In multiple myeloma, B-cell maturation antigen emerges as promising target

This is a Cortellis Market Insight report, an ongoing series featuring expert reviews of hot topics in the biopharma field, with analysis and discussion on the factors currently affecting the industry. Data leveraged for this analysis were gathered from Cortellis from Clarivate Analytics.

There remains an unmet need for patients with multiple myeloma (MM), particularly in the later-line settings, despite several new treatments and improved outcomes. Agents targeting the B-cell maturation antigen (BCMA) marker, which is highly specific for MM, could play a significant role in both relapsed/remitting MM (RRMM) and also earlier disease settings. An analysis of Cortellis Competitive Intelligence identifies several emerging BCMA-targeting agents. Regulatory filings for one BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy and one antibody drug conjugate (ADC) are expected this year, with blockbuster sales forecast for the former.

MM is the second most common hematological cancer. Prevalence is increasing due to better diagnosis, an aging population and newer treatment options improving patient survival. Stem cell transplant plus high-dose chemotherapy is a first-line treatment option in younger and otherwise healthy MM patients. However, drug-based therapies are required in around 70% of patients not eligible for stem cell transplant.


Current approaches to treatment

The mainstays of treatment are immumomodulatory drugs and proteasome inhibitors, led by Revlimid and Velcade, and including Kyprolis, Ninlaro and Pomalyst. Along with the addition of first-in-class monoclonal antibodies Darzalex and Empliciti, Cortellis data show that these treatments achieved combined sales of $15.7 billion in 2017, with sales forecast to top $20 billion by 2020 (Source: Refinitiv I/B/E/S). However, while these agents have significantly improved patient outcomes, MM remains incurable. The majority of patients relapse after multiple lines of therapy and there is a need for innovation and novel targets and therapies.


The majority of MM patients relapse and there is a need for innovation and novel targets and therapies.”


BCMA is one such promising novel target. According to an analysis of Cortellis data, there are currently more than 60 active R&D programs targeting BCMA. The majority of these novel BCMA agents are CAR T-cell therapies, followed by bispecific T-cell engager (BiTE) drugs and other antibody-based therapies targeting BCMA, including ADCs. Other therapeutic approaches include bi/trispecific antibodies targeting BCMA and other immune cells such as natural killer cells (See Figure 1a). Cortellis shows that almost half the agents have not yet entered clinical trials, while just over one third are in phase 1 clinical development and the rest are in phase 1/2 and phase 2 development (See Figure 1b).


Figure 1: Anti-BCMA therapies in development by therapy type (a) and development phase (b). Source: Cortellis Competitive Intelligence


bluebird bio/Celgene’s CAR T-cell therapy bb-2121 and GlaxoSmithKline (GSK)’s ADC GSK-2857916 are the most advanced agents targeting BCMA. bb-2121 uses the personalized immunotherapy approach where a patient’s T cells are engineered ex vivo to express a CAR specific for BCMA so as to target MM cells (See Figure 2).

Figure 2: CAR T-cell therapy approach. a) Although cancer cells express potential targets on their surface, T cells cannot recognize them and thus do not attack. b) Adding CARs onto the T cell enables the T cell to recognize the cancer cell by the targets on its surface and thus attack and destroy it. Source: Cortellis.


GSK-2857916 is a humanized anti-BCMA antibody conjugated to a microtubule disrupting agent, which upon binding to BCMA is rapidly internalized to release the cytotoxic payload. The therapy is additionally modified to enhance antibody-dependent cell-mediated cytotoxicity.

Both bb-2121 and GSK-2857916 have shown impressive data in early studies, with objective response rates of up to 100% for bb-2121 and 60% for GSK-2857916 in heavily pre-treated MM patients. The therapies are in broad development programs, including the registration-enabling phase II KarMMa trial for bb-2121 in third- and later-line RRMM, and the pivotal phase II DREAMM-2 study for GSK-2857916 in fourth-line monotherapy treatment. Data from these studies are expected in 2019, followed by filings later that year. According to Cortellis Analytics – Drug Timeline & Success Rates (DTSR), the probability of U.S. approval of bb-2121 is 84%, with approval forecast for December 2020. Blockbuster sales of $1.031 billion are forecast for 2024 for bb-2121, while sales of $450 million are forecast that year for GSK-2857916.


Awaiting later-stage data for BiTE drugs, ADCs and CAR T-cell therapies

Other approaches to targeting BCMA for MM are being pursued, notably several BiTE drugs. These bispecific antibodies bind targets on both immune cells (mainly CD3 on T cells) and cancer cells (BCMA on MM cells) to enhance tumor cell killing. Amgen’s AMG-420 was the first CD3-binding BCMA-targeted BiTE to enter clinical development and has shown promising early data. Table 1 lists several of the emerging BCMA-targeting agents as identified by Cortellis.


Drug name Company Type of therapy Phase
bb-2121 bluebird bio/Celgene CAR T-cell Pivotal phase II*
P-BCMA-101 Poseida Therapeutics CAR T-cell Phase I
LCAR-B38M Nanjing Legend Biotech/Janssen Biotech CAR T-cell Phase I/II
KITE-585 Kite Pharma /Gilead Sciences CAR T-cell Phase I
JCARH-125 Juno Therapeutics/Celgene CAR T-cell Phase I/II
GSK-2857916 GlaxoSmithKline ADC Pivotal phase II*
HDP-101-ATAC Heidelberg Pharma ADC Phase I to start in 2019
MEDI-2228 MedImmune ADC Phase I
AMG-420 Amgen BiTE Phase I
PF-06863135 Pfizer BiTE Phase I
REGN-5458 Regeneron Pharmaceuticals/Sanofi BiTE Phase I/II
JNJ-64007957 Janssen Research & Development BiTE Phase I
AFM-26 Affimed BiTE Pre-IND

Table 1: Selection of BCMA-targeting therapies in the pipeline. * Filings expected in 2019. Source: Cortellis Competitive Intelligence.


ADCs such as GSK-2857916 have potential advantages versus CAR T-cell approaches, including better scale-up for commercial sale, and the lack of the complex manufacturing/ treatment regimens required for CAR T-cell products. However, the tremendous progress in cellular engineering and the increasing confidence in CAR T-cell therapies, their one-shot administration and the impressive efficacy data as seen with bb-2121, suggest this approach will have significant impact. Later-stage data from all BCMA-targeting agents in development are awaited, and any effective anti-BCMA agent offers promise for patients with MM.

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