Characteristics of 15 Subjects Affected by IgD Multiple Myeloma and the Key Role of the Laboratory in Diagnosis: A Retrospective Study Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting paper looking at the incidence of IgD MM. Overall this is of some interest.

There are two main areas that could be improved. First the description of patient treatments, genetics abnormalities and outcomes could be shown in one table. Second the nomenclature of chemo treated vs transplant is not standard and confusing. better to use transplant vs non transplant. I am note sure why the 2 recent pateints were excluded from the analysis as this should not impact median OS or PFS given short follow up

Finally the Discussion could be tightened up and shortened and focus on 1. its a rare diagnosis so may be missed leading to late presentations/ poor outcomes. 2 whats the impact or modern induction and transplant to negate the impact of poor risk genetic lesions i.e. in the PI era del 13 is no longer poor risk, but bi-allelic del 17p/ p53 abnormalities are increasingly important.

I like the conclusion, if you don't test for it you can't diagnose it

Comments on the Quality of English Language

The English is a bit clumsy in places and careful editing would improve this.

Author Response

Response to reviewers

Dear Editor,

Thank you for having considered our manuscript. We also thank the reviewers for their constructive comments to our work.

We have modified our text according to all the received suggestions. Please find attached to this letter a point-by-point Response to Reviewers.

We hope that this improved version is now suitable for publication in International Journal of Translational Medicine.

Sincerely yours,

Jari Intra

 

Referee: 1

Comments to the Author

This is an interesting paper looking at the incidence of IgD MM. Overall this is of some interest.

There are two main areas that could be improved.

First the description of patient treatments, genetics abnormalities and outcomes could be shown in one table. We agree and Table 2 was changed and improved.

Second the nomenclature of chemo treated vs transplant is not standard and confusing. better to use transplant vs non transplant. We agree and the text was changed.

I am note sure why the 2 recent pateints were excluded from the analysis as this should not impact median OS or PFS given short follow up. The two subjects here mentioned were not inserted in the analysis, since they have been diagnosed as affected by IgD multiple myeloma within the last six months but no treatments have been administered. Therefore, only baseline characteristics were available.

Finally the Discussion could be tightened up and shortened and focus on 1. its a rare diagnosis so may be missed leading to late presentations/ poor outcomes. 2 whats the impact or modern induction and transplant to negate the impact of poor risk genetic lesions i.e. in the PI era del 13 is no longer poor risk, but bi-allelic del 17p/ p53 abnormalities are increasingly important. We agree and the text was changed: “Reviewing the literature, different works analyzed these possible relationships in IgD MM patients. Wang and coauthors described that 1q21 amplification is associated with poor prognosis, while Chen and coauthors reported that deletion of 13q, amplification of 1q21 or translocation t(11;14) had no relationship with prognosis [2,3]. Recently, Liu and coworkers observed that the presence of 13q deletion, 1q21 amplification, and translocation t(11;14) were significantly different between IgD and non-IgD patients, particularly t(11;14) was detected more frequently in IgD patients, although it is not considered a high risk cytogenetic alteration in myeloma and therefore not related to a poor prognosis [6]. Moreover, Corre and coauthors clearly showed the extremely poor outcome of patients displaying the deletion of 17p (17p13(p53)), confirming its value as a prognostic indicator for poor outcome [13]. In fact, our three patients presenting the “double hit” 17p (17p13(p53)) died within two years after the diagnosis of multiple myeloma. The molecular mechanisms in IgD myeloma remains unclear yet, further research is need.

I like the conclusion, if you don't test for it you can't diagnose it. Thank you for your consideration.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

IgD multiple myeloma is rarely observed, therefore analyzing these patients is of potential interest. The authors studied 15 patients with IgD MM retrospectively. The patient number is quite low, and several statements of the manuscript are not precise. Therefore, it is difficult for the reader to go through this paper.

-          The patient number is too low to draw valuable conclusions or make statistical relevant comparisons.

