Anti-BCMA Approaches Ascending in Multiple Myeloma

Sham Mailankody, MBBS

Anti-BCMA directed treatments, including CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates (ADCs), have the potential to revolutionize the multiple myeloma treatment paradigm. At the 37 Annual CFS^®, Sham Mailankody, MBBS, discussed the emerging BCMA-directed therapies that have shown the greatest potential.

CAR T-Cell Therapy

One of the anti-BCMA CAR T-cell therapies that has shown high levels of clinical activity is bb2121, according to Mailankody, an assistant attending physician at Memorial Sloan Kettering Cancer Center. The multicenter phase I CRB-401 trial treated patients with bb2121 at doses of 50 × 10⁶, 150 × 10⁶, 450 × 10⁶, or 800 × 10⁶ CAR-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 (≤10⁻⁴ nucleated cells). Among patients treated with a dose of 150 × 10⁶ to 800 × 10⁶ CAR-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 × 10⁶ CAR-positive T cells (n = 30) compared with 2.6 months (95% CI, 1.1-2.9) among patients receiving <150 × 10⁶ CAR-positive T cells (n = 3). Among the 16 MRD-negative patients, the median PFS was 17.7 months (95% CI, 5.8-NE).³

Mailankody said 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).⁴ Among 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.⁵ The 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 at 37 Annual CFS^®. 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.

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