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Division of Oncology and Hematology
Department of Internal Medicine
University of Nebraska Medical Center
Sarah A. Holstein, MD, PhD, has disclosed that she has received consulting fees from Celgene, Genentech, GlaxoSmithKline, Oncopeptides, and Takeda.
Treatment options for myeloma have expanded rapidly in recent years, with numerous new therapies approved by the FDA and the EMA. In addition to new approvals, ongoing clinical trials are exploring additional novel agents, including 3 classes of BCMA-targeted agents, the new cereblon E3 ligase modulator (CELMoD) iberdomide, and the novel alkylating agent melflufen.
Targeting BCMA in Myeloma
In recent years, BCMA—a member of the TNF receptor family of proteins—has been identified as a therapeutically relevant target in myeloma as it is highly expressed preferentially in malignant plasma cells, though can also be found on mature B-cells and plasma cells. In early clinical trials of BCMA-targeted agents in patients with heavily pretreated myeloma, multiple approaches have uniformly demonstrated robust and durable responses. These include CAR T-cell therapies, bispecific monoclonal antibodies (BsMAb), bispecific T-cell engagers (BiTE), and antibody–drug conjugates (ADCs).
CAR T-Cell Therapy
CAR T-cell therapies targeting BCMA have been investigated in myeloma for some time, and one of these—idecabtagene vicleucel (formerly bb2121) —has received FDA Breakthrough Therapy designation for treating relapsed/refractory myeloma on the basis of data from the phase I CRB-401 trial. Currently, idecabtagene vicleucel is under investigation for treating relapsed/refractory myeloma in the accruing phase III KarMMa-3 trial. Other BCMA-targeted CAR T-cell therapies have also shown encouraging clinical activity in relapsed/refractory myeloma, including LCAR-B38M and bb21217.
The challenge with CAR T-cell therapy is that it is not an “off-the-shelf” therapy: T-cells are collected from individual patients, who then receive lymphodepleting therapy and undergo reinfusion of their cells after the cells have been isolated, engineered to express the CAR, and expanded in an external laboratory. Unfortunately, this process can take a couple weeks, and many patients with relapsed/refractory myeloma may not be able to maintain disease stability for that length of time even with bridging therapy. Right now, CAR T-cell therapy appears to be best suited for those patients with myeloma who have had previous lines of therapy but whose disease is relatively stable. In addition, many patients will not have easy access to centers that perform CAR T-cell therapy infusions. Of note, an allogeneic “off-the-shelf” CAR T-cell therapy with shorter cell preparation time is in early clinical testing, but it is as-yet unknown whether this will provide similar clinical benefit as autologous cells.
In addition, despite hope that BCMA-targeted CAR T-cell therapy will ultimately lead to durable responses, to date, the median PFS with these agents leaves much room for improvement. For example, in the phase I CRB-401 trial enrolling heavily pretreated patients with myeloma, idecabtagene vicleucel yielded an ORR of 85% with a CR rate of 45%, but a median PFS of less than 1 year. Of note, while the majority of responders who were evaluable for minimal residual disease (MRD) did achieve MRD-negative status, 40% of those MRD-negative patients have already progressed.
Bispecific T-Cell Engager Therapy
BsMAb and BiTE technologies may offer an “off-the-shelf” approach to targeting BCMA. BsMAb are engineered antibodies with 2 different antigen binding sites. A BiTE is composed of two single-chain antibody fragments 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 myeloma are from studies of AMG 420, a BiTE with a short half-life that targets BCMA on myeloma cells and CD3 on T-cells. In a phase I trial enrolling patients with relapsed/refractory myeloma, AMG 420 at 400 μg/day demonstrated an ORR of 70% with a median duration of 9 months for patients who received the maximum tolerated dose. However, the need for continuous infusion of this therapy is logistically difficult. There is hope that modified versions with more prolonged half-lives will be developed that are more feasible to administer. Of note, the neurotoxicity that has been seen with CAR T-cell therapy appears to be much less with BiTE therapy; however, AMG 420 was associated with serious infections and some peripheral neuropathy.
In general, ADCs bind to tumor cells expressing the target antigen, are internalized, and release a cytotoxic moiety. In myeloma, ADCs are being developed to target BCMA. For example, belantamab mafodotin (formerly GSK2857916), a humanized monoclonal BCMA antibody, is conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF). Results from the phase I DREAMM-1 trial of belantamab mafodotin (at 3.4 mg/kg Q3W) in 35 patients with heavily pretreated myeloma showed an ORR of 60% with a median duration of response longer than 1 year, which is quite promising for a single-agent therapy in this setting. That said, the response rate was lower (38.5%) when restricted to patients who previously received daratumumab and were refractory to both IMiDs and proteasome inhibitors.