-          Has the project been approved by ethics committee?

-          There are much larger and newer analysis on IgD myeloma which are not mentioned by the authors such as the work by Yan et al (Front Oncol, 2022) encompassing 85 patients with IgD MM

-          What is the meaning of higher frequencies of serum LDH? (abstract)

-          In the M&M section the authors write that `one group received conventional chemotherapy treatments (CHT), and the other group was treated with high dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT)´. Conversely, in the abstract `Patients treated with new drugs and autologous stem cell transplantation presented a higher median survival compared to those that received conventional chemotherapy regimens´. This discrepancy is unclear.

-          Details are missing. How was IgD MM defined? Detection of IgD by IFE? Or by staining of tissue biopsy? How many patients underwent whole body CT and how many only X ray?

-          Around 60% of patients had bone lesions. Therefore, it is unlikely that only stages I and II were observed and no patient had S&D stage III.

-          Serum monoclonal protein should be reported in  g/L and not only in %

-          Did the authors analyze OS? This sentence led to assume that it was analyzed: ´Considering the group of cases which received treatments with new drugs followed by ASCT, the median OS was 48 months…´. However, these data are not shown in the result section nor is OS estimation described in the M&M section.

Comments on the Quality of English Language

IgD multiple myeloma is rarely observed, therefore analyzing these patients is of potential interest. The authors studied 15 patients with IgD MM retrospectively. The patient number is quite low, and several statements of the manuscript are not precise. Therefore, it is difficult for the reader to go through this paper.

-          The patient number is too low to draw valuable conclusions or make statistical relevant comparisons.

-          Has the project been approved by ethics committee?

-          There are much larger and newer analysis on IgD myeloma which are not mentioned by the authors such as the work by Yan et al (Front Oncol, 2022) encompassing 85 patients with IgD MM

-          What is the meaning of higher frequencies of serum LDH? (abstract)

-          In the M&M section the authors write that `one group received conventional chemotherapy treatments (CHT), and the other group was treated with high dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT)´. Conversely, in the abstract `Patients treated with new drugs and autologous stem cell transplantation presented a higher median survival compared to those that received conventional chemotherapy regimens´. This discrepancy is unclear.

-          Details are missing. How was IgD MM defined? Detection of IgD by IFE? Or by staining of tissue biopsy? How many patients underwent whole body CT and how many only X ray?

-          Around 60% of patients had bone lesions. Therefore, it is unlikely that only stages I and II were observed and no patient had S&D stage III.

-          Serum monoclonal protein should be reported in  g/L and not only in %

-          Did the authors analyze OS? This sentence led to assume that it was analyzed: ´Considering the group of cases which received treatments with new drugs followed by ASCT, the median OS was 48 months…´. However, these data are not shown in the result section nor is OS estimation described in the M&M section.

Author Response

Response to reviewers

Dear Editor,

Thank you for having considered our manuscript. We also thank the reviewers for their constructive comments to our work.

We have modified our text according to all the received suggestions. Please find attached to this letter a point-by-point Response to Reviewers.

We hope that this improved version is now suitable for publication in International Journal of Translational Medicine.

Sincerely yours,

Jari Intra

 

Referee: 2

Comments to the Author

IgD multiple myeloma is rarely observed, therefore analyzing these patients is of potential interest. The authors studied 15 patients with IgD MM retrospectively. The patient number is quite low, and several statements of the manuscript are not precise. Therefore, it is difficult for the reader to go through this paper.

1. The patient number is too low to draw valuable conclusions or make statistical relevant comparisons. We agree, and in the text we wrote: “In the group of non-transplant subjects (n = 8) the median OS was 18 months (12-144), while in the group of transplant subjects (n = 5) the median OS was 48 months (36-120), and, although the low number of cases available, the difference in OS between the two groups was significant (p = 0.004). Evaluating the treatment responses, among deceased subjects, a PR or SD were achieved, while the transplant subjects obtained a VGPR or CR (Table 2). We investigated whether the detected chromosomal aberrations had an impact on OS and treatment response, but we did not observe any differences between the two groups. A regression model to determine prognostic factors was not performed, due to the low number of cases.”

