CAR-T a ‘fantastic improvement’ over available therapies for advanced multiple myeloma
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The value of chimeric antigen receptor T-cell therapy for patients with heavily pretreated multiple myeloma can be significant, regardless of whether it leads to a complete and lasting remission.
This was the message imparted during the 2019 ASH Annual Meeting and Exposition by Deepu Madduri, MD, assistant director of the cellular therapy service within Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai.
One year later, Madduri reaffirmed her assessment based on results of the CARTITUDE-1 trial, designed to evaluate the safety and effectiveness of ciltacabtagene autoleucel (JNJ-4528; Janssen, Legend Biotech) — a B-cell maturation antigen-directed CAR T-cell therapy — among patients with relapsed or refractory multiple myeloma.
At this year’s virtual ASH Annual Meeting and Exposition, Madduri — one of the lead investigators of CARTITUDE-1 — reported that response rates in the study remained high and responses appeared deep and durable with more than a year of follow-up.
Despite the positive results, the FDA has yet to approve any CAR T-cell therapy for multiple myeloma.
Madduri spoke with Cell Therapy Next about the progress of CAR T-cell therapies for this disease and how ciltacabtagene autoleucel continues to perform in the trial.
Question: Have you learned anything new in the last year about the effectiveness of ciltacabtagene autoleucel for this patient population?
Answer: The data that we presented in 2019, from the phase 1b portion of the CARTITUDE trial, included only 29 patients. During the virtual ASH meeting in December, we reported combined phase 1b/phase 2 data, which included 97 patients. The median age remained steady at about 61 years; however, median prior lines of therapy increased to six compared with five in 2019. So, the patients remained very heavily pretreated and were extremely refractory to their last line of therapy.
What we have now are more robust data for overall response rate and median PFS. After median follow-up of 12.4 months, we have not yet reached median PFS. This is quite exciting because we know it means most of these patients are doing well at least a year later and perhaps longer as we continue to monitor them.
Q: What do the year-over-year survival rates in the study say about the durability of ciltacabtagene autoleucel?
A: We are seeing deep and durable remissions with just a one-time treatment. I would like to see PFS after longer-term follow-up. We are already at 12 months and have not plateaued yet, so we may have more time before patients in this trial experience disease progression.
As of the data cutoff, 72% of patients are still in the study. Interestingly, we looked at patients with at least 6 months of follow-up and found that most did not have CAR T cells detectable in their peripheral blood. Despite this lack of persistence, patients are still maintaining a deep, durable response to therapy.
Q: What have you learned about ciltacabtagene autoleucel’s safety profile?
A: Most patients experienced grade 1 or grade 2 cytokine release syndrome (CRS), which resolved for all but one patient in the study. Five patients did not experience any CRS. Another interesting result from the phase 1b portion of this study was that the median time to onset of CRS was 7 days. Eighty-nine percent of patients had CRS at day 4 or later after infusion, whereas 74% had CRS at day 6 or later.
About 21% of patients had neurotoxicity of any grade, with 10% of patients experiencing grade 3 or higher neurotoxicity. Our study may be the first to classify neurotoxicity into two groups: ICANS [immune effector cell-associated neurotoxicity syndrome] and other neurotoxicities. There was a significant overlap between patients who had ICANS and other significant neurotoxicities, but the total overall neurotoxicity rate was a little over 20%.
Q: How soon do you expect CAR-T to be commercially available for patients with advanced myeloma?
A: There currently are no approved CAR T-cell therapies for this patient population. Idecabtagene vicleucel (Bristol Myers Squibb/bluebird bio) is perhaps the closest to FDA approval. I believe we will see a decision approving this therapy in March or April, if not sooner.
Q: What are the next steps for the CARTITUDE study?
A: Ciltacabtagene autoleucel is under further investigation in other populations of patients with multiple myeloma, particularly as an earlier line of treatment. It is also being studied with outpatient administration in the CARTITUDE-2 and CARTITUDE-4 studies. Because median time to onset of CRS in CARTITUDE-1 is 7 days, there may be no benefit to having recipients remain as inpatients for the first 10 to 14 days after infusion. The trial protocol currently requires patients be admitted after infusion, but these studies will consider providing outpatient administration of lymphodepletion and the CAR T-cells. Any outpatient administration in these studies would involve monitoring patients daily and admit them only if they have symptoms of CRS that require admission.
Q: Is there value to receiving CAR T-cell therapy for patients with multiple myeloma, even if the therapy fails to provide a cure?
A: Definitely. The reason is, based on the recent MAMMOTH study, patients with relapsed or refractory multiple myeloma have median OS of only 9.2 months if they are triple refractory to treatment and only 5.6 months if they are penta-refractory. Patients given ciltacabtagene autoleucel are showing deep and durable responses at median follow-up of 12 months, which is a fantastic improvement. Subsequent lines of therapy are shorter for patients with multiple myeloma and less effective. We need more therapies like ciltacabtagene autoleucel to help our patients.
Reference:
Gandhi UH, et al. Leukemia. 2019;doi:10.1038/s41375-019-0435-7.
For more information:
Deepu Madduri, MD, can be reached at deepu.madduri@mountsinai.org.
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Madduri D, et al. Abstract 177. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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