BCMA as a Target of Therapy in Multiple Myeloma: Rapidly Emerging Opportunities

Newsletters published on March 23, 2020
Nikhil C. Munshi, MD
Professor of Medicine
Harvard Medical School
Associate Professor, Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
BCMA as a Target of Therapy in Multiple Myeloma: Rapidly Emerging Opportunities

In this newsletter, Dr. Munshi explains why B-cell maturation antigen (BCMA) has become increasingly important as a target of therapy in multiple myeloma, focusing on the unmet need for novel treatments, the rationale for targeting BCMA, and early promising results for BCMA-directed therapeutic strategies. The newsletter contents were adapted from Dr. Munshi’s presentation at the independent satellite symposium entitled, “Targeting B-cell Maturation Antigen in Relapsed/Refractory Multiple Myeloma: New Findings in Clinical Context,” which was presented on September 6, 2019 to a live audience during the ASH Meeting on Hematologic Malignancies in Chicago, Illinois, and is now available online as an enduring activity. To view updates made at the 2019 ASH Annual Meeting, view our Meeting Highlights here.

This is the first in a series of three newsletters based on proceedings from this activity. In subsequent newsletters, Robert Z. Orlowski, MD, PhD, will discuss key efficacy results from clinical trials of BCMA-targeted approaches, and Nina Shah, MD, will discuss the safety of BCMA-directed therapy.

The bench-to-bedside translation of novel agents into clinical care has transformed the treatment of multiple myeloma (MM), with at least 20 novel agents having been approved over the past 20 years. The availability of multiple effective therapies has translated into very high rates of overall response and complete remission, along with a 3- to 4-fold improvement in overall survival (OS), from a median of perhaps 3 years in the era before novel agents, to a median of 8 to 10 years more recently.1

Unfortunately, myeloma remains incurable, and the majority of patients will ultimately relapse due to the presence of residual disease. Numerous options are available for the treatment of relapsed or refractory multiple myeloma, including the proteasome inhibitors bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs that include thalidomide, lenalidomide, and pomalidomide; the histone deacetylase inhibitor panobinostat; monoclonal antibodies daratumumab and elotuzumab; the alkylating agent bendamustine; and very recently, the exportin inhibitor selinexor, along with older agents such as dexamethasone, cyclophosphamide, melphalan, and anthracyclines, along with many more under investigation. These drugs can be given in two-, three-, and four-drug combinations, and to some extent, treatment for relapsed MM can be refined through consideration of factors such as pre-existing conditions including neuropathy or cardiovascular disease, response to treatment in the first line, and patient preferences.

However, there remains an unmet need for well-tolerated treatments that can deepen responses versus simply sustaining an existing response, given that deeper responses, eg, stringent complete responses and minimal residual disease (MRD) negativity, correlate with prolonged progression-free survival (PFS) and perhaps longer overall survival (OS).2,3 Moreover, survival outcomes become compromised with successive lines of therapy, with data now available to demonstrate lower response rates, and shorter durations of disease control duration with each successive treatment regimen, reflecting the progressive development of drug resistance in these patients.4,5

BCMA in MM: Rationale

In the search for promising new targets of therapy, investigators identified B-cell maturation antigen (BCMA), a transmembrane glycoprotein that is a member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17).6 The expression of BCMA is nearly universal on MM cells, and largely restricted to plasma cells and some mature B cells. Two natural ligands of BCMA are a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF). In MM, activation of BCMA via pathways results in upregulation of anti-apoptotic proteins, as well as upregulation of genes linked to activation of angiogenesis and metastasis, adhesion, and osteoclasts, which ultimately lead to myeloma cell growth and survival.7

Serum BCMA (sBCMA) levels, which are increased in patients with monoclonal gammopathies as compared to healthy donors, have been proposed as a potential new biomarker to manage patients with MM. In particular, Ghermezi and colleagues demonstrated that in MM patients, sBCMA levels above the median predicted a substantially shorter PFS (3.6 months, versus 9.0 months below the median; P=.0004), and shorter OS (98 versus 155 months; P=.0108). Moreover, baseline sBCMA levels have been shown to predict response to treatment. Changes in sBCMA are associated with changes in other myeloma tumor markers, and are independent of renal function.8,9

BCMA-Directed Treatment Strategies

There are now multiple immunotherapy-based strategies for targeting BCMA in various stages of investigation in MM trials. These include the development of antibody-drug conjugate (ADC) directed against BCMA, the anti-BCMA bispecific T-cell engager (BiTE) antibody approach, chimeric antigen receptor (CAR) T-cell therapy that targets BCMA, and the use of BCMA peptide-based immunotherapy, as described in further detail below.

