GSK's Blenrep Becomes First BCMA-Targeted Therapy Approved in the EU for Relapsed/Refractory Multiple Myeloma

GlaxoSmithKline (GSK) recently announced that the European Commission (EC) has granted conditional approval for Blenrep (belantamab mafodotin, GSK2857916), an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). The approved indication is as a monotherapy for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38 monoclonal antibody, and who demonstrated disease progression on their last therapy.

In early August this year, Blenrep received accelerated approval from the U.S. FDA through the Priority Review program, for the same indication as mentioned above. The approval of this indication was granted under the Accelerated Approval pathway based on tumor response rate data. Continued approval for this indication will depend on the verification and description of clinical benefit in confirmatory trials.

Notably, Blenrep is the first BCMA-targeted therapy approved globally. This first-in-class humanized anti-BCMA therapy is indicated for patients whose disease has progressed despite receiving current standard of care. Blenrep targets BCMA through a multifaceted mechanism of action. BCMA is a cell surface protein that plays a critical role in plasma cell survival and is expressed on multiple myeloma cells.

Despite advances in clinical treatment, multiple myeloma (MM) remains an incurable and devastating disease, with patients continuing to face cycles of therapy, each relapse leading to a worsening prognosis.

Blenrep is the first globally approved anti-BCMA therapy, featuring a novel mechanism of action and representing a new treatment option. It can be utilized when patients cease to respond to other standard therapies, with the potential to transform clinical management for patients with relapsed or refractory multiple myeloma who have limited treatment options. In the United States and the European Union, Blenrep was granted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) status, respectively, making it the first BCMA-targeted agent to receive both BTD and PRIME designations.

Dr. Hal Barron, Chief Scientific Officer and President of Research and Development at GlaxoSmithKline, stated: “The approval of Blenrep marks an important step forward for patients in Europe, where nearly 50,000 cases of multiple myeloma are diagnosed each year. Unfortunately, the majority of these patients will relapse or stop responding to existing therapies, so I am pleased that today’s news will enable patients with limited treatment options to access the first approved anti-BCMA therapy.”

This approval is based on data from the pivotal DREAMM-2 study, including 13 months of follow-up data. This was a randomized, open-label, two-arm Phase II study that enrolled a total of 196 heavily pretreated patients with relapsed/refractory multiple myeloma (R/R MM). These patients experienced disease progression despite current standard therapy, had received a median of 7 prior lines of therapy, were refractory to immunomodulatory drugs and proteasome inhibitors, and were refractory and/or intolerant to anti-CD38 antibodies. In the study, patients were randomized into two groups to receive Blenrep at a dose of 2.5 mg/kg or 3.4 mg/kg once every three weeks (Q3W).

Study data showed that the overall response rate (ORR) for Blenrep monotherapy at 2.5 mg/kg every three weeks (Q3W) was 32%, with a median duration of response (DoR) of 11 months and a median overall survival (OS) of 13.7 months. The safety and tolerability profile was consistent with previously reported data for Blenrep. The most common adverse reactions (≥20%) observed in the 2.5 mg/kg group were keratopathy/microcyst-like epithelial changes (MEC; 71%), thrombocytopenia (38%), anemia (27%), blurred vision events (25%), nausea (25%), pyrexia (23%), elevated aspartate aminotransferase (AST; 21%), infusion-related reactions (21%), and lymphopenia (20%).

For patients with relapsed/refractory multiple myeloma (R/R MM) whose disease continues to progress despite receiving currently available standard-of-care therapies, treatment options are very limited and the prognosis is poor. The latest follow-up results from the DREAMM-2 study further demonstrate the potential of Blenrep. Its approval and market launch will provide an important new treatment option for these patients, helping to address a significant unmet medical need.

Mechanism of Action of Belantamab Mafodotin

The DREAMM clinical development program comprises 10 clinical studies (DREAMM-1 to DREAMM-10), which are evaluating the efficacy and safety of Blenrep as a monotherapy and in combination regimens for first-line, second-line, and later-line treatment of multiple myeloma (MM). Previously reported updated data from DREAMM-1, the first-in-human clinical study, demonstrated that Blenrep achieved an overall response rate (ORR) of 60% in patients with BCMA-positive relapsed/refractory multiple myeloma (R/R MM).

At the American Society of Clinical Oncology (ASCO) Annual Meeting held in late May this year, GSK also presented data from the DREAMM-6 study. This study evaluated the efficacy and safety of Blenrep (2.5 mg/kg, Q3W) in combination with bortezomib/dexamethasone (BorDex) in patients with relapsed/refractory multiple myeloma (R/R MM) who were refractory to or had relapsed after one or more prior therapies.

Preliminary results showed that the overall response rate (ORR) for Blenrep combined with BorDex (B-Vd) treatment reached 78% (n=14/18; 95% CI: 52.4-93.6), with 50% achieving a very good partial response (VGPR) and 28% achieving a partial response (PR). The proportion of patients who achieved clinical benefit (minimal response or better) was 83% (95% CI: 58.6-96.4). At a median treatment duration of 18.2 weeks, the median duration of response (DoR) had not yet been reached. Grade 3 or higher adverse events included microcystic epithelial changes (MEC; 56%) and thrombocytopenia (61%). There were no cases of grade 4 MEC. These preliminary results confirm the potential of Blenrep combination therapy in early-stage multiple myeloma patients.

BCMA-Targeted Investigational Immunotherapies for Multiple Myeloma (Source: PMID: 31277554)

Multiple Myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin lymphoma. In recent years, despite significant advances in chemotherapy, proteasome inhibitors, immunomodulatory thalidomide derivatives, and CD38-targeted antibodies, nearly all patients eventually experience relapse. Therefore, there is an urgent need for new therapeutic regimens. The MM market was valued at nearly $14 billion in 2017 and is projected to reach approximately $29 billion by 2027.

BCMA is an extremely important B-cell biomarker, widely expressed on the surface of multiple myeloma (MM) cells, and has become a highly prominent immunotherapy target for MM and other hematologic malignancies in recent years. Currently, more than 20 immunotherapies targeting BCMA are under development, primarily categorized into three classes: chimeric antigen receptor T-cell therapy (CAR-T, represented by Bristol Myers Squibb/Bluebird Bio and Novartis), bispecific antibodies (BsAb, represented by Amgen), and antibody-drug conjugates (ADC, represented by GSK).

Blenrep is an antibody-drug conjugate (ADC) composed of a novel humanized, Fc-engineered anti-BCMA monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F (MMAF) via a non-cleavable linker (drug-linker technology licensed from Seattle Genetics). Blenrep binds to BCMA on the surface of multiple myeloma (MM) cells through its anti-BCMA antibody component, is rapidly internalized by MM cells, degraded in lysosomes, and releases non-permeable MMAF intracellularly to exert its therapeutic effect. MMAF is a mitotic inhibitor and an anti-tubulin agent that suppresses cell division by blocking microtubule polymerization, arresting tumor cells in the G2/M phase and inducing caspase-3-dependent apoptosis. Furthermore, Blenrep induces natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP).

Blenrep selectively targets multiple myeloma (MM) cells through multiple cytotoxic mechanisms, offering a highly promising next-generation immunotherapy option for this type of cancer. Currently, Blenrep is also being developed for patients with other advanced hematologic malignancies expressing BCMA. (Bioon.com)

Original Source: European Commission approves BLENREP (belantamab mafodotin) for the treatment of patients with relapsed and refractory multiple myeloma