KarMMa Data in Multiple Myeloma Published as FDA Considers Potential Ide-Cel Approval

Treatment with idecabtagene vicleucel (ide-cel; formerly bb2121) led to deep responses in patients with relapsed and refractory multiple myeloma, according to findings from the phase 2 KarMMa trial (NCT03361748) recently published in The New England Journal of Medicine.1

Twenty-six percent of treated patients achieved minimal residual disease (MRD)–negative status and 79% of the patients who achieved a complete response (CR) or better were MRD negative.

“The fact that MRD-negative responses occurred in approximately a quarter of the patients highlights the depth of response induced by ide-cel,” the study authors, led by Nikhil C. Munshi, MD, wrote in their report.

Ide-cel is an investigational B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy that is currently under a priority review with the FDA for the potential approval as a treatment for adult patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.2 The application was supported by data from the KarMMa trial.

The trial enrolled 140 patients who had received at least 3 prior treatment regimens for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody, and were refractory to their last treatment regimen. Patients received one of 3 doses of ide-cel (150 x 106, 300 × 106, or 450 × 106 CAR-positive T cells) following lymphodepletion with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day). Patients were followed for 24 months or more and then asked to participate in a long-term follow-up study (GC-LTFU-001; NCT03435796).

The primary end point of the study was overall response rate (ORR) by International Myeloma Working Group criteria as assessed by independent review committee, and secondary end points were the rate of complete response (CR) or better, time to response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD), safety, pharmacokinetics, and immunogenicity.

A total of 128 patients received ide-cel infusion, 1 of whom discontinued after unsuccessful management of the CAR T-cell product.

The median patient age was 61 years (range, 33-78) and patients had a median of 6 years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), BCMA expression ≥50% at screening (85%), ECOG performance status of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.

The median number of prior therapies was 6 (range, 3-16) and 94% had previously undergone at least 1 autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy. Eighty-nine percent of patients had double-refractory disease, 84% were triple refractory, and 26% were penta refractory.

Four patients received the lowest dose, 70 received the middle dose, and 54 received the highest dose.

As of the data cutoff, 62 patients were still on study treatment. Patients were followed for a median of 13.3 months (range, 0.2-21.2) and the ORR was 73% (95% CI, 66%-81%; P < .001), CRs or better were reported in 33%. At the lowest dose, the response rate was 50%, 69% responded at the second dose level, and 81% responded at the highest dose level.

Seventy-nine percent of the patients who achieved a CR or better had MRD-negative status at a level of 10-5 or 26% of all treated patients.

Responses were high even across subgroups examined, including older patients, patients with aggressive disease features, and those who required bridging therapy.

The median time to first response was 1.0 month (range, 0.5-8.8) and 2.8 months (range, 1.0-11.8) for a response of CR or better. The median DOR was 10.7 months (95% CI, 9.0-11.3) for all patients and 11.3 months (95% CI, 10.3-11.4) at the highest dose level. Among patients with a CR or better, the median DOR was 19.0 months (95% CI, 11.3-not estimable [NE]).

The median PFS was 8.8 months (95% CI, 5.6-11.6) overall; among patients with a CR or better, the median PFS was 20.2 months (95% CI, 12.3-NE). The median OS was 19.4 months (95% CI, 18.2-NE) and at 12 months, the OS rate was 78%, although OS data are still immature.

Twenty-eight patients were re-treated with higher doses of ide-cel after disease progression and 21% of these patients had a second response with durations of 1.9 to 6.8 months.

All patients treated with ide-cel had an adverse event (AE) and 99% had a grade 3/4 event. The majority of events occurred within 8 weeks of infusion. Most grade 3/4 AEs were hematologic, including neutropenia in 89%, anemia in 60%, thrombocytopenia in 52%, leukopenia in 39%, lymphopenia in 27%, and febrile neutropenia in 16%. These events were considered to be in part due to lymphodepleting chemotherapy. Other frequent grade 3/4 AEs included hypophosphatemia in 16%, hypocalcemia in 8%, hyponatremia in 5%, and cytokine release syndrome (CRS) in 5%.

Among AEs of interest, there were 4 grade 3/4 bleeding events observed, infections of any grade were reported in 69% and were grade 3/4 in severity in 22%, CRS of any grade was reported in 84% and only 1 case was grade 5, and neurotoxicity was reported in 18% at any grade and at grade 3 in 3%.

Thirty-four percent of patients died during the study with most deaths due to complications of myeloma progression, although 2% died from treatment-related AEs of bronchopulmonary aspergillosis, gastrointestinal hemorrhage, and CRS within 8 weeks of infusion.

Maximum CAR-positive T-cell expansion occurred at a median of 11 days from infusion and CAR-positive T cells were detected in 59% of evaluable patients at 6 months and 36% of evaluable patients at 12 months.

Levels of proinflammatory markers increased soon after infusion and decreased by month 1. Peak levels were higher in patients who developed more severe cases of CRS.

Serum BCMA levels decreased rapidly after infusion in all responding patients and nadir values were reached within 3 months. Ninety-five percent of patients who achieved a CR or better had undetectable serum BCMA levels and the duration was correlated with the DOR. Serum BCMA levels were rising in 97% of progressing patients.

The study authors also noted that the efficacy data for ide-cel compare favorably with the results of 2 recently approved regimens in relapsed/refractory multiple myeloma: selinexor (Xpovio) plus dexamethasone and belantamab mafodotin (Blenrep).

_References:

_{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. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121). News Release. Bristol Myers Squibb. September 22, 2020. Accessed March 2, 2021. https://bit.ly/3kDhakH}