Treatment with the B-cell maturation antigen−targeted chimeric antigen receptor (CAR) T-cell therapy idecabtagene ciloleucel (ide-cel) showed encouraging efficacy in patients with heavily pretreated relapsed and/or refractory multiple myeloma (MM), according to results from the phase II KarMMa study published in the New England Journal of Medicine. These findings supported the U.S. Food and Drug Administration’s decision to approve ide-cel in late March 2021, as the first cell-based gene therapy approved for MM.
“The 450×106 dose appeared to be somewhat more effective than the other doses,” with slightly deeper and more frequent responses observed in patients who received this dose of CAR-positive T-cells, said lead investigator Nikhil C. Munshi, MD, from the Dana-Farber Cancer Institute in Boston.
Eligible patients had received at least three previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody; had adequate organ function; had measurable disease; and had disease that had progressed within 60 days after their last dose of therapy according to International Myeloma Working Group (IMWG) criteria.
The patients’ median age was 51 years (range = 33-78 years). About half of participants (51%) had a high tumor burden, 39% had extramedullary disease (n=50), 16% had stage III disease at screening as defined by the revised International Staging System (n=21), and 35% had a high-risk cytogenetic abnormality (n=45). Most patients (94%; n=120) had previously undergone autologous hematopoietic stem cell transplantation. During the manufacturing period, 112 patients (88%) received bridging therapy for a median of 15 days (range = 1-33) which stopped at least 14 days prior to lymphodepletion.
Between December 13, 2017, and November 13, 2018, 140 patients were enrolled in the KarMMa trial and underwent lymphodepletion with fludarabine (30 mg/m2 per day) and cyclophosphamide (300 mg/m2 per day) for three days. After two days of rest, 128 patients received CAR-positive T cells at one of the following target doses:
- 150×106 (n=4)
- 300×106 (n=70)
- 450×106 (n=54)
Twelve participants discontinued the trial before infusion with ide-cel, including one patient who left after unsuccessful manufacturing of CAR T cells.
After treatment with ide-cel, patients were followed for at least 24 months, then asked to participate in an additional long-term follow-up study.
The primary endpoint of the study was overall response as defined by the IMWG Uniform Response Criteria for Multiple Myeloma. Secondary endpoints included complete response or better, time to response, duration of response, progression-free survival (PFS), overall survival, measurable residual disease (MRD), safety, pharmacokinetics, and immunogenicity.
“The fact that MRD-negative responses occurred in approximately a quarter of the patients highlights the depth of response induced by ide-cel.”
—Nikhil C. Munshi, MD
At a median follow-up of 13.3 months (range = 0.2-21.2), 73% of patients (n=94) had a response (p<0.001). This included one-third of patients (n=42) who had a complete response (CR) or stringent CR (sCR). The authors noted that the response rate was slightly higher in patients who received the 450×106 dose, with an overall response rate of 81% and a CR or better achieved by 39% of patients.
Of the 42 patients with a CR or sCR, 33 (26%) achieved MRD-negative status (to a level of <10-5 sensitivity). “The fact that MRD-negative responses occurred in approximately a quarter of the patients highlights the depth of response induced by ide-cel,” the authors wrote.
Among all participants who were treated with ide-cel, the estimated median PFS was 8.8 months. It was 12.1 months for patients receiving the 450×106 dose versus 20.2 months for patients who achieved a CR or sCR.
The researchers noted that responses occurred rapidly, with a median time to first response of one month (range = 0.5-8.8 months) and a median time to CR or sCR of 2.8 months (range = 1.0-11.8 months). Overall, the median duration of response was 10.7 months, and slightly higher at the 450×106 dose, at 11.3 months. Response duration increased with depth of response, the authors noted.
At 12 months follow-up, 36% of evaluable patients had detectable CAR-positive T cells in their blood, but, according to the investigators, “The presence of these cells did not guard against recurrence; it is unclear whether the myeloma cells became resistant to the CAR T cells or the T cells became functionally compromised in some way.
All 128 patients experienced adverse events (AEs), with 127 (99%) reporting grade 3 or 4 AEs. These included neutropenia (89%), anemia (60%), and thrombocytopenia (52%). Cytokine release syndrome (CRS) was common, occurring in 107 patients (84%), although the authors noted that a small portion of these were grade 3 or higher (n=7; 5%). They added that high-grade events were largely transient. Forty-four patients (34%) died during the study. Most of the deaths (n=27) were related to complications of MM progression, according to the investigators. Within two months of treatment with ide-cel, three patients died from treatment-related bronchopulmonary aspergillosis, gastrointestinal hemorrhage, and CRS, respectively. Between two and six months from ide-cel one patient died from cytomegaloviral pneumonia. Six months after infusion, five patients died from unrelated AEs and eight from disease progression.
“Data on overall survival are immature, with data for 84 patients (66%) censored, including 39 of 54 patients (72%) at the 450×106 dose,” the authors wrote, noting a potential limitation of these findings.
The authors report relationships with bluebird bio and Celgene, which funded the study.
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.