In the pivotal phase II KarMMa study reported in The New England Journal of Medicine, Nikhil C. Munshi, MD, and colleagues found that the B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel produced high response rates in patients with triple-class–exposed relapsed or refractory multiple myeloma.
Nikhil C. Munshi, MD
Study Details
The multinational study included 140 patients with disease after at least three previous regimens—including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody—enrolled between December 2017 and November 2018. After lymphodepletion with fludarabine and cyclophosphamide for 3 consecutive days, patients received idecabtagene vicleucel target doses of 150 × 106 to 450 × 106 CAR T cells after a 2-day rest period.
The primary endpoint was overall response of partial response or better on International Myeloma Working Group criteria. The null hypothesis was a best overall response of partial response or better of ≤ 50%.
Responses
Among 140 patients undergoing leukapheresis, 128 received idecabtagene vicleucel infusions at target doses of 150 × 106 (n = 4), 300 × 106 (n = 70), and 450 × 106 (n = 54) CAR T cells. Median follow-up was 13.3 months.
Partial response or better was achieved in 94 (73%) of 128 patients (P < .001), with a complete or stringent complete response observed in 42 patients (33%). Very good partial response or better was observed in 67 patients (52%). At the target doses of 150 × 106, 300 × 106, and 450 × 106 CAR T cells, response and complete response were observed in 50% and 25%, 69% and 29%, and 81% and 39% of patients.
Median time to first response was 1.0 month. Median duration of response was 10.7 months among all responders, including 4.5 months, 10.4 months, and 19.0 months in patients with partial response, very good partial response, and complete response. Measurable residual disease (MRD)-negative status (< 10-5 nucleated cells) was confirmed in 33 patients, including 26% of all patients and 79% of those with complete response or better.
Median progression-free survival was 8.8 months overall (95% confidence interval [CI] = 5.6–11.6 months), including 20.2 months (95% CI = 12.3 months–not estimable) in patients with complete or stringent complete response. Kaplan-Meier estimated median overall survival was 19.4 months (95% CI = 18.2 months–not estimable), with a 12-month rate of 78%.
Cellular kinetic analysis showed persistence of CAR T-cells in 29 (59%) of 49 patients at 6 months and 4 (36%) of 11 patients at 12 months after infusion.
KEY POINTS
- Partial response or better was achieved in 73% of patients, with complete or stringent complete response observed in 33%.
- Median response durations were 10.7 months overall, including 4.5 months, 10.4 months, and 19.0 months in patients with partial response, very good partial response, and complete response.
Toxicity
Grade 3 or 4 adverse events occurred in 99% of patients receiving treatment; most were hematologic adverse events, including neutropenia in 89%, anemia in 60%, and thrombocytopenia in 52%, considered at least partially related to lymphodepleting chemotherapy. Most adverse events—apart from hypogammaglobulinemia (any grade in 21%, grade 3 or 4 in < 1%) and infections—occurred within 8 weeks after infusion.
Cytokine-release syndrome occurred in 84% of patients and was grade ≥ 3 in 5%. Neurotoxic events occurred in 18% and were grade 3 in 3%. Infections occurred in 69% of patients and were grade 3 or 4 in 22%. Grade 3 or 4 bleeding events occurred in four patients.
Death occurred in three patients (2%) within 8 weeks after infusion from idecabtagene vicleucel–related adverse events (bronchopulmonary aspergillosis, gastrointestinal hemorrhage, and cytokine release syndrome); one patient (1%) died between 8 weeks and 6 months after infusion from an idecabtagene vicleucel–related adverse event (cytomegalovirus pneumonia).
The investigators concluded, “Idecabtagene vicleucel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine-release syndrome.”
Disclosure: The study was funded by bluebird bio and Celgene, a Bristol Myers Squibb company. For full disclosures of the study authors, visit nejm.org.
