Anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety
, Sikander Ailawadhi 1, Taimur Sher 1, Vivek Roy 1, Andre Fernandez 1 and Ricardo D. Parrondo 1,2,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors reported two cases of the first successful use of anti-BCMA CAR-T therapy on patients with AL amyloidosis and concurrent relapsed/refractory Multiple Myeloma. This is important to the field and the presentation of results is adequate, so I would recommend accepting the manuscript with minor changes.
1. In the introduction, please include the rationale/explanation for the successful use of anti-BCMA CAR-T therapy on AL amyloidosis patients, how the safety and toxicity concerns are addressed in the current study. (e.g., patient selection, supportive treatment for CRS)
2. Are these two cases the only AL amyloidosis patients that received the anti-BCMA CAR-T treatment or there are other cases?
3. Please proofread for minor typos.
Comments on the Quality of English LanguageAdequate but has some typos.
Author Response
Reviewer #1
The authors reported two cases of the first successful use of anti-BCMA CAR-T therapy on patients with AL amyloidosis and concurrent relapsed/refractory Multiple Myeloma. This is important to the field and the presentation of results is adequate, so I would recommend accepting the manuscript with minor changes.
- In the introduction, please include the rationale/explanation for the successful use of anti-BCMA CAR-T therapy on AL amyloidosis patients, how the safety and toxicity concerns are addressed in the current study. (e.g., patient selection, supportive treatment for CRS)
Response to reviewer: Thank you for your comment. We have added rationale/explanation for the successful use of anti-BCMA CAR-T on AL amyloidosis patients in the introduction as follows.
Page 2, Line 58: “Medical optimization of organ function as well as CRS prophylaxis may mitigate CAR-T toxicity and may possibly make CAR-T cell therapy a safe therapeutic strategy for patients with AL amyloidosis. Herein we describe the outcomes of two patients with primary systemic AL amyloidosis with coexistent multiple myeloma who had medical optimization of cardiac and renal function, received corticosteroid CRS prophylaxis and subsequently underwent anti-BCMA CAR-T cell therapy with manageable toxicity and achievement of a minimal residual disease (MRD) negative state.”
- Are these two cases the only AL amyloidosis patients that received the anti-BCMA CAR-T treatment or there are other cases?
Response to reviewer: Thank you for your comment. These are the only two cases at our institution. There is one other published case of CAR-T used for AL amyloidosis and it is cited in reference 12 as well as a recent clinical trial report presented at the International Myeloma Society 2023 Meeting regarding use of the novel, academic anti-BCMA CAR T NXC-201 in 9 patients with relapsed/refractory AL amyloidosis (reference 17).
- Please proofread for minor typos.
Response to reviewer: Thank you for your comment. We have looked through the manuscript and corrected all minor typos.
Reviewer 2 Report
Comments and Suggestions for AuthorsDas, S., et al. reported two cases of AL amyloidosis associated with relapsed/refractory multiple myeloma. These patients were treated with anti-BCMA CAR-T cell therapy either ide-cel or cilta-cel as salvage therapy. Although these patients had heart and renal failure, CRS could be prevented by premedication with DEX in case 1 and controlled with tocilizumab in case 2. Based on these observations, the authors concluded that anti-BCMA CAR-T cell therapy might be a safe and effective therapeutic strategy in patients with AL amyloidosis associated with multiple myeloma. However, there are several concerns regarding the paper that the authors need to clarify.
1. Since Dara-VCD is established as standard of care for AL amyloidosis, it should be mentioned in the Introduction and in the Discussion including evaluation of the present cases.
2. The description of response as multiple myeloma was not consistent (MRD negative or VGPR in case 1) and should be described according to the IMWG criteria. Any new lesions would be considered progressive disease in case 2.
3. It is recommended to describe hematologic and organ response such as cardiac and renal response of AL amyloidosis at longer time points according to the criteria (Palladini G, et al.).
4. Additional discussion should be given to the appropriateness of CAR-T cell therapy in patients with organ damage, for example, with reference to eligibility for autologous stem cell transplantation.
