Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Noopur Raje, MD, has disclosed that she has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda.
In recent years, B-cell maturation antigen (BCMA), a member of the TNF receptor family of proteins, has been identified as a therapeutically relevant target in multiple myeloma (MM) as it is highly expressed on mature B-cells and preferentially plasma cells. Preclinical work has shown that BCMA specifically plays a role in the survival of malignant plasma cells in MM when it is bound by its ligands, BAFF and/or APRIL. Therefore, BCMA seems to be a good therapeutic target for MM treatment from a functional standpoint. In early-stage clinical trials of BCMA-targeted agents in patients with heavily pretreated MM, multiple approaches have uniformly demonstrated robust and durable responses. In this commentary, I review several approaches to target BCMA in MM, including antibody–drug conjugate (ADC), bispecific T-cell engager (BiTE), and CAR T-cell therapy.
One of the most promising approaches to target BCMA is using ADCs such as belantamab mafodotin (formerly GSK2857916), a humanized monoclonal BCMA antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF). Following binding to BCMA on the cell surface, belantamab mafodotin is rapidly internalized and releases the cytotoxic moiety MMAF, leading to cell apoptosis. The phase I DREAMM-1 trial of belantamab mafodotin in 35 patients with heavily pretreated MM showed an ORR of 60% with a median duration of response longer than 1 year, which is quite remarkable for a single‑agent therapy in this setting. The most frequent adverse events noted with this agent were thrombocytopenia and ocular toxicities, which were generally manageable. Based on initial results from this phase I trial, the FDA has granted belantamab mafodotin Breakthrough Therapy Designation for the treatment of relapsed/refractory MM. In August 2019, it was announced that the pivotal phase II DREAMM-2 trial investigating 2 doses of belantamab mafodotin in 196 patients with heavily pretreated MM met its primary endpoint of ORR and regulatory filing is expected for later this year. We look forward to seeing more data on this agent and several other ADCs targeting BCMA that are currently in either preclinical or early clinical development.
Bispecific T-Cell Engagers
BiTE is another off-the-shelf approach to targeting BCMA for treating MM. A BiTE molecule has 2 arms that link to both an antigen on tumor cells and a cell-surface receptor on T-cells, thereby activating T-cells and engaging them with tumor cells. The most mature data using this approach in MM are from AMG 420 (formerly BI 836909), a BiTE with a short half-life that targets BCMA on MM cells and CD3 on T-cells. AMG 420 has been granted Fast Track Designation by the FDA. In a phase I trial enrolling patients with relapsed/refractory MM, AMG 420 at 400 μg/day demonstrated an ORR of 70% with a median duration of 9 months. Remarkably, one half of the patients achieved a measurable residual disease (MRD)–negative CR. The deep responses with the potential for MRD‑negative disease in these heavily pretreated patients with MM were previously thought to be impossible to achieve. Regarding safety, AMG 420 was associated with serious infections and some peripheral neuropathy. One caveat with AMG 420 is that it is short acting and requires continuous infusion. Other BiTE molecules including some with longer half-lives are in early stages of development.
CAR T-Cell Therapies
CAR T-cell therapies targeting BCMA have also been investigated in MM including idecabtagene vicleucel (formerly bb2121) that received FDA Breakthrough Therapy Designation for treating relapsed/refractory MM. In the phase I CRB-401 trial enrolling heavily pretreated patients with MM, idecabtagene vicleucel yielded an ORR of 85% with a CR rate of 45%. Notably, all responders who were evaluable for MRD had MRD-negative status and the median PFS was almost 1 year. An initial concern with CAR T-cell therapies in MM was whether they would cause adverse events, such as severe cytokine-release syndrome (CRS) and neurologic toxicities as seen with CD19-directed CAR T-cell therapies in other hematologic malignancies. However, it was found that both CRS and neurologic toxicities associated with idecabtagene vicleucel were mostly grade 1/2 and very manageable. We recently published the results from this phase I trial in the New England Journal of Medicine. Currently, idecabtagene vicleucel is under investigation for treating relapsed/refractory MM in the pivotal phase II KarMMa trial that is fully accrued, and the phase III KarMMa-3 trial is enrolling patients with pretreated MM.
Other BCMA-targeted CAR T-cell therapies that have shown encouraging clinical activity in relapsed/refractory MM include LCAR-B38M and bb21217, the latter has the same CAR construct as idecabtagene vicleucel but is enriched for T-cells with a memory-like phenotype.
My hope is that some of these BCMA-targeted agents will become available in the clinic within the next 1-2 years given that the promising results seen in early-phase studies hold up in the pivotal trials. If they were approved by the FDA for relapsed/refractory MM, the indication would most likely reflect the parameters of the clinical trials. For example, I expect patients would need to have been exposed to a proteasome inhibitor, an immunomodulatory agent, and a CD38 antibody to be eligible for idecabtagene vicleucel. We have learned that CAR T-cell therapy is relatively safe and well tolerated in relapsed/refractory MM. If approved, I would consider using CAR T-cell therapy in many of my patients with relapsed/refractory MM as long as it is feasible. My sense at this time is that belantamab mafodotin and AMG 420 will be reserved for patients who are frail and cannot be apheresed for CAR T-cell therapy and those with very low blood counts or any neurotoxicity, which would prevent the use of CAR T-cell therapy.
Currently, CAR T-cell therapies under clinical investigation to target BCMA in MM use autologous cellular products, but allogeneic, off-the-shelf CAR T-cell therapies directed against BCMA are in preclinical development with clinical development expected to start soon. As multiple different options are becoming available to target BCMA in MM, the approach of using BCMA-targeted agents in tandem seems appealing. In the future, I could foresee this strategy being explored to prolong the duration of responses. Combination strategies with agents from different classes are also being investigated in ongoing clinical trials. In my opinion, the future of BCMA-targeted therapies in MM looks very bright.
What are your questions and thoughts on these new BCMA-targeted agents for treating patients with relapsed/refractory MM? I encourage you to answer the polling question and post your questions and thoughts in the comments box below.