Andrew Kin, MD, medical oncologist, Barbara Ann Karmanos Cancer Institute, discusses clinical implications of the FDA approval for teclistamab-cqyv (Tecvayli) in relapsed/refractory multiple myeloma.

teclistamab became the first BCMA-/CD3-targeted bispecific antibody to

 for the treatment patients with relapsed/refractory multiple myeloma who received at least 4 previous lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. This regulatory decision was based on data from the single-arm, multicenter, phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098), in which teclistimab produced an objective response rate of 61.8% (95% CI, 52.1%-70.9%). Of these responses, 28.2% of patients achieved a complete response (CR) or better, 29.1% achieved a very good partial response, and 4.5% achieved a partial response. At a median follow-up of 7.4 months, the 6-month duration of response (DOR) rate at 6 months with teclistamab was 90.6%, and the 9-month DOR rate was 66.5%.

The approval of teclistamab signifies a potential role for this class of BCMA-targeted agents and other bispecific T-cell engagers for patients with heavily pretreated multiple myeloma, Kin states. Agents like teclistamab contain dual binding sites for BCMA and CD3, Kin continues. Similar to monoclonal antibodies, teclistamab targets BCMA expressed on the surface of myeloma cells at one bindings site, and targets CD3 expressed on the surface of T cells at the other. In doing so, the agent redirects CD3+ T cells to BCMA+ myeloma cells, which promotes T-cell activation and tumor cell lysis, Kin explains.

Notably, the primary toxicity observed with these T-cell–based products is cytokine release syndrome (CRS), Kin adds. Early identification and management of CRS events is vital for improving patient outcomes, he says. However, the advantage of teclistamab and other T-cell engaging products is their ability to produce significant and deep responses, Kin emphasizes. Moreover, they can also result in minimal residual disease (MRD) negativity. MRD-negative responses are not only uncommon at this disease stage but are also infrequent in heavily pretreated patients, he states. Accordingly, the bispecific T-cell–engager platform has been shown to be a highly active and viable option for these patients, who historically lack effective therapeutics, Kin concludes.

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Andrew Kin, MD, discusses clinical implications of the FDA approval for teclistamab-cqyv in relapsed/refractory multiple myeloma.

Dr Kin on Clinical Implications of the FDA Approval of Teclistamab in R/R Multiple Myeloma

Andrew Kin, MD, medical oncologist, Karmanos Cancer Institute, discusses the limitations and unmet needs associated with the use of BCMA-targeted therapies in relapsed/refractory multiple myeloma.

The BCMA-directed CAR T-cell therapies ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), as well as the BCMA/CD3-targeted bispecific antibody teclistamab-cqyv (Tecvayli), are all approved by the FDA for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 4 previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. However, not every patient in this setting is going to be a candidate for BCMA-targeted therapy, Kin begins. These 3 BCMA-targeted agents are high-intensity regimens that are associated with adverse effects such as cytokine release syndrome (CRS), which require close monitoring during these treatments, Kin explains.

The BCMA-targeted antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) previously held accelerated approval for patients with relapsed/refractory multiple myeloma; however, 

GlaxoSmithKline plc initiated the process to withdraw the United States marketing authorization

 for the ADC within this space, based on results from the phase 3 DREAMM-3 trial (NCT04162210), which did not meet its primary end point of progression-free survival for belantamab mafodotin compared with pomalidomide (Pomalyst) plus low-dose dexamethasone. Belantamab mafodotin is under exploration in other clinical trials in multiple myeloma with the hope that it will gain reapproval, which could represent another BCMA-targeted therapy that is not associated with CRS, Kin adds.

Although BCMA-targeted therapies can produce responses, response rates could drop for patients who have had exposure to a prior BCMA-targeted therapy, Kin says. Developing other bispecific antibodies, CAR T-cell therapies, and other agents with different targets outside BCMA could provide other treatment options after BCMA-targeted therapy, Kin concludes.

Andrew Kin, MD, discusses the limitations and unmet needs associated with the use of BCMA-targeted therapies in relapsed/refractory multiple myeloma.

Dr Kin on the Limitations of BCMA-Targeted Therapies in Myeloma

Andrew Kin, MD, medical oncologist, Karmanos Cancer Institute, discusses the withdrawal of the United States marketing authorization of belantamab mafodotin-blmf (Blenrep) for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

In August 2020, the FDA granted accelerated approval to the antibody-drug conjugate (ADC) in this indication. However, in November 2020, 

initiated the process to withdraw the United States marketing authorization for belantamab mafodotin

 for the treatment of this population. The decision was made following a request from the FDA, based on results from the phase 3 DREAMM-3 trial (NCT04162210), which did not meet its primary end point of progression-free survival (PFS) for belantamab mafodotin compared with the combination of pomalidomide (Pomalyst) plus low-dose dexamethasone.

Belantamab mafodotin is a BCMA-targeted ADC linking a microtubule-disrupting chemotherapy agent to a monoclonal antibody, that had generated similar response rates to what has previously been seen with other drugs in the penta-refractory space, Kin says. Although belantamab mafodotin is associated with unique corneal-related toxicities, the ocular adverse effects were not related to the decision to remove the agent from its indication in multiple myeloma, Kin explains.

DREAMM-3 served as head-to-head comparison for belantamab mafodotin vs the combination of pomalidomide plus low-dose dexamethasone, which is a highly active regimen in this setting, Kin notes. Findings from the confirmatory trial showed that the median PFS for patients treated with belantamab mafodotin was 11.2 months vs 7.0 months with pomalidomide plus dexamethasone (HR, 1.03; 95% CI, 0.72-1.47). Although these outcomes represented a numerical improvement for belantamab mafodotin, the findings were not statistically superior, Kin emphasizes.

Although belantamab mafodotin has been removed from the market, the agent is currently being explored in ongoing clinical trials, which could pave the way for future FDA approvals, Kin concludes.

Andrew Kin, MD, discusses the withdrawal of the United States marketing authorization of belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Dr Kin on the Withdrawal of Belantamab Mafodotin in R/R Multiple Myeloma

Andrew Kin, MD, assistant professor, Karmanos Cancer Institute, discusses triplet regimens for the treatment of patients with relapsed multiple myeloma.

Almost all of the recent clinical trials in the relapsed setting have been looking at 3-drug regimens versus dual combinations, Kin says. These triplet combinations have usually been adding to a backbone of lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone. Across the board, data show an improvement in outcomes for patients treated with a triplet versus a doublet. Kin says it’s pretty clear that if a patient is fit enough and doesn’t have any preexisting toxicity issues, then they should be treated with a 3-drug regimen.

Data with daratumumab (Darzalex), bortezomib, and dexamethasone have also been impressive, Kin adds, in terms of depth and duration of response. There is also the potential to de-escalate daratumumab dosing and utilize it as an essential second maintenance phase.

Andrew Kin, MD

Articles

Dr Kin on Clinical Implications of the FDA Approval of Teclistamab in R/R Multiple Myeloma

Dr Kin on the Limitations of BCMA-Targeted Therapies in Myeloma

Dr Kin on the Withdrawal of Belantamab Mafodotin in R/R Multiple Myeloma

Dr. Kin on Triplet Regimens for Relapsed Multiple Myeloma