“Our study presents some limitations that should be considered. The work was retro-spective and performed in a single-center, and the small sample size, missing data, and heterogeneous treatments limited the statistical analysis. A larger number of individuals is needed in order to improve the knowledge of this rare subtype of myeloma and the ac-curacy of our results.”

2. Has the project been approved by ethics committee? “Informed Consent Statement: The local ethics committee did not require informed consent because all subjects' data were retrospective and de-identified.”
3. There are much larger and newer analysis on IgD myeloma which are not mentioned by the authors such as the work by Yan et al (Front Oncol, 2022) encompassing 85 patients with IgD MM. We agree and the reference was added.
4. What is the meaning of higher frequencies of serum LDH? (abstract) We agree and the text was changed: “The median age was 69 years, and higher frequencies of bone lesions, renal impairments, Bence-Jones proteinuria, and increased serum LDH were observed.”
5. In the M&M section the authors write that `one group received conventional chemotherapy treatments (CHT), and the other group was treated with high dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT)´. Conversely, in the abstract `Patients treated with new drugs and autologous stem cell transplantation presented a higher median survival compared to those that received conventional chemotherapy regimens´. This discrepancy is unclear. We agree and the text was changed: “Patients treated with new chemotherapeutic drugs and autologous stem cell transplantation presented a higher median survival compared to those that only received chemotherapy regimens.”

In M&M section we wrote: “For the analysis of therapy responses and OS, the patients were divided into two groups: one group received chemotherapy treatments (named non-transplant group), and the oth-er group was treated with new chemotherapeutic drugs followed by autologous stem cell transplantation (ASCT) (named transplant group).”

6. Details are missing. How was IgD MM defined? Detection of IgD by IFE? Or by staining of tissue biopsy? How many patients underwent whole body CT and how many only X ray?

Following IMWG guidelines it can be possible to diagnose a subject as affected by MM. Therefore, each subject was evaluated after laboratory data (CRAB), immunofixation (detection of IgD) and clinical findings (bone lesions, presence of plasma cells), and after that a patient was diagnosed as affected by IgD MM.

In M&M section we wrote: “A retrospective analysis of 15 patients admitted to the San Gerardo Hospital, Monza, Italy, from 2008 to 2022, who were diagnosed affected by IgD MM using the International Myeloma Working Group (IMWG) diagnostic criteria, was performed [9].”

We agree and the text was changed: “Fifteen patients diagnosed by clinical findings (bone marrow biopsy, X-ray and computed tomography), serum immunofixation and laboratory data to be affected by IgD multiple myeloma, which accounts for about 1 % of all cases of MM detected in our hospital, were retrospectively enrolled in this study.”

7. Around 60% of patients had bone lesions. Therefore, it is unlikely that only stages I and II were observed and no patient had S&D stage III. We agree and the text was corrected: “Collectively, two patients were classified as Stage II, while the others seven as Stage III.”
8. Serum monoclonal protein should be reported in g/L and not only in % We agree and the table 1 was edited.
9. Did the authors analyze OS? This sentence led to assume that it was analyzed: ´Considering the group of cases which received treatments with new drugs followed by ASCT, the median OS was 48 months…´. However, these data are not shown in the result section nor is OS estimation described in the M&M section. In M&M section we wrote: “Overall survival (OS) was calculated starting from the date of the first treatment to the date of death or the date the patient was known to be alive. For the analysis of therapy responses and OS, the patients were divided into two groups: one group received chemo-therapy treatments (named non-transplant group), and the other group was treated with new chemotherapeutic drugs followed by autologous stem cell transplantation (ASCT) (named transplant group).”

