dates when patients were diagnosed.

Please disclose the median time of SPM development from diagnosis.

Please specify in the text whether the study was retrospective or prospective observational.

The English is mostly fine, although there are a few minor errors.

Author Response

Reviewer 2

Comments and Suggestions for Authors

The project examined potential associations of various patient characteristics on overall survival. The authors found an association between second primary malignancies and lower overall survival. The authors did not find an association between frailty and lower overall survival, in contrast to some previous reports.

Line 38, I would not say that side effects are limited, as the drugs can still confer some serious side effects.

Response: Thank you for your review. We agree with your suggestion. In the Introduction section, we changed the word "limited" to "decreased" on line 38.

Line 78, It seems that quite a few patients were excluded. Could you tell us how many patients were excluded. In the Discussion, please discuss how the exclusion of these patients may (or may not) have affected the lack of a detected association between frailty and overall survival.

Response: We rewrote the study's exclusion criteria in more detail. A Consort Diagram for Study Data and different exclusion stages were prepared as a Figure 1 and added to the study. In the limitations part of the Discussion section, we discussed how exclusion of patients may or may not have influenced the absence of an identified association between frailty and overall survival.

Please disclose the median and range of dates when patients were diagnosed.

Response: Added to “Results” section.

Please disclose the median time of SPM development from diagnosis.

Response: Added to “Results” section.

Please specify in the text whether the study was retrospective or prospective observational.

Response: The study is in a retrospective design and we mentioned it in the Material and Methods section of the text.

Comments on the Quality of English Language

The English is mostly fine, although there are a few minor errors.

Response: We have re-checked the article with the support of a native English speaker and some corrections were made.

Reviewer 3 Report

This is a nice study with valid information. There are some grammatical errors that require correction.

Questions:

1.It is stated in the abstract that: Elderly patients with MM had a high prevalence 19 of SPM and frailty. SPM development was also found to negatively impact survival in MM; how- 20 ever, frailty was not found to be associated with survival.. Could the author clarify this sentence?

2. Are there any correlation between cytogenetic-molecular genetic aberrations and the development of SPM?

3. Why did the author choose VCD as induction therapy and exactly which patients receive consolidation therapy? 

4. What was the rationale for choosing type of consolidation therapy?

The paper needs minor language revision.

Author Response

Reviewer 3

Comments and Suggestions for Authors

This is a nice study with valid information. There are some grammatical errors that require correction.

Response: We sincerely thank the reviewer for their corrections and contributions. We have re-checked the article with support from a native English-speaking colleague and some corrections have been carried out.

Questions:

1. It is stated in the abstract that: Elderly patients with MM had a high prevalence of SPM and frailty. SPM development was also found to negatively impact survival in MM; however, frailty was not found to be associated with survival. Could the author clarify this sentence?

Response: Our study population consisted of elderly (>65 years) MM patients. To broadly re-phrase and explain the situation, we are providing a detailed account of these data: As we showed in the Results section, 73.6% of our patients had frailty and 9.7% had SPM. The phrase "in our study" was missing in the relevant sentence of the abstract section and we have now added it. In our study, we showed that the development of SPM negatively affects overall survival in an “independent” manner. The overall survival of patients who developed SPM was 35.29 (19.66 - 50.91) months, while the overall survival of patients without SPM was 51.05 (46.70 - 55.40) months (p=0.018). However, we observed that frailty did not affect the overall survival in an “independent” manner (in further analyses). The overall survival of patients with frailty was 48.49 (43.51 - 53.48) months, compared to 49.73 (40.92 - 58.53) months in patients without (p=0.908). The relevant sentence has been corrected and rewritten to include “independent” in both instances.

2. Are there any correlation between cytogenetic-molecular genetic aberrations and the development of SPM?

Response: Added to the “Results” section.

3. Why did the author choose VCD as induction therapy and exactly which patients receive consolidation therapy?

Response: Since in our country, only VCD is covered by the social security institution, this regimen was used as the standard induction regimen. Maintenance therapy was applied to all patients with at least partial response after autologous stem cell transplantation. We tried to choose the treatment regimen in which we could obtain the least side effects and the most efficacy according to the collective variables, not according to a single variable. For example, we examined whether the patient's age or physical condition is suitable for autologous transplantation. There are drugs that we do not specifically prefer for patients with certain clinical conditions. For example, we did not prefer a regimen with carfilzomib to patients with heart failure, or we did not administer bortezomib to patients with significant neuropathy. We preferred pomalidomide over lenalidomide in the patients with low renal function.

We also added this information into the manuscript.

4. What was the rationale for choosing type of consolidation therapy?

Response:

Choosing the type of consolidation therapy was based on the patient's eligibility for autologous stem cell transplantation, previous or current heart failure, ECOG performance score, age, physical condition, fragility, response level to previous medications, relapse status, comorbidities, presence of kidney failure or neuropathy, oral or IV treatment, and social support. We also added this data to the study.

Comments on the Quality of English Language

The paper needs minor language revision.

Response: As mentioned, this has been done. Thank you.

Round 2

Reviewer 1 Report

Dear Authors, most of my concerns were addressed satisfactorily. Regards.