BCMA-directed CAR-T shows ‘impressive’ durability for advanced multiple myeloma
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More than 80% of patients with relapsed or refractory multiple myeloma remained alive 18 months after receiving a single infusion of ciltacabtagene autoleucel, according to the latest results of a phase 1/phase 2 clinical trial.
Data from the CARTITUDE-1 study — presented during the virtual ASCO Annual Meeting — also showed encouraging durability among patients who received the chimeric antigen receptor T-cell therapy, with two-thirds of patients remaining progression-free at 18-month follow-up.
Ciltacabtagene autoleucel (Janssen, Legend Biotech — also known as cilta-cel — is an autologous, gene-edited CAR T-cell therapy that targets the B-cell maturation antigen (BCMA) on the surface of cancer cells. The manufacturer completed a rolling submission to the FDA of the biologics license application for cilta-cel to treat adults with relapsed or refractory multiple myeloma, and the therapy has been granted priority review by the regulator for the indication.
The FDA set a target action date of Nov. 29 for commercial approval of cilta-cel.
The updated results of CARTITUDE-1 were “quite impressive,” according to Saad Z. Usmani, MD, FACP, chief of the plasma cell disorders program and director of clinical research in hematologic malignancies at Levine Cancer Institute at Atrium Health, clinical professor of medicine at University of North Carolina School of Medicine and a HemOnc Today Editorial Board Member.
“The fact that we are seeing these responses in patients with highly refractory melanoma is remarkable,” Usmani told Healio.
During ASCO, Usmani and colleagues presented longer-term follow-up data from CARTITUDE-1, a phase 1b/phase 2 study that evaluated the safety and efficacy of cilta-cel among adults with relapsed or refractory multiple myeloma who received at least three previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
The final analysis included 97 patients (median age, 61 years; range, 43-78; 59% men; 17.5% Black) who received a median six (range, 3-18) previous lines of therapy; 66% had received five or more lines of previous therapy. Eighty-seven percent of patients had triple-class refractory disease and 42% had penta-refractory disease.
Safety and confirmation of the recommended phase 2 dose of cilta-cel served as primary objectives of the phase 1b portion of the study, whereas evaluation of efficacy served as the primary objective of the phase 2 portion.
Study participants underwent lymphodepletion chemotherapy with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by an infusion of cilta-cel at a median dose of 0.71 × 106 CAR T cells/kg (range, .0.51 × 106-0.95 × 106).
Results showed a 97.9% overall response rate, including a stringent complete response rate of 80.4%. Nearly 95% of patients had at least a very good partial response to therapy.
Median duration of response was 21.8 months (95% CI, 21.8-not evaluable) and had not yet been reached among patients who had a stringent complete response to therapy.
Seventy-three percent of patients did not experience disease progression and remained alive 12 months after treatment.
Among 61 patients eligible for minimal residual disease (MRD) evaluation, 91.8% were MRD-negative, including 89.4% of MRD-evaluable patients with a stringent complete response. This equated to an MRD-negativity rate of 57.7% for the entire study group.
"The depth of response with increased follow-up time has improved,” Usmani said, adding that the MRD-negativity rate among evaluable patients at the data cutoff date was the highest it had been at any time during the study.
Researchers reported an 18-month PFS rate of 66% (95% CI, 54.9-75) among all patients and 75.9% (95% CI, 63.6-84.5) among patients who had a stringent complete response. The 18-month OS rate was 80.9% (95% CI, 71.4-87.6) for all patients.
Safety results were similar to a previous analysis of the CARTITUDE-1 study. The most frequent grade 3 or grade 4 treatment-related hematologic adverse events included neutropenia (94.8%), anemia (68%) and thrombocytopenia (59.8%).
Ninety-five percent of patients experienced cytokine release syndrome, with most (95%) having grade 1 or grade 2 CRS. Median time to onset of CRS was 7 days (range, 1-12), with a median duration of 4 days (range, 1-97).
Twenty patients (20.6%) had some form of neurotoxicity after receiving cilta-cel, including 10 patients with grade 3 or greater neurotoxicity. Sixteen patients (16.5%) had immune effector cell-associated neurotoxicity syndrome, two cases of which were grade 3 or greater.
According to Usmani, there have been capacity issues with idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio), which earlier this year became the first CAR-T approved by the FDA for commercial use for patients with multiple myeloma. FDA approval of cilta-cel would help ease the demand and provide another treatment option for patients with heavily pretreated multiple myeloma, he said.
“I'm quite hopeful [cilta-cel] will get an affirmative nod from the FDA later this year,” Usmani told Healio. “This will be an exciting year if that happens — to have two CAR T-cell therapies approved for patients with multiple myeloma within the same year.”
Perspective
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Surbhi Sidana, MD
Patients with triple-class refractory multiple myeloma have poor outcomes. In the MAMMOTH study, these patients had median OS of 8.6 months and the response rate to the next line of therapy was about 30% on average, with median PFS of 3.4 months.
In March, FDA approved idecabtagene vicleucel — also known as ide-cel — as a first-in-class CAR T-cell therapy directed against BCMA for multiple myeloma. This approval was based on results of the KarMMa trial, which included a heavily pretreated patient population, with most patients having triple-class refractory disease.
The response rates seen with ide-cel in this population were unprecedented, with an overall response rate of 73% and a complete response rate of 33%. Median PFS was 8.8 months.
However, we did not see a plateau in the curves and continue to see relapses. Nevertheless, the bar for triple-class refractory myeloma has now been set high.
Usmani and colleagues presented results of cilta-cel, which is a different CAR T construct. The response rates with cilta-cel also were unprecedented.
With great responses seen with bispecific antibodies and CAR T-cell therapy, the big question remains: Which should you choose for your patient?
Each has its advantages and limitations. The biggest advantage with CAR T-cell therapy is that it is a one-and-done therapy, but the limitation is that it requires time for manufacturing.
High response rates have been reported with both types of therapy, but response rates have been higher overall with CAR T-cell therapy. Responses with CAR T-cell therapy appear to be durable, although it is too early to say for bispecific antibodies, as the follow up is not mature. It is possible that bispecific antibodies may be more suitable for less fit patients, although clinical trials usually exclude these patients.
In terms of other special populations, it is challenging to use CAR T-cell therapy in patients with renal dysfunction, as it is limited by use of lymphodepletion therapy below a certain creatinine clearance. Although bispecific antibody trials have excluded patients with advanced renal dysfunction, it may be possible to use it in this patient population and should be investigated.
We are seeing relapses after BCMA-targeted therapies, and this has become a new unmet need in multiple myeloma, with patients having quad-class refractory and hexa-refractory disease. I think we need to understand the mechanisms of relapse with BCMA-targeted therapies, which could include antigen escape, lack of CAR T-cell persistence or exhaustion of CAR T-cell or endogenous T cells.
In addition, as we integrate these therapies into our clinical practice, we need to focus on evaluating and addressing quality of life and other late side effects with these new treatments.
References:
Gandhi UH, et al. Leukemia. 2019;doi:10.1038/s41375-019-0435-7.
Munshi NC, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2024850.
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Usmani SZ, et al. Abstract 8005. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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