Author Response
Reviewer #2
Das, S., et al. reported two cases of AL amyloidosis associated with relapsed/refractory multiple myeloma. These patients were treated with anti-BCMA CAR-T cell therapy either ide-cel or cilta-cel as salvage therapy. Although these patients had heart and renal failure, CRS could be prevented by premedication with DEX in case 1 and controlled with tocilizumab in case 2. Based on these observations, the authors concluded that anti-BCMA CAR-T cell therapy might be a safe and effective therapeutic strategy in patients with AL amyloidosis associated with multiple myeloma. However, there are several concerns regarding the paper that the authors need to clarify.
- Since Dara-VCD is established as standard of care for AL amyloidosis, it should be mentioned in the Introduction and in the Discussion including evaluation of the present cases.
Response to reviewer: Thank you for your comment. We have added a discussion about Dara-VCD in the introduction of the article (Page 1, Line 40).
- The description of response as multiple myeloma was not consistent (MRD negative or VGPR in case 1) and should be described according to the IMWG criteria. Any new lesions would be considered progressive disease in case 2.
Response to reviewer: Thank you for your comment. We have corrected the responses for Case 1 and Case 2 based on the IMWG 2016 criteria in the manuscript as well as in Table 2. Case 1 is VGPR. Case 2 is disease progression based on development of new lytic bone disease. Case 2 ultimately achieved stringent complete response, as the FDG avid lytic bone disease resolved on subsequent PET-CT scan. We have added this information to the article. Nonetheless, both patients did achieve MRD negativity to 10-5 in the bone marrow on day +30.
- It is recommended to describe hematologic and organ response such as cardiac and renal response of AL amyloidosis at longer time points according to the criteria (Palladini G, et al.).
Response to reviewer: We have added responses for the patients in the manuscript. For case 1, the patient achieved stable renal disease and a cardiac response as evidenced by a >30% decrease in NT-ProBNP (from 8831 pg/mL to 3167 pg/mL) at 9 months post-CAR-T based on validated organ response criteria for AL amyloidosis. For Case 2, the patient achieved a cardiac response as evidenced by NT-ProBNP decreasing by >30% to 1677 pg/mL at 9 months post-CAR-T. We have also added two references (ref 13-14) regarding cardiac and renal response criteria for AL amyloidosis.
[13] Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD, Vidus Rosin M, Albertini R, Moratti R, Merlini G, Schönland S. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-32.
[14] Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U, Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;30(36):4541-9.
- Additional discussion should be given to the appropriateness of CAR-T cell therapy in patients with organ damage, for example, with reference to eligibility for autologous stem cell transplantation.
Response to reviewer: Thank you for your comment. We have changed the discussion section to add recent data presented at the International Myeloma Society 2023 Meeting regarding use of the novel, academic anti-BCMA CAR T NXC-201 in 9 patients with relapsed/refractory AL amyloidosis, including patients with organ damage and advanced stage amyloidosis. The following statements have been added to the discussion section:
Early data from a phase I clinical trial (NCT04720313) evaluating the feasibility of the novel, academic anti-BCMA CAR T NXC-201 in patients with relapsed/refractory AL amyloidosis has been reported.17 Nine evaluable patients (2 of which had concurrent multiple myeloma and 4 of which had Mayo-stage IIIa/IIIb disease) who had received a median of 6 prior lines of therapy (range: 3-10) achieved a hematologic overall response rate (ORR) of 100% with 6 CR, 2 VGPR, and 1 PR. At day 30, all 6 patients in CR were MRD negative. The median follow-up was 7.3 months (range: 2.5- 16.5) and the median duration of response was 5 months (range: 2.5- 16.5). Organ responses were observed in 6 patients. Seven patients experienced CRS that was grade 1 (n = 2), grade 2 (n = 3), or grade 3 (n = 2). The median time to onset of CRS was 2 days (range, 1-3), and the median duration of CRS was 1 day (range, 1-4). There were no instances of ICANS. Within the initial 2 weeks, 2 patients experienced AL-related acute renal failure and 1 patient had grade 3 hepatic dysfunction that subsequently resolved. There were no treatment-related deaths.17
