Outcomes of Double-Hit and Single High-Risk Cytogenetic Newly Diagnosed Myeloma in Transplant-Eligible Patients

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This retrospective chart review is evaluating outcomes in patients with double hit versus single hit high risk multiple myeloma, defined as having the following cytogenetic abnormalities: deletion 17p, translocations t(4;14), t(14;16) and t(14;20, gain or amplification of chromosome 1q, and deletion of of chromosome 1p. The authors found similar PFS, OS and depth of response between both groups, which contradicts similar literature with double hit HRMM. 

Overall, the authors have published a high quality review, which was expertly written, with good statistical analysis. The nature of studying high risk myeloma means that the the sample size is fairly low over a 15 year period, which limits the amount of analyses that can be run on the data. That being said, they were able to analyze important outcomes in myeloma, namely PFS and OS with a long follow up period. 

Some critiques are the following:

1) The data seems to contradict the literature for high risk myeloma, even when accounting for contemporary treatments during similar time periods.  Similar studies have found that double hit genetics were associated with a significantly shortened progression-free survival and overall survival compared to patients with single hit disease (one example is Kaiser et al. Hemasphere. 2023). The authors also note the significant difference with FORTE data. As such, I think understanding the inductions utilized would be of great importance. How many patients received quadruplets versus triplets? Did utilization of Carfilzomib upfront affect outcomes? The same would be true of maintenance (single versus doublet). I understand sample size will be limited for this kind of analysis, but its not clear what is driving the better outcomes in this cohort.

2) Unfortunately, there is not a truly novel analysis in this paper. 

3) Was the population representative of the real world transplant eligible patient? The transplant eligible criteria was based on baseline data, which will inevitably will exclude patients with higher disease burden given the cytopenia/creatinine and transaminitis criteria. Patients who received tandem transplant were also excluded. Are patients with double risk, of del17p at these centers more likely to receive tandem? Could this be impacting the data?

4) Given the IMWG has changed the risk criteria in 2025, the newer criteria should be mentioned, as what was considered double hit previously is now changed. 

5) Would like to see baseline data on EMD. 

Author Response

RESPONSE TO REVIEWERS

We sincerely thank the reviewers for their thorough evaluation of our manuscript and for their constructive and insightful comments. We have carefully addressed each point and revised the manuscript accordingly. All changes have been incorporated into the revised manuscript and are highlighted with track changes. Below, we provide a detailed, point-by-point response.

 Reviewer 1

We thank the reviewer for the positive assessment of our work and for the thoughtful and constructive comments.

Comment 1

Reviewer comment:

The data seems to contradict the literature for high risk myeloma, even when accounting for contemporary treatments during similar time periods.  Similar studies have found that double hit genetics were associated with a significantly shortened progression-free survival and overall survival compared to patients with single hit disease (one example is Kaiser et al. Hemasphere. 2023). The authors also note the significant difference with FORTE data. As such, I think understanding the inductions utilized would be of great importance. How many patients received quadruplets versus triplets? Did utilization of Carfilzomib upfront affect outcomes? The same would be true of maintenance (single versus doublet). I understand sample size will be limited for this kind of analysis, but its not clear what is driving the better outcomes in this cohort.

Response:

We thank the reviewer for this important and insightful comment. We agree that prior studies, including Kaiser et al. Hemasphere 2023 and the FORTE trial, have demonstrated inferior progression-free survival (PFS) and overall survival (OS) in patients with double-hit high-risk multiple myeloma.

To address the reviewer’s request regarding treatment patterns, we have expanded the manuscript to include a detailed breakdown of induction regimens (Table 4). As shown, the majority of patients in our cohort received contemporary triplet-based induction therapy, most commonly bortezomib, lenalidomide, and dexamethasone (60% overall; 64% in the double-hit group), with additional use of cyclophosphamide, bortezomib, and dexamethasone and smaller proportions receiving carfilzomib-based regimens. A subset of patients also received quadruplet therapy with daratumumab-based combinations.

We acknowledge that prior studies also incorporated proteasome inhibitor (PI) and immunomodulatory drug (IMiD)-based regimens. However, important differences remain in treatment delivery and context. Our cohort reflects a contemporary real-world treatment paradigm characterized by broad and consistent use of triplet-based induction,more heterogenous population, routine incorporation of maintenance therapy, and access to multiple effective salvage therapies across the disease course. These factors, which are not uniformly captured or standardized in prior studies, may contribute to improved outcomes and attenuate the adverse prognostic impact of multiple high-risk cytogenetic abnormalities. Finally, In the FORTE trial, induction was based on carfilzomib-containing regimens, including carfilzomib, lenalidomide, and dexamethasone (KRd) or carfilzomib, cyclophosphamide, and dexamethasone (KCd), followed by transplant and consolidation.

