Results of a phase 2 trial testing the efficacy of idecabtagene vicleucel in patients with heavily pretreated myeloma are reported.
Chimeric antigen receptor (CAR) T-cell therapy with idecabtagene vicleucel (ide-cel) induced responses in almost 75% of patients with multiple myeloma following relpase on multiple prior lines of therapy, according to data from the phase 2 KarMMa trial (NCT03361748) that was published in the New England Journal of Medicine.1
Results of this trial also support an application that is now with the FDA for approval of ide-cel as therapy for this patient group, with a decision date already set for March 27, 2021.2
“Despite numerous advances in the treatment of multiple myeloma, relapses are common. Patients whose disease continues to worsen after receiving standard therapy have relatively few treatment options that provide high response rates,” Nikhil Munshi, MD, of Dana-Farber Cancer Institute, said in a press release. “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
At a median follow-up of 13.3 months, responses were observed in 94 (73%) out of a total of 128 patients who had received ide-cel at target doses of 150 × 106 to 450 × 106 CAR-positive T cells. Furthermore, minimal residual disease (MRD)–negative status, which was defined as less than 10-5 nucleated cells, was confirmed in 33 patients (26%); amongst the 42 patients with a complete response, MRD-negativity was achieved at a rate of 79%.
The median time to first response was 1.0 month (range, 0.5-8.8) and the median time to a complete response or better was 2.8 months (range, 1.0-11.8).
The estimate for median duration of response (DOR) was 10.7 months for all patients and 11.3 months (95% CI, 10.3-11.4) in those receiving the highest target dose. Response duration increased in step with response depth, with those having partial responses, very good partial responses, and complete or stringent complete responses seeing median DORs of 4.5 months (95% CI, 2.9-6.7), 10.4 months (95% CI, 5.1-11.3), and 19.0 months (95% CI, 11.3-NE), respectively.
Median progression-free survival was 8.8 months (95% CI, 5.6-11.6), 12.1 months (95% CI, 8.8-12.3) at the 450×106 dose, and 20.2 months (95% CI, 12.3-not estimable [NE]) in patients having a complete or stringent complete response.
All treated patients reported adverse events (AEs) to therapy, and grade 3/4 AEs were noted in 127 patients (99%). Most events happened in the first 8 weeks of therapy, except for those of hypogammaglobulinemia and infections. Grade 3/4 AEs were mostly hematologic in nature, including neutropenia (89%), anemia (60%), and thrombocytopenia (52%). In patients with persistent neutropenia or thrombocytopenia, the median time to recovery, which was defined as downgrading to grade 2 or lower in severity, was 1.9 months (range, 1.2-5.6).
Cytokine release syndrome (CRS), a common toxicity associated with CAR T-cell therapy administration, was noted in 84% of patients, but was mostly composed of grade 1/2 AEs. Grade 3 CRS occurred in 5 patients (4%), grade 4 in 1 (<1%), and 1 patient experienced a grade 5 event at the 300 × 106 dose. Median time of CRS onset was 1 day (range, 1-12) with a 5-day median duration (range, 1-63). Management involved tocilizumab in 52% and corticosteroids in 15%.
Another common toxicity with CAR T-cell therapy, neurotoxicity, was noted in 18% of patients, of whom only 3% had grade 3 and none had grade 4 or 5 severity events. Median onset time of neurotoxic events was 2 days (range, 1-10) and the median duration was 3 days (range, 1-26).
“Cytokine release syndrome of grade 3 or higher and neurotoxic effects were observed in no more than 6% of patients at all doses of CAR(-positive) T cells,” the investigators wrote. “High-grade hematologic toxic effects were common but transient. A small number of adverse events were fatal.”
Ide-cel is a B-cell maturation antigen–targeting CAR T-cell therapy. Patients treated as part of this trial received lymphodepletion with fludarabine (30 mg/m2 daily) and cyclophosphamide (300 mg/m2 daily) on 3 consecutive days followed by 2 days of rest before ide-cel infusion and the indicated doses ranges. The primary end point of the trial was overall response rate.
“Results of the KarMMa study support substantial antitumor activity for ide-cel across a target dose range of 150 × 106 to 450 × 106 CAR+ T cells,” the investigators concluded. “The 450 × 106 dose appeared to be somewhat more effective than the other doses.”
1. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi: 10.1056/NEJMoa2024850
2. CAR T-cell therapy generates lasting remissions in patients with multiple myeloma. News release. Dana-Farber Institute. February 25, 2021. Accessed February 25, 2021. https://bit.ly/3pMXM76