We agree and the text was changed: “Eleven of 15 patients died (73.3 %), and, taking into consideration that two cases were identified in the last year and currently they are alive, therefore not included in data analysis, the overall median (Interquartile range, IQR) OS was 24 months (12-144). Due to the low number of cases, we did not perform the Kaplan-Meier method to determine the survival difference between the two groups, but we analyzed the median OS values ob-ained. In the group of non-transplant subjects (n = 8) the median OS was 18 months (12-144), while in the group of transplant subjects (n = 5) the median OS was 48 months (36-120), and, although the low number of cases available, the difference in OS between the two groups was significant (p = 0.004). Evaluating the treatment responses, among deceased subjects, a PR or SD were achieved, while the others obtained a VGPR or CR (Table 2).”

 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Data presentation and analysis for rare subgroup of MM patients is very significant, and the authors have attempted to provide such an analysis. 

However, the numbers are too small, and to make the data presentation meaningful, they have to be presented and compared to non-IgD myeloma patients. I would, therefore, recommend re-designing the manuscript to present and compare data (responses, OS, PFS, time to next treatment line, etc.) between IgD and non-IgD myeloma patients. 

Significant English language reviewing is required. 

Comments on the Quality of English Language

Data presentation and analysis for rare subgroup of MM patients is very significant, and the authors have attempted to provide such an analysis. 

However, the numbers are too small, and to make the data presentation meaningful, they have to be presented and compared to non-IgD myeloma patients. I would, therefore, recommend re-designing the manuscript to present and compare data (responses, OS, PFS, time to next treatment line, etc.) between IgD and non-IgD myeloma patients. 

Significant English language reviewing is required. 

Author Response

Response to reviewers

Dear Editor,

Thank you for having considered our manuscript. We also thank the reviewers for their constructive comments to our work.

We have modified our text according to all the received suggestions. Please find attached to this letter a point-by-point Response to Reviewers.

We hope that this improved version is now suitable for publication in International Journal of Translational Medicine.

Sincerely yours,

Jari Intra

 

Referee: 3

Comment to the Author

 

Data presentation and analysis for rare subgroup of MM patients is very significant, and the authors have attempted to provide such an analysis.

However, the numbers are too small, and to make the data presentation meaningful, they have to be presented and compared to non-IgD myeloma patients. I would, therefore, recommend re-designing the manuscript to present and compare data (responses, OS, PFS, time to next treatment line, etc.) between IgD and non-IgD myeloma patients. We agree that the comparison between IgD and non-IgD myeloma patients might be interesting and useful, but the number of our cases is too low to obtain accurate and statistically significant results. Different studies reported the analysis of data of subjects suffering from IgD MM, without the comparison between IgD and non-IgD myeloma. On the other hand, other authors reported the differences between IgD and non-IgD myeloma, showing the different characteristics and poorer outcomes in IgD MM cases.

IgD MM is a rare MM subtype, and, as our perspective future work, increasing the number of cases will allow us to obtain more data and to compare IgD and non-IgD myeloma results.

Significant English language reviewing is required. We agree and the text was changed and corrected.

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

My only comment is that in tabel 2 outcomes, numbers of pateints with each response should be added

Author Response

Response to reviewers

Dear Editor,

Thank you for having considered our manuscript. We also thank the reviewers for their constructive comments to our work.

We have modified our text according to all the received suggestions. Please find attached to this letter a point-by-point Response to Reviewers.

We hope that this further improved version is now suitable for publication in International Journal of Translational Medicine.

Sincerely yours,

Jari Intra

 

Referee: 1

Comments to the Author

 

My only comment is that in table 2 outcomes, numbers of patients with each response should be added. We agree and Table 2 was changed and improved.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

from my point of view the patient number is too low to make significant conclusions. Patient allocation and definition of group is still not clear for me. In the revised version the authors now write: "...one group received chemotherapy treatments (named non-transplant group), and the other group was treated with new chemotherapeutic drugs followed by autologous stem cell transplantation (ASCT) (named transplant group). This intention is not clear. Was the intention to compare ASCT vs. non-ASCT? or novel agents vs. other?

