Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a very well-written manuscript that summarizes data regarding the two CART cell therapies approved for the treatment of MM. My only comment would be to slightly reduce the word count overall. Perhaps the sections Population in Need and Practical Basics could be reduced in terms of word count.
Two points that would be worth adding
- the issue worth discussing and elaborating more regards the timing of CART cell therapy and what follows after that (could add data from clinical trials) and also
- future CART constructs in development (third, fourth generation) that could have fewer side effects
Author Response
Comment 1: “This is a very well-written manuscript that summarizes data regarding the two CART cell therapies approved for the treatment of MM. My only comment would be to slightly reduce the word count overall. Perhaps the sections Population in Need and Practical Basics could be reduced in terms of word count.”
Response 1: Thank you for your positive review and constructive feedback. In this revision, the overall word count has ended up increasing in order to incorporate all the reviewer’s suggested additions to the manuscript.
Comment 2: Two points that would be worth adding - the issue worth discussing and elaborating more regards the timing of CART cell therapy and what follows after that (could add data from clinical trials) and also
Response 2: We have inserted the paragraph below into lines 589 – 590 so that timing of CAR T cell therapy and the logistics around it is a bit more clear for the community providers
“Given the logistical complexities of CAR T-cell therapy and likely limited treatment slots per month at each CAR T centre, early inquiries or referrals from community providers should be encouraged. Naturally, the process from referral to CAR T-cell infusion is likely to take more than 6 weeks, thus close communication between the referring centre and CAR T centre should be maintained throughout. After baseline evaluation, there is a washout period for anti-myeloma therapies to ensure T cell fitness prior to leukapheresis. During the 4-6 week manufacturing period, the most appropriate bridging therapy should be made on a case by case basis between the referring physician and CAR T provider. The bridging therapy may be provided by the referring centre. Once the CAR-T product is ready, close coordination is required to ensure adequate washout, availability of hospital bed at CAR T centre and timely release of the product for infusion (45).”
In terms of choosing therapies for relapse following CAR T cell therapy, this is certainly a hot topic that is evolving, and probably deserves a separate manuscript on its own. We have inserted the following on lines 608 to 610 to mention this topic to the reader.
“Sequencing of therapies before and after CAR T-cell therapy are still under investigation. BiTE and other novel emerging agents may be considered for relapse(s) after CAR T-cell therapy.”
Comment 3: Future CART constructs in development (third, fourth generation) that could have fewer side effects
Response 3: We have inserted the following in lines 660 to 662 to make brief mention of this area which is under active research.
"Finally, newer generations of CAR constructs are under investigation to improve immunogenicity, efficacy and persistence of CAR T-cells as well as reducing unwanted side effects (52)."
Reviewer 2 Report
Comments and Suggestions for AuthorsCongratulations on this timely review. Some suggestions:
1.Please, revise some typos:
Line 10: Use abbreviation MM
Line 12: ABECMAâ
Line 13: CARVYKTIâ
Line 39: FDA (no need to add abbreviation)
Line 98: GMP (“)
Line 244 & 323: grade 3 or more?
Line 260: CARTITUDE-1.
Line 350: for
Line 400: had
Line 455/456: abbreviation already described (line 132).
2. Please, consider adding the following reference and its message:
Although chimeric antigen receptor T therapy (CAR-T) cells are an established
therapy for relapsed/refractory multiple myeloma (RRMM), there are no
established models predicting outcome to identify patients who may benefit the
most from CAR-T. Gagelman N et al- JCO 2024;42(14):1665-1675. DOI https://doi.org/10.1200/JCO.23.02232.
The use of this model (MyCARe) could help to optimize the implementation of the CART program in patient-specific subgroups.
3. I miss a figure describing/ summarizing the key challenges to afford.
4. Several recent papers deal the topic of the potential replacement of ASCT by CART. This probably deserves a comment in the discussion.
Author Response
Comment 1:
Please, revise some typos:
Line 10: Use abbreviation MM
Line 12: ABECMAâ
Line 13: CARVYKTIâ
Line 39: FDA (no need to add abbreviation)
Line 98: GMP (“)
Line 244 & 323: grade 3 or more?
Line 260: CARTITUDE-1.
Line 350: for
Line 400: had
Line 455/456: abbreviation already described (line 132).
Response 1: We have amended the above typos that you have mentioned. Please also note the following.
For line 39 - We have checked with the editor, and the preference of the journal is to spell out “Food and Drug Administration” when first mentioned, then to use FDA afterwards. Therefore, we have included the abbreviation. Of note, we have deleted “FDA” from line 11 so that line 39 is the first time it is mentioned.
For line 98 - we have deleted the abbreviation GMP as this has not been mentioned again in the rest of the article.
For line 244 and 323 - Although the reported figures for infection most resemble the numbers for grade 3 or higher in other studies. However, the original sources do not explicitly state this or imply this, hence we cannot state this.
Line 350 – we have rewritten the sentence so that this is more clear.
Comment 2:
Please, consider adding the following reference and its message:
Although chimeric antigen receptor T therapy (CAR-T) cells are an established
therapy for relapsed/refractory multiple myeloma (RRMM), there are no
established models predicting outcome to identify patients who may benefit the
most from CAR-T. Gagelman N et al- JCO 2024;42(14):1665-1675. DOI https://doi.org/10.1200/JCO.23.02232.
The use of this model (MyCARe) could help to optimize the implementation of the CART program in patient-specific subgroups.
Response 2: Thank you very much for informing us of this predictive model. A paragraph on this has been inserted to lines 574 to 582
"Gagelman et al (43) has recently proposed the MyCARe model, a simple scoring system incorporating disease, treatment, and inflammation-related variables to stratify patients into those at low, intermediate and high risk of early treatment failure (defined as relapse or progression within 5 months from infusion) (43). This prognostic model has been externally validated and maintains prognostic utility across different CAR-T products, treatment regions (Europe and US) and penta-refractory status (43). The MyCARe model may assist with patient selection and optimal timing of CAR T-cell therapy in patient-specific subgroups, (43). However, it should not be used to exclude patients from such therapy."
Comment 3: I miss a figure describing/ summarizing the key challenges to afford.
Response 3: Thank you for suggesting that we insert a table 3 to summarise the key challenges and solutions. This has now been inserted (see line 482 – 483)
Comment 4: Several recent papers deal the topic of the potential replacement of ASCT by CART. This probably deserves a comment in the discussion. Response 4: We have inserted a paragraph to lines 638-645, briefly mentioning CAR T trials in frontline setting
"Trials are also under way investigating the use of Ide-cel and Cilta-cel for frontline therapy in those with newly diagnosed multiple myeloma (NDMM). KarMMA-4 trial is a phase I study investigating Ide-cel in patients with high risk NDMM. The CARTITUDE-5 trial is a phase III randomised clinical trial studying the efficacy of Cilta-cel in patients with transplant-ineligible NDMM. CARTITUDE-6 is the first randomised clinical trial comparing CAR T-cell therapy against autologous stem cell transplant (ASCT) in NDMM. Long term follow-up and cost-efficacy studies would be required to determine whether ASCT would be fully replaced by CAR T-cell therapy (50)."
