BCMA-Directed Therapies Taking Hold in Multiple Myeloma

There are at least two dozen different B-cell maturation antigen-directed therapies being explored in clinical trials, Sham Mailankody, MBBS, told attendees at the 37 Annual CFS. Mailankody, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, highlighted the most promising anti-BCMA agents across several modalities, including CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates.

Sham Mailankody, MBBS

There are at least two dozen different B-cell maturation antigen (BCMA)-directed therapies being explored in clinical trials, Sham Mailankody, MBBS, told attendees at the37 AnnualCFS®.1Mailankody, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, highlighted the most promising anti-BCMA agents across several modalities, including CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates (ADCs).

CAR T-Cell Therapy

One of the anti-BCMA CAR T-cell therapies that has shown high levels of clinical activity is bb2121, Mailankody noted. The multicenter phase I CRB-401 trial treated patients with bb2121 at doses of 50 × 106, 150 × 106, 450 × 106, or 800 × 106CAR-positive T cells.2

The objective response rate (ORR) was 85% across all treatment doses, including a complete response (CR) rate of 45% (n = 15). The median duration of response was 10.9 months. At the time of the data reporting, 6 of the 15 patients who achieved a CR had relapsed. All 16 responders evaluable for minimal residual disease (MRD) were MRD-negative (≤10−4nucleated cells). Among patients treated with a dose of 150 × 106to 800 × 106CAR-positive T cells, the ORR was 90% including a stringent CR (sCR) of 40% and a CR rate of 10%.

The median patient age was 60 years (range, 37-75), 45% of patients had a high-risk cytogenetic profile, 64% of patients had progressive disease during their most recent line of therapy, and 97% of patients had prior autologous stem-cell transplantation (ASCT). Prior therapies patients had been exposed to included bortezomib (Velcade; 100%), carfilzomib (Kyprolis; 91%), lenalidomide (Revlimid; 100%), pomalidomide (Pomalyst; 94%), and daratumumab (Darzalex; 82%).

The median progression-free survival (PFS) was 11.8 months (95% CI, 6.2—not evaluable [NE]) among patients treated with ≥150 × 106CAR-positive T cells (n = 30) compared with 2.6 months (95% CI, 1.1-2.9) among patients receiving <150 × 106CAR-positive T cells (n = 3). Among the 16 MRD-negative patients, the median PFS was 17.7 months (95% CI, 5.8-NE).3

Mailankodysaid the median PFS “was good, but slightly underwhelming considering the CR/sCR rate was about 50% in the population. So that is of some concern—there is a high proportion of patients who respond, a high proportion of patients who have a CR, but progressions are common and there does not appear to be a plateau of the curve of this study and others that have been reported in myeloma.”

Grade 3/4 cytokine release syndrome (CRS) with bb2121 occurred in 6% of patients and all-grade neurotoxicity occurred in 42% of patients.2

The other anti-BCMA CAR T-cell therapies that have been tested in the largest studies to date are JCARH125, LCAR-B38M, and P-BCMA-101. In a 44-patients study, JCARH125 achieved an ORR of 82% and very good partial response (VGPR) or better rate of 48%. Nine percent of patients had grade 3/4 CRS, with 25% having neurotoxicity of any grade. LCAR-B38M reached an ORR of 88% in a 57-patient trial, with a ≥VGPR rate of 73%. The grade 3/4 CRS rate was 7%, and 2% of patients experienced neurotoxicity of any grade. With P-BCMA-101, the ORR was 61% among 23 patients, with a ≥VGPR rate of 22%. No patients had grade 3/4 CRS and 5% had any grade neurotoxicity.1

Bispecific Antibodies

In a 42-patient phase I trial of the bispecific T-cell engager (BiTE) antibody construct AMG 420 in patients with relapsed or refractory disease, the ORR was 31% (13 of 42 patients).4Among patients treated with the maximum-tolerated dose of 400 µg/day, the ORR was 70% (7 of 10), including 5 MRD-negative CRs, 1 VGPR, and 1 partial response. The median duration of response was 9 months (range, 5.8-13.6).

Baseline characteristics included a median age of 65 (range, 39-79), 45% of patients with intermediate- or high-risk cytogenetics, and a median number of prior lines of therapy of 4 (range, 2-13). Some of the prior therapies received included daratumumab (26%), elotuzumab (10%), and ASCT (86%). Fifty-five percent of patients were refractory to immunomodulatory drugs (IMiDs) and 45% were refractory to proteasome inhibitors.

There were 15 cases of grade 1/2 CRS and 1 case of grade 3 CRS. Two patients had grade 3 treatment-related peripheral neuropathy and 1 patient had grade 3 treatment-related edema. There were no observed cases of grade 3/4 CNS toxicities.

Other anti-BCMA bispecific antibodies being explored in clinical trials include AMG 701, PF-06863135, CC-93269, and, REGN-5458.

Antibody-Drug Conjugates

The third anti-BCMA treatment modality Mailankody covered was ADCs. Data from the phase I DREAMM-1 trial showed that the anti-BCMA ADC belantamab mafodotin (GSK2857916) elicited an ORR of 60%, including 3 CRs and 2 sCRs.5The median PFS was 12 months (95% CI, 3.1-NE), and the median duration of response was 14.3 months (95% CI, 10.6-NE).

Among heavily pretreated patients who were refractory to both an IMiD and a proteasome inhibitor (n = 32), the median PFS was 7.9 months (95% CI, 2.3-NE) and the ORR was 56.3%. In patients who did not receive prior treatment with daratumumab (n = 21), the ORR was 71.4% and the median PFS was 15.7 months (95% CI, 2.3—NE). Patients who were double refractory and were previously treated with daratumumab (n = 13) had a median PFS of 6.2 months (95% CI, 0.7-7.9) and an ORR of 38.5%. In those patients who did previously receive daratumumab, the median PFS was 6.8 months (95% CI, 1.3–NE).

In August 2019, GSK, the manufacturer of belantamab mafodotin announced that the ADC had met the primary endpoint of demonstrating a clinically meaningful ORR in patients with relapsed/refractory multiple myeloma enrolled in the phase II DREAMM-2 trial.6

The FDA granted belantamab mafodotin a breakthrough therapy designation in November 2017 for the treatment of patients with relapsed/refractory multiple myeloma who have failed ≥3 prior lines of therapy, including an anti-CD38 antibody, and who are refractory to a proteasome inhibitor and an IMiD.

References

  1. Mailankody S. Which BCMA therapy is best: CAR T, ADC, bispecific antibodies. Presented at37 AnnualCFS&reg;. November 6-8, 2019. New York, New York.
  2. Raje N, Berdeja J, Lin Y, Siegel D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma.N Engl J Med. 2019;380(18):1726-1737. doi: 10.1056/NEJMoa1817226.
  3. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study.J Clin Oncol. 2018;36 (suppl; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.
  4. Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.J Clin Oncol.2019;37 (suppl; abstr 8007). 10.1200/JCO.2019.37.15_suppl.8007.
  5. Trudel S, Lendvai N, Popat R, et al. Antibody—drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study.Blood Cancer J. 2019;9(37). doi:10.1038/s41408-019-0196-6.
  6. GSK announces positive headline results from the pivotal DREAMM-2 study for multiple myeloma [news release]. London, UK: GlaxoSmithKline; August 23, 2019. bit.ly/30ul1qB.