Emerging data in a small number of patients is showing the safety, tolerability, and efficacy of anti-BCMA CAR-T in patients with relapsed/refractory AL amyloidosis, including those with advanced stage disease. Importantly, our report and the phase I trial of NXC-201 show that a high proportion of patients treated with anti-BCMA CAR-T achieve an MRD negative state, which is key for patients with AL amyloidosis as MRD negativity has been associated with improved organ responses.18 The available data, including this report, suggest that anti-BCMA CAR-T can be well tolerated by heavily pre-treated AL amyloidosis patients with organ dysfunction and that CRS is manageable as no treatment-related deaths have been reported. However, how best to optimize organ function prior to and during CAR-T therapy and strategies to mitigate CRS remain unknown. More prospective data will be needed regarding the safety, efficacy and management of CAR-T therapy for patients with AL amyloidosis, however AL amyloidosis is a rare disease and large controlled clinical trials are difficult to conduct .19 Perhaps the field will have to rely on small trials, pooled data and expert opinion to devise selection criteria for the use of CAR-T cell therapy for patients with AL amyloidosis as improved patient selection and defined eligibility criteria has allowed ASCT to be used in patients with AL amyloidosis.20-21
Reviewer 3 Report
Comments and Suggestions for AuthorsThe Communication article “Anti-BCMA CAR-T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety” reported that BCMA CART was tolerable and effective for two cases with myeloma and amyloidosis. This case series was very interesting and so I considered that this article was suitable for publishment. However, there was several minor issues as below.
1. How about organ response for AL amyloidosis after BCMA-CART? I understand that the follow-up time after CART was not enough to evaluate organ response, of course. For example, the author could add data about change of urinary protein in case 1 if you have.
2. I considered that the prophylaxis for CRS and ICANS in ZUMA-1 cohort6 was very key in this article. Therefore, I recommended that the author should describe the prophylaxis for CRS and ICANS in the ZUMA-1 cohort6 in detail.
3. In line 100-101, Was the phrase “daratumumab, daratumumab plus lenalidomide” correct?
Author Response
Reviewer #3
The Communication article “Anti-BCMA CAR-T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety” reported that BCMA CART was tolerable and effective for two cases with myeloma and amyloidosis. This case series was very interesting and so I considered that this article was suitable for publishment. However, there was several minor issues as below.
- How about organ response for AL amyloidosis after BCMA-CART? I understand that the follow-up time after CART was not enough to evaluate organ response, of course. For example, the author could add data about change of urinary protein in case 1 if you have.
Response to reviewer: Thank you for your comment. We have added responses for the patients in the manuscript. For case 1, the patient achieved stable renal disease and a cardiac response as evidenced by a >30% decrease in NT-ProBNP (from 8831 pg/mL to 3167 pg/mL) at 9 months post-CAR-T based on validated organ response criteria for AL amyloidosis. For Case 2, the patient achieved a cardiac response as evidenced by NT-ProBNP decreasing by >30% to 1677 pg/mL at 9 months post-CAR-T. We have also added two references (ref 13-14) regarding cardiac and renal response criteria for AL amyloidosis.
- I considered that the prophylaxis for CRS and ICANS in ZUMA-1 cohort6 was very key in this article. Therefore, I recommended that the author should describe the prophylaxis for CRS and ICANS in the ZUMA-1 cohort6 in detail.
Response to reviewer: Thank you for your comment. We have added the following statement to the article:
Page 5, Line 176: “We borrowed the CRS prophylaxis strategy from cohort 6 of the ZUMA-1 trial where patients with relapsed/refractory large B-cell lymphoma received the anti-CD19 CAR-T cell axicabtagene ciloleucel (axi-cel) and received once-daily oral dexamethasone 10 mg on days 0 (before axi-cel), 1 and 2. With prophylactic dexamethasone, no grade 3 or higher CRS occurred and there was no compromise in clinical efficacy.12”
- In line 100-101, Was the phrase “daratumumab, daratumumab plus lenalidomide” correct?
Response to reviewer: Thank you for your comment. We have corrected this and it now reads “…received single-agent daratumumab, daratumumab plus lenalidomide,…”
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors revised the manuscript appropriately according to the reviewers' comments.