ADCs generally consist of monoclonal antibodies bound to a payload of cytotoxic chemicals that, once the ADC is bound to a surface antigen and absorbed, are released and kill the tumor cells. The first anti-BCMA ADC to be investigated, belantamab mafodotin (previously referred to as GSK2857916), consists of a humanized IgG1 monoclonal antibody with a non-cleavable linker and the microtubule-disrupting agent monomethyl auristatin F (MMAF) as a payload. Belantamab mafodotin induces strong anti-MM effects via multiple mechanisms of action with minimal impact on BCMA-negative normal cells. This anti-BCMA ADC was shown in two murine models to rapidly eliminate MM cells, and in mice, it was shown to significantly prolong survival, and its cytotoxicity is enhanced when combined with lenalidomide.7,10

In a phase 1, first in human, open-label study, belantamab mafodotin showed encouraging single-agent activity, with an overall response rate ( ORR) of 60% that included deep responses (51% ≥ very good partial response [VGPR]) and durable responses in heavily pre-treated patients with relapsed/refractory MM. The safety profile was manageable, with the most commonly reported adverse events being thrombocytopenia or decreased platelet count and corneal events that were low grade. These encouraging results support further study of this ADC approach, including a phase 3 study that was discussed at the symposium and will be described in an upcoming newsletter.11

By contrast, BiTEs are composed of two linked antibodies, one of which targets CD3 on the surface of T-cells, and the other of which targets a tumor-specific antigen. AMG 420 (formerly BI 836909) is a novel BCMA/CD3 BiTE being developed for the treatment of MM. induces selective lysis in vitro and in vivo. Preclinical investigations demonstrated that AMG 420 selectively induced lysis of BCMA-expressing MM cells without affecting BCMA-negative cells, while stimulating cytokine release and proliferation of T-cells; moreover, this agent prolonged survival in a mouse xenograft model.12

In a first-in-human, phase 1 dose escalation study, AMG 420 had a maximum tolerated dose of 400 mcg/d, with dose-limiting toxicities of cytokine release syndrome and polyneuropathy observed at 800 mcg/d; clinical activity was encouraging in patients with heavily pretreated MM, including responses observed in 13 of 42 patients overall, and 7 of 10 patients (70%) treated with the 400 mcg/d dose that was recommended for further investigation.13

The CAR T-cell approach has proven successful in certain leukemias and lymphomas as a strategy to exploit native antibody or T-cell recognition and signaling pathways; the introduction of unique genes through viral vectors allows recognition of tumor cells, resulting in dramatic post-infusion expansion of CAR T-cells and effective tumor cell killing. There are now multiple BCMA-directed CAR T-cell studies throughout the world, primarily in the United States and China, which have very similarly shown significant, rapid activity with high rates of response characteristic toxicities that include cytokine release syndrome and neurotoxicity.14-17 Of note, very low-level BCMA expression appears to be sufficient to trigger the killing activity, as suggested by one study in which the CAR T-cell therapy bb2121 recognized tumor cells expressing as few as 222 BCMA molecules per cell.18

One final approach of interest is represented by the development of a targeted MM cancer vaccine and antigen-specific T-cell immunotherapy. Specifically, investigators have identified HLA-A2-specific BCMA peptides, native and engineered, that induce BCMA antigen-specific CD8+ cytotoxic T lymphocytes (CTLs). In preclinical investigations, engineered BCMA72-80 peptide-specific CTLs induced robust cytolytic activities in response to MM tumor cells. According to investigators, this immunogenic BCMA peptide will be used in clinical vaccine or adoptive T-cell immunotherapy protocols.19

References

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  3. Mewawalla P, Chilkulwar A. Maintenance therapy in multiple myeloma. Ther Adv Hematol. 2017;8(2):71-79. doi:10.1177/2040620716677244
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  9. Sanchez E, Gillespie A, Tang G, et al. Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma. Clin Cancer Res. 2016;22(13):3383-3397. doi:10.1158/1078-0432.CCR-15-2224
  10. 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
  11. Trudel S, Lendvai N, Popat R, et al. Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159. Blood. 2017;130(Supplement 1):741-741. doi:10.1182/blood.V130.Suppl_1.741.741
  12. Hipp S, Tai Y-T, Blanset D, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31(8):1743-1751. doi:10.1038/leu.2016.388
  13. 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
  14. Brudno J, Lam N, Wang M, et al. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor with a CD28 Costimulatory Moiety Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. Blood. 2017;130(Supplement 1):524-524. doi:10.1182/blood.V130.Suppl_1.524.524
  15. 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
  16. Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results. J Clin Oncol. 2017;35(15_suppl):3010-3010. doi:10.1200/JCO.2017.35.15_suppl.3010
  17. 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
  18. Friedman KM, Garrett TE, Evans JW, et al. Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells. Hum Gene Ther. 2018;29(5):585-601. doi:10.1089/hum.2018.001
  19. Bae J, Hideshima T, Tai Y-T, Munshi N, Anderson K. Abstract B100: Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides. Cancer Immunol Res. 2019;7(2 Supplement):B100-B100. doi:10.1158/2326-6074.CRICIMTEATIAACR18-B100
Last modified: March 23, 2020