Although this agent is feasible to administer in a community practice, it carries a risk of corneal toxicity. In fact, approximately one half of patients enrolled on the DREAMM-1 trial reported blurred vision, although this can be managed by partnering with an ophthalmologist. A pivotal phase II trial, DREAMM-2, investigating 2 doses of belantamab mafodotin in 196 patients with heavily pretreated myeloma recently met its primary endpoint of ORR, and regulatory filing is expected for later this year.
New IMiD (aka CLEMoD): Iberdomide
Another myeloma therapy that I think shows promise is iberdomide (CC-220). Broadly speaking, iberdomide belongs to the class of drugs referred to as IMiDs, which include lenalidomide and pomalidomide. Iberdomide is a small molecule inhibitor of cereblon E3 ligase modulator (CLEMoD) and binds cereblon with higher affinity than either lenalidomide or pomalidomide. An initial dose-escalation phase Ib/IIa study of iberdomide was conducted in 51 patients with myeloma and at least 2 previous lines of therapy including lenalidomide and/or pomalidomide as well as a proteasome inhibitor. Early results suggest a promising adverse event profile; this regimen was associated with some hematologic toxicity, notably neutropenia (grade 3: 15.2%; grade 4: 13.6%) and infections (any grade: 47%; grade 3/4: 25.7%). In addition to appearing to be well tolerated, it is an oral agent, which will be attractive to patients. Although the ORR was only approximately 30% in this heavily pretreated patient population, a fair number of patients (n = 45) achieved disease control (defined as stable disease or better), suggesting a different mechanism of action than the other IMiDs. There is great interest in moving this agent forward into earlier lines of treatment, and with its relatively mild adverse event profile, it should be feasible to combine with other myeloma agents in triplet or quadruplet combinations. Questions on long-term efficacy, how to sequence this therapy with the other IMiDs, and the best combinations with iberdomide will hopefully be addressed in additional clinical trials.
Peptide-Conjugated Alkylator: Melflufen
Melflufen is a first-in-class lipophilic peptide-conjugated alkylating agent, which has been granted orphan drug designation for the treatment of relapsed/refractory myeloma. Essentially, melflufen provides a novel way to specifically direct the alkylating agent melphalan to malignant plasma cells. Melflufen contains melphalan conjugated to a lipophilic peptide. The peptide moiety allows access inside the cell, and then the active agent is released following cleavage by aminopeptidases. Myeloma cells express high levels of these aminopeptidases, and so the use of this conjugated agent achieves much higher levels of the active agent melphalan in myeloma cells vs other, normal cells. Oral melphalan had been used as an antimyeloma therapy for many years, although it is rarely used as an antimyeloma therapy in practice today. That said, high-dose IV melphalan remains the standard conditioning regimen prior to autologous stem cell transplantation. One of the issues with long‑term melphalan use is off‑target toxicity, so the possibility of using melflufen to more specifically target myeloma cells while sparing the rest of the body the toxicity associated with standard melphalan therapy is attractive.
The single-arm phase II HORIZON study evaluated melflufen in 95 patients with myeloma who were heavily pretreated; in fact, the majority were penta-refractory. Approximately 30% of patients responded. Of interest, a recent update from IMW 2019 suggested similar efficacy in patients with extramedullary disease, which remains very difficult to treat. Ongoing studies in relapsed/refractory myeloma are evaluating melflufen in combination with other agents, for example, the phase I ANCHOR study of melflufen, daratumumab, and bortezomib, and the phase III OCEAN study of melflufen vs pomalidomide in patients with relapsed lenalidomide-refractory myeloma. I think there will be a role for melflufen in the relapsed/refractory setting.
In addition, there’s a great deal of interest in determining whether high‑dose melflufen could be a safer alternative to high‑dose melphalan as conditioning therapy for stem cell transplantation. Off‑target toxicity associated with high‑dose melphalan includes gastrointestinal adverse events and mucositis, and it is hypothesized that these toxicities might be less with melflufen.
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To see what 5 experts would recommend for patients with myeloma in different clinical scenarios, visit the Interactive Decision Support Tool: Induction, Maintenance, and Relapsed/Refractory Therapy for Multiple Myeloma. Bookmark this link and check back for an updated myeloma tool coming soon!