In contrast, our cohort reflects real-world practice patterns, with predominant use of bortezomib-based triplet regimens and variable incorporation of carfilzomib-based therapy. Additionally, our study captures broader treatment exposure beyond induction, including routine use of maintenance therapy and access to multiple effective salvage therapies.

Given the retrospective design and sample size, we did not perform comparative subgroup analyses by specific induction regimens; however, the treatment distribution is now transparently presented to allow interpretation of outcomes within the context of contemporary therapeutic exposure. These additions have been incorporated into the Results (Table 4) and (Lines 276-290) and added in the discussion (Lines 436 – 439)

Comment 2

Reviewer comment:

Unfortunately, there is not a truly novel analysis in this paper.

Response:

We thank the reviewer for this comment. While prior studies have evaluated outcomes in high-risk and double-hit multiple myeloma, including real-world cohorts and transplant-based analyses, we believe our study provides novel insight through the specific combination of study design and population.

Several real-world studies, such as Panopoulou et al. 2023, have demonstrated inferior outcomes in patients with double-hit disease. Similarly, transplant-focused analyses have also reported worse survival in this population. However, these studies often include heterogeneous populations, are not restricted to transplant-eligible patients, or do not specifically evaluate intra–high-risk heterogeneity.

In contrast, our study focuses specifically on a contemporary, multicenter, real-world cohort of transplant-eligible patients undergoing upfront autologous stem cell transplantation and directly compares outcomes between single-hit and double-hit cytogenetic subgroups. This approach allows for a more clinically relevant assessment of risk stratification within a uniformly treated high-risk population.

We have clarified this in the original manuscript (lines 124-142). Also heterogeneity explained more in the beginning of the discussion (Lines: 410 – 415)

Comment 3

Reviewer comment:

Was the population representative of the real world transplant eligible patient? The transplant eligible criteria was based on baseline data, which will inevitably will exclude patients with higher disease burden given the cytopenia/creatinine and transaminitis criteria. Patients who received tandem transplant were also excluded. Are patients with double risk, of del17p at these centers more likely to receive tandem? Could this be impacting the data?

Response:

We thank the reviewer for this important and insightful comment. We agree that several factors related to patient selection and treatment strategy may influence the interpretation of our findings.

First, we acknowledge that restricting the cohort to transplant-eligible patients based on baseline organ function and clinical criteria may introduce selection bias, as patients with more advanced disease burden or significant comorbidities may be underrepresented. However, our study was intentionally designed to evaluate outcomes in a clinically relevant population of transplant-eligible patients undergoing upfront autologous stem cell transplantation in a real-world setting.

Second, we recognize that these eligibility criteria may preferentially select for patients with better performance status and organ function, which may influence overall outcomes compared with unselected populations.

Third, regarding tandem transplantation, this approach was not uniformly applied across participating centers and was therefore excluded to maintain cohort consistency. We agree that patients with higher-risk cytogenetic features, including del(17p) or double-hit disease, may be more likely to receive tandem transplantation in certain settings. As such, we cannot exclude the possibility that exclusion of tandem transplant recipients may have impacted the observed outcomes.

These considerations have now been explicitly addressed in the Limitations section of the revised manuscript (Lines 508–524).

Comment 4

Reviewer comment:

Given the IMWG has changed the risk criteria in 2025, the newer criteria should be mentioned, as what was considered double hit previously is now changed.

Response:

We thank the reviewer for this important suggestion. We acknowledge that risk stratification in multiple myeloma continues to evolve, including recent updates from the International Myeloma Working Group (IMWG).

In this study, cytogenetic risk definitions were based on established criteria in use during the study period and at the time of data collection (2009 – 2024) and was mentioned (lines 156 - 158). We have now clarified this in the Methods section (Lines 184–187) to reflect that more recent IMWG/IMS consensus recommendations have further refined the definition of high-risk disease, which may influence risk classification and interpretation of results.

Comment 5

Reviewer comment:

Would like to see baseline data on EMD.

Response:

We thank the reviewer for this important suggestion. We agree that extramedullary disease (EMD) is a clinically relevant feature in high-risk multiple myeloma.

Baseline EMD characteristics have now been included in the revised manuscript as a separate table (Table 2). A corresponding description has also been added to the Results section to summarize the distribution of EMD across the study population, and line (248-252)

Reviewer 2 Report

Comments and Suggestions for Authors

This retrospective multicenter study evaluated outcomes in transplant-eligible patients with high-risk multiple myeloma (HRMM) undergoing upfront autologous stem cell transplantation, comparing single-hit versus double-hit cytogenetic profiles. The authors report that while post-transplant overall response rates were higher in the single-hit group, no significant differences in progression-free survival or overall survival were observed between the two groups, suggesting that the number of high-risk cytogenetic abnormalities alone may not fully determine post-transplant prognosis in the contemporary treatment era.

