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Investigators have turned their attention to B-cell maturation antigen, which offers an ideal target for multiple myeloma therapy because of its restricted expression pattern.
Despite several decades of groundbreaking new drug approvals spanning novel therapeutic classes, multiple myeloma remains an incurable malignancy for most patients. In an effort to address this need, investigators have turned their attention to B-cell maturation antigen (BCMA), which offers an ideal target for multiple myeloma therapy because of its restricted expression pattern.
Thus far, the leading strategy for exploiting BCMA in multiple myeloma has been with chimeric antigen receptor (CAR)-expressing T-cell immunotherapies similar to those that have generated excitement in leukemia and lymphoma. Remarkable responses have been achieved in early-stage clinical trials, and several companies anticipate regulatory filings in the coming year.
The enthusiasm is tempered by the inability of BCMA CAR T cells to achieve the same long-lasting effects as their CD19-targeted counterparts in leukemia and lymphoma in clinical trials to date. The search for explanations for this phenomenon has led to the development of novel CAR T-cell designs that, it is hoped, will overcome this challenge.
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Other enhanced antibody formats are in development, including AMG 420, a bispecific T-cell engager (BiTE), and several other types of bispecific antibodies (TABLE). Each of these drugs offers unique benefits and challenges, and together they could transform the multiple myeloma treatment paradigm as we move into a new decade.
An Ideal Target
The identification of cell-surface antigens with properties that make them ideal therapeutic targets, such as CD19 and CD20, has driven major advancements in the treatment of hematologic malignancies.1,2 BCMA has become one of these highly sought-after antigens for multiple myeloma, which is the second most common hematologic malignancy in the United States, expected to account for around 2% of all new cancer diagnoses in 2020.3,4
BCMA, also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a transmembrane receptor found almost exclusively on the surface of differentiated plasma cells, the antibody- producing effector cells of the adaptive immune response, and their precursors, plasmablasts. Key to its potential in multiple myeloma treatment, BCMA is highly expressed on the surface of the malignant plasma cells that characterize this cancer type.5-8
BCMA is 1 of 3 membrane receptors—the others are B-cell activating factor receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)—that facilitate the proliferation, survival, and maturation of B cells, as well as their differentiation into plasma cells, via the binding of 2 ligands, BAFF and a proliferation-inducing ligand (APRIL).5-8
Each of the 3 receptors acts at a different stage of B-cell development. BCMA is expressed at the later stages of B-cell maturation, after commitment to plasma cell differentiation. It is vital for the long-lasting survival of plasma cells but is dispensable for the health and homeostasis of B cells as a whole.5-7
Downstream of BCMA, the AKT, ERK1/2, and NFκB pathways become activated and drive upregulation of antiapoptotic proteins (Figure5). These prosurvival effects drive the overexpression of BCMA on multiple myeloma cells.6-8
The therapeutic potential of BCMA has long been recognized, but until recently it has largely been eclipsed by interest in development of drugs targeting other molecules, such as CD38 and SLAMF7, as well as proteasome inhibitors and immunomodulatory drugs (IMiDs).6,8 Although remarkable improvements in patient outcomes have been achieved with these therapies, the development of drug resistance ultimately leads to relapse in the vast majority of patients with multiple myeloma.9
CAR T-Cell Therapies
CARs are genetically engineered receptors designed to combine the antigen specificity of an antibody with the potent antitumor effects of cytotoxic T cells. CARs are introduced into a patient’s T cells, usually via a viral vector, outside the body; the resulting CAR T cells are infused back into the patient, where they specifically kill cells expressing the target antigen.10
The key to success with CAR T cells is the identification of an ideal target antigen. The recognition of BCMA as just such a protein in multiple myeloma led investigators at the National Institutes of Health to pursue testing of BCMA-targeted CAR T cells. They hoped to duplicate their success with CD19-targeted CAR T cells in other types of hematologic malignancy.
A first-in-human trial conducted in patients with relapsed/refractory, heavily pretreated multiple myeloma provided proof of concept. In 16 patients treated at the highest dose level of 9 × 106 CAR T cells/kg, the overall response rate (ORR) was 81%, with 63% of patients experiencing a very good partial response (VGPR) or complete response (CR).11,12
Celgene, which is now part of Bristol-Myers Squibb (BMS), is investigating various BCMA-targeted therapies, including idecabtagene vicleucel (ide-cel; bb2121), one of the most advanced in terms of development stage. The FDA granted the drug a breakthrough therapy designation in 2017.13
Preliminary results for the first 33 patients treated in a phase I trial (NCT02658929) of idecabtagene vicleucel were recently published. Patients with relapsed/refractory multiple myeloma who had received at least 3 prior lines of therapy, including a proteasome inhibitor and an IMiD, were treated with a single infusion of 50 to 800 × 106 (dose escalation) and 150 to 450 × 106 CAR T cells (dose expansion). The objective response rate was 85%, including a 45% CR rate, and the median progression-free survival (PFS) was 11.8 months. All responding patents who could be assessed for minimal residual disease (MRD) were MRD negative.
