Belantamab mafodotin (GSK2857916) is a novel BCMA ADC that has been shown to have potent, selective antimyeloma activity through multiple cytotoxic mechanisms of action.1 In a phase 1 dose escalation and expansion trial including 73 multiple myeloma (MM) patients with progressive disease, belantamab mafodotin was well tolerated and had favorable clinical activity. The patient population in this study was heavily pretreated, with more than half receiving five or more previous lines of therapy.
Despite this difficult patient population with few remaining therapeutic options, the confirmed overall response rate (ORR) among patients in the dose expansion phase of this phase 1 study was 60%, or 21 of 35 patients, including 3% stringent complete response (CR), 6% CR, 43% very good partial response (VGPR), and 9% partial response (PR).2
While subgroup analyses largely showed no significant differences in response rate by age group, sex, ethnic group, or other variables, patients with previous daratumumab exposure appeared to have a lower response rate; of note, an emerging concept in the field of MM research is that patients who have daratumumab refractory disease may have particularly aggressive myeloma, according to Dr. Orlowski.
The phase 1 study also evaluated safety of belantamab mafodotin and found very few grade 3 and 4 toxicities, Dr. Orlowski added. Corneal events were common, though most were grade 1/2 and did not lead to discontinuation of treatment, while the most common grade 3/4 events were thrombocytopenia and anemia.2
Updated data from this phase 1 study were recently published, showing that patients are able to stay on belantamab mafodotin treatment for two or three years in some cases, Dr. Orlowski said. The reported data from the dose expansion phase include a median progression-free survival (PFS) of 12 months and a median duration of response of 14.3 months among these heavily pretreated patients, with no new safety signals. According to the report, 52% of patients had blurred vision, 37% had dry eyes, and 29% had photophobia.3
Other ADCs targeting BCMA may be coming to the clinic, according to Dr. Orlowski. Among these is HDP-101, a novel BCMA-targeted antibody conjugated to α-amanitin that has demonstrated activity in preclinical models of myeloma.4
AMG 420 is the first BiTE that has substantial data in myeloma. In a phase 1 trial including 42 patients with relapsed/refractory MM including at least two prior lines of therapy, this anti-BCMA BiTE was given as a continuous infusion over a 4-week period, followed by a 2-week break, for up to 5 cycles or longer.5
The median prior lines of therapy in this patient population was four, indicating that the patients were probably not quite as refractory as those in the previously described trial of belantamab mafodotin, said Dr. Orlowski. At the recommended dose of 400 mcg/day, responses were achieved in 7 of 10 patients (70%), including 5 minimal residual disease (MRD)-negative CRs, 1 VGPR, and 1 PR. Responses were rapid, with a median time to response of one month. The median duration of MRD-negative CR was 9.6 months.
Dose-limiting toxicities at an 800 mcg/day dose included one case of grade 3 cytokine release syndrome (CRS), a complication seen with both BiTEs and CAR T-cell therapies, and one case of grade 3 peripheral neuropathy. Overall, CRS was seen in 16 patients (38%), of which 13 were grade 1. Grade 2/3 infections were seen in 13 patients (31%) and there were 2 patients with peripheral neuropathy (5%).
BCMA-Directed CAR T-Cell Therapy
The first reported trial of CAR T-cells targeting BCMA in humans, by Ali and colleagues at the National Cancer Institute, included 12 patients treated at one of four dose levels.
Two patients with chemotherapy-resistant MM were treated at the fourth (highest) dose level of 9 x 106 CAR T-cells/kg body weight. Following CAR T-cell therapy, one patient experienced a stringent CR that lasted 17 weeks, while in the other patient, bone marrow plasma cells were not detectable on flow cytometry, and serum monoclonal
protein had decreased by more than 95%, with the patient in an ongoing VGPR at the time of the report.6
Subsequently, a phase 1 dose escalation study of the anti-BCMA CAR T-cell therapy bb2121 was conducted, with results recently published in the New England Journal of Medicine by Raje and co-authors.7 The 33 patients in this study were heavily pretreated, with a median of seven prior antimyeloma regimens, and nearly all (32, or 97%) had undergone autologous stem cell transplantation previously. The ORR was 85%, including CRs in 45%. Objective response rates of 91% to 100% were reported for patients in the higher dose cohorts of 450 x 106 and 800 x 106 CAR T-cells. Of 16 responding patients evaluable for MRD, all had achieved MRD-negative status. Many of the responses were durable, with a median PFS of 11.8 months reported in the study. Toxicities included CRS in about 70% of the patients, though most were grade 1/2, with only 2 (6%) reaching grade 3.
Another data set for targeting BCMA with CART-cells comes from the LEGEND-2 study of LCAR-B38M, a phase 1 study conducted at four sites in China.8 LCAR-B38M has two BCMA targeting domains, and therefore may theoretically have an advantage over a CAR T-cell therapy with one binding domain, according to Dr. Orlowski.