Comments on the Quality of English Language

minor issues

Author Response

Response to reviewers

Dear Editor,

Thank you for having considered our manuscript. We also thank the reviewers for their constructive comments to our work.

We have modified our text according to all the received suggestions. Please find attached to this letter a point-by-point Response to Reviewers.

We hope that this improved version is now suitable for publication in International Journal of Translational Medicine.

Sincerely yours,

Jari Intra

 

Referee: 2

Comments to the Author

 

From my point of view the patient number is too low to make significant conclusions. We agree and we know that the number of patients is low, but we think that more data are available about IgD MM more precise might be the treatment and more improved patient’s outcome. In the text we wrote in the previous revision: “Our study presents some limitations that should be considered. The work was retrospective and performed in a single-center, and the small sample size, missing data, and heterogeneous treatments limited the statistical analysis. A larger number of individuals is needed in order to improve the knowledge of this rare subtype of myeloma and the ac-curacy of our results.”

 

Patient allocation and definition of group is still not clear for me. In the revised version the authors now write: "...one group received chemotherapy treatments (named non-transplant group), and the other group was treated with new chemotherapeutic drugs followed by autologous stem cell transplantation (ASCT) (named transplant group). This intention is not clear. Was the intention to compare ASCT vs. non-ASCT? or novel agents vs. other? Our intention is to report the differences between patients who were treated with chemotherapy regimens versus subjects who were treated with new drugs and by ASCT. Using transplant versus non-transplant is useful to underline that one of the two group received the autologous stem cell transplantation after drug treatments.

We edited the text:

In M&M section: “The population study was divided into two groups: one group received chemotherapy treatments (named non-transplant group), and the other group was treated with chemo-therapeutic drugs followed by autologous stem cell transplantation (ASCT) (named trans-plant group). For the analysis of the association between the type of treatment and OS, the population study was divided into three groups: the first group received conventional chemotherapy treatment, the second group was treated with new chemotherapeutic drugs, and third group included subjects who received chemotherapeutic drugs followed by ASCT.”

In result section: “Eleven of 15 patients died (73.3 %), and, taking into consideration that 11 cases pre-sented severe pathologies at the moment of diagnosis of IgD MM and that two cases were identified in the last year and currently they are alive, therefore not included in data anal-ysis of OS, the overall median (Interquartile range, IQR) OS was 24 months (12-144). Due to the low number of cases, we did not perform the Kaplan-Meier method to determine the survival differences between the transplant and non-transplant groups, but we analyzed the median OS values obtained. In the group of non-transplant subjects (n = 8) the median OS was 18 months (12-144), while in the group of transplant subjects (n = 5) the median OS was 48 months (36-120), and, although the low number of cases available, the differ-ence in OS between the two groups was significant (p = 0.004). Evaluating the treatment responses, using also deceased subjects, a PR or SD were achieved in non-transplant group, while in the transplant group the patients obtained a VGPR or CR (Table 2). More-over, considering the type of treatment, we observed an increased median OS from 12 months in the subject treated with conventional chemotherapy, to 30 months (12-84) in patients treated with new drugs, to 48 months (36-120) in individuals treated with chemotherapeutic drugs followed by ASCT (p < 0.05). Finally, we investigated whether the detected chromosomal aberrations had an impact on OS and treatment response, but we did not observe any statistically significant differences (p > 0.05).”

In discussion section: “However, considering the patients treated with new chemotherapeutic drugs and those who received chemotherapy drugs followed by ASCT, the median OS increased to 48 months, a result that is double compared to our overall average and more in agreement with the literature data [7,8,19,20]. However, the matter remains open to debate, and fur-ther research is needed to unravel biological mechanisms that link treatments to survival.”

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

please see my comments before

Comments on the Quality of English Language

please see above and my comments before

Author Response

Please see the attachment.

Author Response File: Author Response.docx