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Hot on the heels of this drug is LCARB38M (JNJ-4528; JNJ-68284528), a CAR T-cell therapy being jointly developed by Janssen Pharmaceuticals and a Chinese company, Legend Biotech, through a licensing agreement.15 LCAR-B38M has a novel design based on an unusual type of antibody found in llamas (and other members of the Camelidae family) that lacks light chains and is composed of 2 heavy chains.
Two llama-derived heavy-chain variable fragments (otherwise known as nanobodies), each targeting a different BCMA epitope, were linked to create LCAR-B38M. This design has several advantages over the single-chain variable fragment (scFv) format typical of CAR constructs, including double the number of antigen-binding regions, greater binding avidity, bispecificity, and smaller size.16,17
The phase I LEGEND-2 trial of LCAR-B38M (NCT03090659) was carried out at 4 different sites in China by 2 independent groups. The results were recently published, with separate reports for 2 patient groups: 57 patients treated at the main study site and 17 treated at the other sites.17,18
In the first report, the ORR was 88% using a 3-infusion delivery protocol. CRS was a common AE (90%), but only 8% of cases were grade ≥3. Neurotoxicity was observed in only 1 patient.17
The second report showed a similar ORR (88.2%), with 13 stringent CRs (sCRs) and 2 VGPRs; 8 responses were ongoing at 11 months after LCAR-B38M CAR T-cell infusion. Protocols delivering the CAR T cells in 1 infusion or splitting the same total dose into 3 infusions were compared in this study. No differences in efficacy or toxicity were observed, and the 1-infusion protocol showed advantages of significantly lower cost and greater convenience. The rate of CRS was 100%, with 41% of patients experiencing grade ≥3 CRS.18 A phase II study of LCAR-B38M, CARTIFAN-I (NCT03758417), is ongoing in China, as is the global phase I/II CARTITUDE-1 trial (NCT03548207).
Another CAR T-cell therapy being developed in China is CT053 (CARsgen Therapeutics). In a study presented at the 2018 Annual Meeting of the American Society of Hematology (2018 ASH), CT053 demonstrated an ORR of 100% among 13 evaluable patients. CRS occurred in 19% of patients, including one grade 3 case, and there was no neurotoxicity.19
The results from a single-arm, open-label, 3-site, phase I trial (NCT03716856, NCT03302403, and NCT03380039) evaluating CT053 were also recently reported. A total of 24 consecutive patients enrolled across the 3 studies were treated with 1.5 × 108 CT053 CAR T cells; the exceptions were 3 patients who received 0.5 × 108, 1 × 108, or 1.8 × 108 cells. The objective response rate was 87.5%, including a CR rate of 70.8%. CRS occurred in 62.5% of patients, all grade 1 or 2. Three patients experienced neurotoxicity, which was grade 3 and reversible in only 1 patient.20
Results from ongoing phase I clinical trials of 2 other CAR T-cell therapies, JCARH125 (orva-cel; orvacabtagene autoleucel) and FCARH143, were also presented at 2018 ASH. The only difference between these 2 therapies is that during the FCARH143 manufacturing process, CD4-positive and CD8-positive cells are maintained in separate cultures and then mixed in a 1:1 ratio prior to infusion. When a dose of 150 × 106 cells was administered, JCARH125 demonstrated an objective response rate of 82%; at a lower dose of 50 × 106 cells, the rate was 79%. Data for 7 FCARH143-treated patients showed an ORR of 100%. As with other BCMA CAR T-cell therapies, CRS occurred at a high rate in both trials but was predominantly low grade. The rate of neurologic toxicity was 25% (grade ≥3, 7%) for JCARH125 and absent for FCARTH143.21-23
The Challenge of Durability
Despite promising efficacy and safety, concerns remain about the durability of BCMA CAR T-cell therapy. Clinical experience to date suggests that, even among patients who demonstrate the best responses, the effects are not as long-lasting as those of CD19-targeted CAR T cells. In the phase I trial of idecabtagene vicleucel, for example, the median time to progression was just under a year.14
Investigators are working to better understand the underlying reasons for relapse. In the majority of cases, multiple myeloma cells continue to express BCMA after relapse, although BCMA-negative relapses have also been reported. For example, in the phase I study of FCARH143, a tumor biopsy taken from a patient who had relapsed at the time of publication contained a BCMA-negative plasma cell population. The biopsy also revealed a 70% reduction in the number of multiple myeloma cells expressing BCMA and a 5-fold reduction in the BCMA antigen binding capacity of the multiple myeloma cells that still expressed BCMA.21,22
BCMA CAR T-cell efficacy may be limited by gamma secretase—mediated cleavage of cell-surface BCMA to a soluble form that could act as a decoy receptor, preventing the ability of CAR T cells to target tumor cells.24 Juno Therapeutics, also part of BMS, is testing its CAR T-cell therapy alongside a gamma secretase inhibitor, JSMD194, to help reduce soluble BCMA and increase target membranebound BCMA levels. Initial data from 6 heavily pretreated patients (including 2 who had received previous BCMA-targeted therapy) demonstrated an ORR of 100%, including 5 VGPRs and 1 PR, and 5 of the patients were MRD negative. CRS occurred in all patients but was predominantly grade 1 or 2, and neurotoxicity occurred in 70% of patients.25
In terms of durability, studies have suggested that specific subsets of T cells contained within the CAR T-cell population may be particularly important for ensuring the in vivo expansion and persistence of the CAR T cells. Naïve T cells, stem memory T cells, and central memory T cells have been shown to have the best proliferation potential, and the percentage of CD8-positive T cells with a naïve or stem memory phenotype at the time of leukapheresis is associated with improved outcomes.21,26,27
P-BCMA-101 is a novel CAR T-cell therapy that uses a Centyrin, a proprietary molecule, rather than an scFv. Centyrins are scaffold proteins based on a fibronectin domain that have high specificity and high binding affinities but are smaller, more stable, and potentially less immunogenic than scFvs.28 P-BCMA-101 also uses a nonviral system to transfect the CAR into the patient’s T cells. Both of these factors are designed to result in higher levels of stem memory T cells in the CAR T-cell population in an effort to boost persistence.