The manuscript is well-structured, with a clear presentation of background, methods, and results. The study addresses a clinically relevant question regarding risk stratification in HRMM. The methods are described in sufficient detail, including cytogenetic definitions, treatment exposures, and statistical approaches. The use of restricted mean survival time analyses alongside conventional Kaplan-Meier estimates is appropriate given the follow-up duration. Figures are clear and effectively illustrate the survival comparisons. The discussion is balanced and correctly interprets the findings, acknowledging heterogeneity within double-hit disease and the potential impact of modern induction, maintenance, and salvage therapies.

Several limitations warrant consideration. First, the study population is heterogeneous with respect to induction regimens, maintenance strategies, and treatment eras spanning 2009–2024, which may introduce variability in outcomes not captured by cytogenetic subgrouping alone. Second, the lack of measurable residual disease data limits assessment of depth of response, which is increasingly recognized as a critical prognostic factor independent of cytogenetic risk. Third, although the authors appropriately report no significant differences in PFS or OS between single- and double-hit groups, the absence of a standard-risk comparator group substantially limits interpretability. Without inclusion of patients with standard-risk cytogenetics from the same centers, it remains unclear whether the comparable outcomes reflect a genuinely improved prognosis for double-hit patients or simply indicate that both high-risk subgroups fared similarly but still worse than standard-risk patients. This omission weakens the ability to contextualize the findings relative to established benchmarks. To strengthen the manuscript, I recommend adding a comparison of PFS and OS outcomes between the single-hit, double-hit, and a standard-risk cytogenetics cohort treated during the same period at the participating centers. Even a descriptive comparison would enhance the clinical relevance of the findings. Additionally, acknowledging the lack of such a comparator more explicitly in the limitations section would improve transparency. 

Author Response

Reviewer 2

We sincerely thank the reviewer for the thorough and insightful evaluation of our manuscript and for recognizing the strengths of the study.

Comment 1

Reviewer comment:

First, the study population is heterogeneous with respect to induction regimens, maintenance strategies, and treatment eras spanning 2009–2024, which may introduce variability in outcomes not captured by cytogenetic subgrouping alone.

Response:

We thank the reviewer for this important observation. We agree that heterogeneity in treatment exposure represents an inherent limitation of retrospective real-world studies.

To address this, we have expanded the reporting of treatment characteristics, including induction regimens and maintenance strategies, and have added a statement in the Limitations section acknowledging the potential impact of treatment heterogeneity across the study period (2009–2024) (Lines 508–524) and (Lines 410 – 415).

Comment 2

Reviewer comment:

Second, the lack of measurable residual disease data limits assessment of depth of response, which is increasingly recognized as a critical prognostic factor independent of cytogenetic risk.

Response:

We agree that measurable residual disease (MRD) is an important prognostic factor in multiple myeloma. However, MRD data were not uniformly available across participating centers and throughout the study period.

We have now explicitly acknowledged this limitation in the Discussion and highlighted the need for future studies incorporating standardized MRD assessment (Lines 508–524).

Comment 3

Reviewer comment:

Third, although the authors appropriately report no significant differences in PFS or OS between single- and double-hit groups, the absence of a standard-risk comparator group substantially limits interpretability. Without inclusion of patients with standard-risk cytogenetics from the same centers, it remains unclear whether the comparable outcomes reflect a genuinely improved prognosis for double-hit patients or simply indicate that both high-risk subgroups fared similarly but still worse than standard-risk patients. This omission weakens the ability to contextualize the findings relative to established benchmarks. To strengthen the manuscript, I recommend adding a comparison of PFS and OS outcomes between the single-hit, double-hit, and a standard-risk cytogenetics cohort treated during the same period at the participating centers. Even a descriptive comparison would enhance the clinical relevance of the findings. Additionally, acknowledging the lack of such a comparator more explicitly in the limitations section would improve transparency.

Response:

We thank the reviewer for this important and thoughtful comment. We agree that inclusion of a standard-risk comparator cohort would provide additional context for interpreting outcomes.

However, the primary objective of this study was to evaluate heterogeneity within a high-risk population. Accordingly, the study was intentionally designed to focus on comparisons between single-hit and double-hit cytogenetic subgroups within a uniformly high-risk, transplant-eligible cohort. As such, inclusion of a standard-risk group was intentionally outside the predefined scope of the study.

We acknowledge that the absence of a standard-risk comparator limits broader contextual interpretation. To address this, we have revised the Discussion to (1) clarify the study design and its focus on intra–high-risk risk stratification, (2) contextualize our findings relative to outcomes reported in standard-risk populations in prior studies, and (3) explicitly acknowledge the lack of a standard-risk comparator as a study limitation.

These revisions have been incorporated into the Discussion and Limitations sections of the revised manuscript (Lines 508–524). Furthermore, the aim of the study was clearly stated that this study is a comparison between between patients with single-hit and double-hit high-risk cytogenetics (Lines 124 – 142)