In the reported 57-patient experience with a 12-month follow-up, the median prior lines of therapy was three, likely reflecting the fact that some novel drugs used in the United States are not yet routinely available in China, Dr. Orlowski said. The median dose of LCAR-B38M was 0.5 x 106 cells/kg delivered in divided doses on days 1 (20%), 3 (30%), and 7 (50%).
The ORR was 88%, and the majority of responses were MRD-negative CRs. Responses were robust even at lower dosing levels, and even in patient with extramedullary disease. The PFS was 15 months, which he said was similar to or perhaps somewhat better than the 11.8 months seen in the aforementioned bb2121 trial, possibly because patients in LEGEND-2 were not as heavily pretreated. While CRS was seen in 51 patients (90%), only four cases (7%) reached grade 3.
The University of Pennsylvania experience with BCMA CART-cell therapy includes a phase 1 study of 25 MM subjects treated with a BCMA-specific CAR including CD3ζ and 4-1BB signaling domains. These were heavily pretreated patients, with a median of seven prior lines of therapy, and 96% had high-risk cytogenetics. The CAR T-cells were nevertheless clinically active in many cases, with responses seen in 12 patients, three of which were ongoing at 11, 14, and 32 months. Grade 3/4 CRS was reported in eight patients (32%), while three (12%) had grade 3/4 neurotoxicity.9
One other approach of interest is represented by P-BCMA-101, a CAR T-cell therapy produced using a system that in the future could allow for the targeting of more than one antigen (eg, CD38 or SLAMF7), according to Dr. Orlowski. In a phase 1 dose-escalation trial, tumor responses were seen in 43% to 100% of patients, depending on dose cohort, and CRS in 2 of 21 patients (9%), of which none reached grade 3 or higher.10 Other BCMA-targeted CAR T-cell therapies reported include bb21217, JCARH125, KITE-585, and MCARH171, among others.11
BCMA-Targeted Therapy in MM: Take-Home Messages
The BCMA-directed therapies in all three of the formats discussed have all shown strong activity in patients that generally have very advanced MM. These treatments provide unprecedentedly high rates of responses that are rapid and durable. Although some CRS is seen with the BiTE and CAR T-cell therapies, the severity generally appears to be lesser than in the lymphoma experience where CD19 is the target of therapy, according to Dr. Orlowski.
While the durability of response with BCMA-targeted therapy is better than with any other therapies in advanced patients, unfortunately no patients appear to be cured of their disease with current approaches. Further investigation and follow-up are required to evaluate the long-term effects of BCMA-directed therapies in MM. Beyond current strategies, future approaches may include the use of BCMA-targeting treatments earlier in the disease course; gamma secretase inhibition to increase BCMA expression, combination regimens with immunomodulatory agents or other treatments to reduce T-cell exhaustion, the targeting of more than one antigen simultaneously (eg, adding CD38 or SLAMF7), and the engineering of T-cells to optimize activity and persistence.
- Tai Y-T, Mayes PA, Acharya C, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128-3138. doi:10.1182/blood-2013-10-535088
- Trudel S, Lendvai N, Popat R, et al. Targeting B-Cell Maturation Antigen with GSK2857916 Antibody-Drug Conjugate in Relapsed or Refractory Multiple Myeloma: A Dose-Escalation and Expansion Phase 1 Trial (BMA117159). Lancet Oncol. 2018;19(12):1641-1653. doi:10.1016/S1470-2045(18)30576-X
- 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(4):37. doi:10.1038/s41408-019-0196-6
- Singh RK, Jones RJ, Hong S, et al. HDP101, a Novel B-Cell Maturation Antigen (BCMA)-Targeted Antibody Conjugated to α-Amanitin, Is Active Against Myeloma with Preferential Efficacy Against Pre-Clinical Models of Deletion 17p. Blood. 2018;132(Supplement 1):593-593. doi:10.1182/blood-2018-99-118412
- 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(15_suppl):8007-8007. doi:10.1200/JCO.2019.37.15_suppl.8007
- Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128(13):1688-1700. doi:10.1182/blood-2016-04-711903
- Raje N, Berdeja J, Lin Y, 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
- Zhao W-H, Liu J, Wang B-Y, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11(1):141. doi:10.1186/s13045-018-0681-6
- Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;130. doi:10.1172/JCI126397
- Gregory T, Cohen AD, Costello CL, et al. Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM). Blood. 2018;132(Supplement 1):1012-1012. doi:10.1182/blood-2018-99-111419
- Ghobrial I, Cruz CH, Garfall A, et al. Immunotherapy in Multiple Myeloma: Accelerating on the Path to the Patient. Clin Lymphoma Myeloma Leuk. 2019;19(6):332-344. doi:10.1016/j.clml.2019.02.004