Preliminary results from a phase I trial of P-BCMA-101 were presented at 2018 ASH. The investigators reported an objective response rate of 63% among the 19 patients evaluable for response, with a low rate of CRS (9.5%). Poseida Therapeutics expects to file a biologics license application for P-BCMA-101 in 2020.29 Its fiercest competitor, Celgene/bluebird bio, is developing bb21217, a CAR T-cell therapy generated by culturing idecabtagene vicleucel with a PI3K inhibitor, which is designed to increase the proportion of memory- like T cells in the final product.30
Many patients who relapse have BCMApositive multiple myeloma cells and detectable circulating BCMA CAR T cells, suggesting that the problem is not loss of target antigen or CAR T-cell durability in those instances but possibly another factor, such as the effects of an immunosuppressive microenvironment.21,26
Although it can be an incredibly powerful approach, CAR T-cell therapy has the disadvantage of needing to be customized to each patient, which is expensive and time-consuming. Several off-the-shelf strategies are also being developed in the BCMA sphere. These include ADCs, recombinant antibodies that are covalently bound to cytotoxic drugs (known as a payload) to facilitate their targeted release within tumor cells.
The lead ADC candidate is belantamab mafodotin, which received breakthrough therapy designation in 2017.31 It is a humanized BCMA-targeted antibody conjugated to monomethyl auristatin F, a microtubule-disrupting agent.32 Encouraging updated phase I trial results were recently reported; among 35 heavily pretreated patients with relapsed/ refractory disease, the ORR was 60% and median PFS was 12 months. The most common AEs were corneal events, thrombocytopenia, and anemia.32,33 A pivotal trial is ongoing, and the company is expected to file for regulatory approval upon its completion toward the end of 2020.6
Bispecific antibodies are also in development, including BiTEs, which target a tumor-associated antigen (such as BCMA) on cancer cells and the CD3 protein on the surface of T cells. This design brings cytotoxic immune cells and tumor cells within close proximity so that an immunological synapse can form to facilitate immune-directed tumor cell killing.
The leader of this pack is AMG 420 (Amgen), which is being evaluated in an ongoing phase I clinical trial (NCT03836053). According to the most recent update, 42 patients have been treated at dosages of 0.2 to 800 mcg/day. For the entire cohort, the ORR was 30.9%, including 6 sCRs, 3 CRs, 2 VGPRs, and 2 PRs. Among 10 patients who received 400 mcg/day (the recommended dose for future studies), the ORR was 70%, including 5 MRD-negative sCRs, 1 VGPR, and 1 PR, with some responses lasting more than a year.34
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Gainesville, Florida.
Two of the most common and potentially fatal adverse events (AEs) associated with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity. CRS occurred in 76% of patients in this trial but was grade 1 or 2 in 92%, and neurologic events, also almost exclusively low grade, occurred in 42% of patients.14 Two phase II trials, KarMMa (NCT03361748) and KarMMa-2 (NCT03601078), are ongoing, as is the phase III KarMMa-3 (NCT03651128) trial comparing idecabtagene vicleucel with standard triplet therapy, which is expected to enroll 381 patients.
Meanwhile, other types of BCMA-targeted therapies are also entering the field. The front-runner, belantamab mafodotin (GSK2857916), is an antibody-drug conjugate (ADC) that exploits BCMA expression on multiple myeloma cells to target delivery of a cytotoxic payload. In January, the FDA agreed to a priority review of the biologics license application for the firstin- class drug as a treatment for relapsed/ refractory myeloma.