Elranatamab May Represent Next Breakthrough in Relapsed/Refractory Myeloma

Alexander M. Lesokhin, MD

The BCMA/CD3 bispecific antibody elranatamab (PF-06863135) showed promising preliminary efficacy and tolerability when used in patients with relapsed/refractory multiple myeloma, according to Alexander M. Lesokhin, MD, who added that the agent is now under evaluation in the phase 2 MagnetisMM-3 trial (NCT04649359).

Data from the phase 1 MagnetisMM-1 trial (NCT03269136), which were presented during the 2021 ASCO Annual Meeting, showed that when elranatamab was given in doses up to 1000 µg/kg, the agent exhibited a manageable safety profile with no dose-limiting toxicities.¹

Additionally, at doses 215 µg/kg and higher, the agent elicited an overall response rate (ORR) of 70%, and complete response (CR)/stringent CR rate of 30%. At the recommended phase 2 dose, which was 1000 µg/kg, the agent induced an ORR of 83.3% Notably, 3 of 4 patients enrolled on the study who had received prior treatment with a BCMA-targeted therapy achieved a response.

Now, MagnetisMM-3 trial will evaluate the safety and efficacy of the agent, administered subcutaneously, in patients with multiple myeloma that is refractory to at least 1 agent in each of the 3 major classes of drugs approved for the disease: an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.² The estimated primary completion date for the trial is June 2022.³

“It is likely that treatments like CAR T-cell therapy and bispecific engagers like elranatamab will move into earlier lines of treatment as time goes on, [so that we can] evaluate their impact on longevity and improvement of overall quality of life,” Lesokhin said. “The important thing to note with elranatamab is that it is extremely well tolerated.”

In an interview with OncLive^®, Lesokhin, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, discussed the promise of elranatamab in the treatment of patients with relapsed/refractory multiple myeloma, the objective of MagnetisMM-3, and other emerging approaches that are generating excitement in the paradigm.

OncLive^®: How do you approach the treatment of patients with triple-refractory multiple myeloma in practice, particularly those who have received prior anti-BCMA treatment?

Lesokhin: This is obviously the current area of medical need for our patients. Those who are triple refractory, meaning they have been refractory to at least 1 IMiD, 1 PI, and an anti-CD38 [monoclonal antibody], require considerable attention. The current available options for those patients are BCMA directed and include the antibody-drug conjugate [ADC] belantamab mafodotin-blmf [Blenrep], and more recently, the FDA-approved CAR T-cell therapy idecabtagene vicleucel [ide-cel; Abecma].

For those who have [already] received those agents, other treatments are available, including selinexor [Xpovio], melphalan flufenamide [Melflufen], which was recently FDA approved, and combinations with cyclophosphamide and a PI, or cyclophosphamide and an IMiD. These agents have activity, but many more exciting treatment approaches are emerging in this space as well, and all are [being investigated] in clinical trials.

Among the emerging novel agents is elranatamab. What is the mechanism of action of this agent and what is the hope for its use in this paradigm?

Elranatamab is in a class of agents called bispecific engagers. There is a group of these molecules, of which there are various formats, but the concept is that they bind at 2 specific moieties: 1 on the tumor cell, and 1 on an immune cell. Elranatamab binds BCMA on myeloma cells, and CD3 T cells, thereby bringing together T cells, and activating them in the vicinity of the myeloma cell resulting in cell kill.

Elranatamab has been evaluated in a dose-escalation trial and using a subcutaneous administration approach. The observation was that at doses above 215 µg/kg, efficacy was observed. Of patients treated in the phase 1 study at doses above this range, there was a 70% response rate, which in a highly refractory patient population with a median number of 8 prior therapies, is quite exciting.

It is also important to note that in the patients treated above that dose threshold, 4 had received prior BCMA-directed therapy, including a CAR T-cell therapy or an ADC; of those patients, 3 also responded. This demonstrates that sequential administration of BCMA-directed therapies is a potential future treatment strategy that can be employed. As such, this is a very exciting compound.

