Multiple myeloma is the third most common blood cancer and is generally considered treatable, but not curable. Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments. This results in a major unmet medical need. [1][2]

At the virtual 2020 annual meeting of the American Society of Clinical Oncology (ASCO), investigators from GlaxoSmithKline (GSK) presented the latest updated data from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) clinical program for Belantamab Mafodotin.

The presented results highlighted the potential of a novel, investigational anti-BCMA agent against B-cell maturation antigen, belantamab mafodotin, for the treatment of patients with relapsed/refractory multiple myeloma both as a monotherapy and in combination therapies.

Structure of conjugate of monomethyl auristatin F MMAF with a monoclonal antibody. In International Nonproprietary Names (INN) for an MMAF-antibody-conjugates, such as belantamab mafodotin, the name mafodotin refers to MMAF plus its attachment structure to the antibody. The attachment group consists of maleimide and caproic acid.

Belantamab mafodotin is an investigational antibody-drug conjugate or ADC. The drug includes a humanized anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin F (MMAF) via a non-cleavable linker.*[3]

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The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival. BCMA expression is limited to B cells at later stages of development and expressed at varying levels in myeloma patients. BCMA membrane expression is universally detected in myeloma cell lines.[4]

DREAMM-2
In the 13-month follow-up data from the DREAMM-2 study (abstract #8536), treatment with single-agent belantamab mafodotin, administered as a 2.5 mg/kg dose every three weeks (Q3W), showed a median duration of response (DoR) of 11 months (95% CI, 4.2–not reached) and median overall survival (OS) of 14.9 months (95% CI, 9.9–not reached) in a heavily pre-treated patient population who received a median of seven prior lines of treatment and were refractory to an immunomodulatory drug, a proteasome inhibitor and an anti-CD38 antibody.[4]

The overall response rate (ORR) was consistent with the six-month data at 32% (31 out of 97 patients). Of these patients, the majority (58%) had a very good partial response or greater, including two stringent complete responses and five complete responses. The proportion of patients achieving clinical benefit (minimal response or better) was 36% (95% CI, 26.6–46.5).

“The updated results from the DREAMM-2 study… demonstrate the potential of belantamab mafodotin to help address a significant unmet need for patients whose multiple myeloma continues to progress despite available treatment options,” noted Axel Hoos, M.D, Ph.D.,  Senior Vice President and Head of Oncology R&D, GSK.

“We are encouraged by these data as we work to bring belantamab mafodotin to patients suffering from this aggressive disease,” he added.

With a longer follow-up of the trial, the investigators did not identify new safety signals with belantamab mafodotin.

Adverse events
The most commonly reported grade 3 or higher adverse events (occurring in more than 10% of patients) in patients receiving the 2.5 mg/kg dose were keratopathy/microcyst-like epithelial changes (MECs) (46%), thrombocytopenia (22%), anaemia (21%), lymphocyte count decreased (13%) and neutropenia (11%). The first event of keratopathy (MECs) – characterized as changes in the corneal epithelium as seen on eye examination which can manifest with or without symptoms – had resolved in 77% of patients in the 2.5 mg/kg arm at the time of data cut-off and no permanent loss of vision has been reported to date.

“Despite our best efforts, a significant number of patients will relapse following treatment with an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 antibody. For this reason, we need novel therapies that not only induce responses, but maintain them as long as possible,” explained Sagar Lonial, M.D., Chief Medical Officer of the Winship Cancer Institute of Emory University and principal investigator of the DREAMM-2 study.

“These latest results from DREAMM-2 continue to reinforce that belantamab mafodotin has the potential to be an important treatment option for patients whose disease continues to progress despite currently available therapies,” Lonial added.

Biologics License Application
The DREAMM-2 study serves as the basis for the belantamab mafodotin Biologics License Application and Marketing Authorisation Application, which are currently under review by the US Food and Drug Administration and European Medicines Agency, respectively.

DREAMM-6
Initial study-results from another trial  – the DREAMM-6 study (abstract #8502) with belantamab mafodotin confirmed clinical benefit.

The DREAMM-6 study examines belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) in patients whose disease has become refractory or relapsed after one or more prior lines of treatment. In this analysis, belantamab mafodotin 2.5 mg/kg Q3W plus BorDex (B-Vd) resulted in an ORR of 78% (14 out of 18 patients), with 50% achieving a very good partial response and 28% achieving a partial response (95% CI, 52.4–93.6). The proportion of patients achieving clinical benefit (minimal response or better) was 83% (95% CI 58.6–96.4). The median DoR has not yet been reached at a median of 18.2 weeks on treatment.

Grade 3 or greater adverse events included keratopathy (MECs) (56%) and thrombocytopenia (61%). There were no cases of grade 4 keratopathy (MECs).

“We are encouraged by these initial results from the DREAMM-6 study showing the potential of combination therapy with belantamab mafodotin in patients with earlier stages of multiple myeloma and look forward to sharing the full data once it is available,” Hoos concluded.

*The drug linker technology used in belantamab mafodotin is licensed from Seattle Genetics and the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa.

References
[1] Estimated number of incident cases worldwide, both sexes, all ages. World Health Organization. Online. Last accessed on May 29, 2020
[2 Nooka A, Kastritis E, Dimopoulos M, Lonial S. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20):3085-3099. doi:10.1182/blood-2014-11-568923.
[4] NCI Drug Dictionary – Anti-BCMA Antibody-Drug Conjugate GSK2857916. National Cancer Institute. Online. Last accessed on May 29, 2020.
[3] 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 Journal. 2019;9(4). doi:10.1038/s41408-019-0196-6.