sBCMA Plasma Level Dynamics and Anti-BCMA CAR-T-Cell Treatment in Relapsed Multiple Myeloma

Round 1

Reviewer 1 Report

The authors of this manuscript present case studies of the first five Swiss patients receiving the CAR-T cell product Ide-cel for treatment of advanced multiple myeloma with largely good responses and manageable side effect profiles. Moreover, they investigate ddPCR-based quantification of CAR-T cells and ELISA-based soluble BCMA levels in the peripheral blood as potential predictive biomarkers for therapy monitoring. Although quantification of soluble target antigen as well as CAR T cells is not outstanding new and has been already investigated in myeloma and lymphoma (doi: 10.1111/j.1365-2141.2012.09241.x, doi: 10.3324/haematol.2016.150896, doi: 10.1200/JCO.2018.36.15/suppl.e24313, doi: 10.1016/j.omtm.2021.10.009), predictive and surrogate biomarkers have not yet been established in multiple myeloma and are needed for this novel treatment approach. In fact, sBCMA and presence of BCMA CAR-T cells seem to partially correlate with outcome in this small cohort. Thus, this work may support the selection of these biomarker candidates to be further validated in the context of BCMA-directed CAR-T-cell therapy.

Methodically, the manuscript still can be improved. First, primer sequences should be published, accordingly. Moreover, controls used for ddPCR and ELISA should be described and shown in the Figures.

Moreover, Figure 1C is unclear in its visualization (missing axis labelling). The two parameters compared in their dynamics in Figure 1C (CART copies/ng gDNA and sBCMA in ng/ml) might be easier to distinguish when depicting them on two differently labelled axes within the graph. The figure legend of Figure 2 may be erroneously (“which bind Table 13”).

Especially the course of the deceased patient C-91 is highly interesting for further improvement of CAR-T cell therapy and for understanding dynamics in non-responders. If tumor material from the time before CAR-T cell administration is still available, further investigation of BCMA-levels on the MM cells would be of great interest to better understand differences between responders and non-responders. Moreover, additional information about potential differences of the CAR T cell products (transduction rates or other qualitative differences) of the five different patients may further provide interesting information to select sBCMA and quantification of CAR T cells as novel biomarker candidates to be further validated in future.

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

I read with interest the study entitled “sBCMA plasma level dynamics and anti-BCMA treatment in 2 relapsed Multiple Myeloma”. In this study, the authors are reporting the results of anti-BCMA CAR-T therapy in 5 patients with relapsed/refractory myeloma. It appears that the authors have tried to highlight the potential of soluble BCMA (sBCMA) as a potential tool for monitoring response to anti-BCMA CAR-T cell therapy. Given the scarcity of such trials, the reported results are valuable and may be interesting to the readers; however, there are major concerns that leave me uneasy deciding on the suitability of the manuscript:

• Given that the potential value of sBCMA as a tool for response monitoring has been previously shown, what would be the novelty of the current work compared to previous studies? For instance, in reference number 9, the authors have clearly stated similar results with even larger number of patients (12 patients).
• Considering the major aim of the study, which is the evaluation of sBCMA as a response monitoring marker, the number of the patients is too limited and is not adequate to draw powerful conclusions regarding the biomarker value of sBCMA.
• It is not clear whether the major aim of the manuscript is to evaluate sBCMA as a response monitoring tool or as an early predictor of response (as has been stated in the first line of the Methods section). Neither the patient number nor the study methodology support any of these aims.
• Even with the limited number of patients, which largely limits our ability to evaluate the biomarker value of sBCMA, there are a few inconsistencies that need to be addressed. For instance, although complete remission has been reported in 4 out of 5 studied patients, it is not clear how the authors justify the subsequent rise in sBCMA levels after initial decline in 3 out of 5 patients, while those patients were still in complete remission?
• It will be also helpful to provide more details on the timepoint(s) at which patient response has been evaluated and reported. Furthermore, the authors should provide details of the criteria used for response determination.
• Considering that 2 out of 5 patients including the patient without clinical response (C-91) had higher baseline sBCMA, compared to others, the authors need to discuss if and how this could affect the therapeutic efficacy. This is missing and needs to be discussed more in the discussion section.
• The discussion is too short and needs to be largely improved addressing the points mentioned above.
• The sections on the importance of TACI and g-secretase (including Figure 2) seem to be unnecessary and not in line with the aims of the study.
• The authors need to provide more details including the primer sequences used for their ddPCR.

Several minor points:

1. The language of the manuscript needs to be edited by a native speaker.
2. There are numerous abbreviation errors such as the use of abbreviations before their first mention in extended form, which need to be carefully corrected. Just an example to mention:

The use of “flow techniques” instead of “flow cytometry techniques” in the abstract.

3. The axis labels in figure 1 (C) are missing and need to be added.

 

 

 

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

All aspects sufficiently answered.

Author Response

We thank the reviewer for evaluating the revised manuscript.

Reviewer 2 Report

Although some of the points have been addressed, the methodology and small number of samples is still a major limitation of this work. 

Furthermore:

1- The language still has flaws and needs to be polished. 

2- The discussion is still superficial and needs to be extended.   

 

Author Response

Reviewer 2, Round 2

 

Comments and Suggestions for Authors

Although some of the points have been addressed, the methodology and small number of samples is still a major limitation of this work. 

Response: We agree with the reviewer that larger number of samples are required to derive definitive conclusions on the suitability of sBCMA levels as response monitoring tool and/or predictor of response. We have stated this explicitly in the discussion section.

Furthermore:

1- The language still has flaws and needs to be polished. 

2- The discussion is still superficial and needs to be extended. 

Response: In the 3 days granted for the second revision we focused on improving the structure and depth of the discussion. The text has been edited by a native English speaker.

Author Response File: Author Response.pdf