The agent is under evaluation in MagnetisMM-3. Could you provide an overview of the trial? What are the eligibility criteria?

This is a phase 2 registration study that is designed to have 2 specific cohorts: 1 for patients who have not received prior BCMA-directed therapies, and another for those that have. Eligibility for this trial includes having relapsed multiple myeloma that is refractory to the most recent therapy, or relapsed on the most recent therapy, and is refractory to an IMiD, PI, and anti-CD38 drug.

Previously, subcutaneous dosing of elranatamab demonstrated efficacy with a tolerable safety profile. It was also noted that step-up dosing may be one way to mitigate cytokine release syndrome. How might the future dosing of the agent be approached based on these findings?

A variety of step-up dose administrations are being explored with this agent. It remains to be seen precisely which one will be used, but I suspect that there will be a step-up dose that will ultimately be utilized with the administration of this agent. It should be said that this is a strategy that is being used across the board with similar agents with this type of mechanism of action, so this is not unique to elranatamab.

Incidences of peripheral neuropathy have also been reported. Going into the phase 2 study, are there any best practices for managing this toxicity?

A partial FDA hold [had been] placed on the phase 1 and phase 2 programs [because of] 3 cases of peripheral neuropathy; 2 of those [cases] were patients who were treated [with the agent] in combination with pomalidomide [Pomalyst]. All patients had prior peripheral neuropathy and all improved once therapy was stopped. The hold has now been lifted, and all those data have been presented to the FDA. Some mitigation strategies [have been discussed], the main one being to exclude patients with significant prior peripheral neuropathy from participation at this time. All patients that were on treatment [at the time] were made aware of this toxicity, and all elected to continue treatment.

This is an illustration of the caution with which we need to [have when] developing new agents. If there is suspected new toxicity, it needs to be thoroughly evaluated, mitigation strategies need to be considered, and causative combinatorial agents need to be thoroughly examined. This was done here. Patients derive significant benefit from this drug, and they are excited to see this compound, as well as others in this class, proceed forward in development.

How might this therapy impact the treatment paradigm for this patient population?

In the triple-refractory space, this and therapies of this type are very likely to become highly utilized. They are off-the-shelf, immediately available treatments. In this space we have belantamab mafodotin and we have CAR T-cell therapy, and different treatments will be appropriate for different patients. Moreover, the location of patients, meaning their relative proximity to a treatment center that can deliver CAR T-cell therapy, will determine utilization of one over another therapy in the future.

Are any other novel targets emerging in multiple myeloma that you find particularly exciting?

The bispecific engager concept is one that is being explored with non-BCMA targets as well, including FcRH5 and GPRC5D. This is a very exciting area [of research]. In addition, a GPRC5D-targeted CAR T-cell therapy is also in development, and data on that [product] will be presented at the 2021 ASH Annual Meeting. Overall, the immunotherapeutic approaches are really paradigm shifting in myeloma.

Where do you foresee CELMoDs fitting into the paradigm for this population?

CELMoDs are interesting. [These agents] are active in patients who are refractory to prior lenalidomide [Revlimid] or pomalidomide, and they may serve as additional options in that line of combinatorial partners. It remains to be seen how they will combine with these various other immunotherapy approaches and other monoclonal antibodies [available]. This is all worth investigating, and I expect that studies of this nature will commence in the coming years.

References

1. Bahlis NJ, Raje NS, Costello C, et al. Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8006. doi:10.1200/JCO.2021.39.15_suppl.8006
2. MagnetisMM-3: study of elranatamab (PF-06863135) monotherapy in participants with multiple myeloma who are refractory to at least one PI, one IMiD and one anti-CD38 mAB. ClinicalTrials.gov. Updated August 12, 2021. Accessed August 17, 2021. https://clinicaltrials.gov/ct2/show/NCT04649359
3. Pfizer initiates pivotal phase 2 MagnetisMM-3 trial of BCMA-CD3 bispecific antibody elranatamab (PF-06863135) in multiple myeloma. News release. Pfizer Inc. February 17, 2021. Accessed August 17, 2021. https://bit.ly/2W6yGal