Elranatamab Represents Another Off-the-Shelf Option for Heavily Pretreated R/R Myeloma

Elranatamab-bcmm (Elrexfio) represents another treatment strategy for heavily pretreated patients with relapsed/refractory multiple myeloma that could continue to be integrated into the community setting as clinicians become more familiar with managing the toxicities associated with bispecific antibodies, according to Ajay Kumar Nooka, MD, MPH, FACP.

On August 14, 2023, the FDA granted accelerated approval to elranatamab for the treatment of adult patients with relapsed/refractory multiple myeloma who have previously received at least 4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.1,2 The regulatory decision was supported by data from the phase 2 MagnetisMM-3 trial (NCT04649359), where patients naïve to BCMA-targeted therapies (n = 97) achieved an overall response rate (ORR) of 57.7% (95% CI, 47.3%-67.7%), including a complete response rate of 25.8%.

Regarding adverse effects (AEs), the most common toxicities reported in at least 10% of patients who received elranatamab on the study included cytokine release syndrome (CRS; any grade, 58%; grade 3 or 4, 0.5%), hypogammaglobulinemia (13%; 2.2%), fatigue (43%; 6%), injection site reactions (37%; 0%), pyrexia (21%; 2.7%), edema (18%; 1.1%), diarrhea (36%: 1.1%), nausea (22%; 0%), constipation (15%; 0%), vomiting (14%; 0%), upper respiratory tract infection (34%; 4.9%), pneumonia (32%; 19%), sepsis (15%; 11%), urinary tract infection (12%; 4.4%), musculoskeletal pain (34%; 2.7%), reduced appetite (26%; 1.1%), rash (25%; 0%), dry skin (13%; 0%), skin exfoliation (10%; 0%), cough (24%; 0%), dyspnea (15%; 3.3%), headache (18%; 0.5%), encephalopathy (15%; 2.7%), sensory neuropathy (13%; 0.5%), motor dysfunction (13%; 2.2%), cardiac arrhythmia (16%; 2.2%), hemorrhage (13%; 1.6%), insomnia (13%: 0%), and fall (10%; 0.5%). Notably, elranatamab has a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity.

“BCMA-targeted bispecific antibodies [represent] revolutionary approvals. [These agents] can be given in the community, where patients [may] not need [to travel] to the academic setting,” Nooka explained in an interview with OncLive®. Nooka is a professor and director of the Myeloma Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia.

In the interview, Nooka, who also serves as the scientific director of Winship Data and Technology Applications Shared Resource at Winship Cancer Institute of Emory University, highlighted the significance of the FDA approval of elranatamab for select patients with relapsed/refractory multiple myeloma and shed light on the agent’s role in the expanding field of T cell–redirecting therapies approved for the treatment of this patient population.

OncLive: What is the significance of the FDA approval of elranatamab for patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy?

Nooka: This is a great moment for us in the myeloma community. Elranatamab is a CD3- and BCMA-directed bispecific antibody. This has been approved for patients who have received 4 prior lines of therapy, including an IMid, a CD38 monoclonal antibody, and a PI. There were several approvals that we’ve had over the last 2 years [in multiple myeloma]. However, [elranatamab] is unique for our patients is the sense that we [now] have an off-the-shelf bispecific antibody that could be given as an outpatient [treatment], with an initial step-up dosing that could be given as an inpatient [treatment], based on risk-mitigation strategy that was [implemented] for elranatamab.

The reality is, we did not have a lot of [treatment] options for this [population of] patients before [this approval]. Two-thirds of these patients are responding to an off-the-shelf bispecific antibody, and that is big news for us. [Elranatamab] is probably what I would offer to most patients who could potentially tolerate it. The AE profile is manageable, and it makes us feel more comfortable to offer this [bispecific antibody] to heavily refractory patients.

Could you expand on the mechanism of action of elranatamab?

Elranatamab is a BCMA/CD3 bispecific antibody that targets the BMCA on the myeloma cell and CD3 on the T cell, bringing them together to enhance or facilitate T cell–mediated killing. We do have one [previously] approved agent, teclistamab-cqyv [Tecvayli], and elranatamab is in the same category.

What were the key efficacy findings from MagnetisMM-3 that supported this approval?

There were 123 patients enrolled in [cohort A of] this single-arm, multicenter trial who fit the criteria of [having received] more than 3 prior lines of therapy, and [they] should have been exposed and refractory to an IMiD, PI, and CD38 monoclonal antibody.

If you look at the specific indication for the approval of elranatamab, 97 [of these] patients qualified for this indication [and had not received prior BCMA-directed therapy]. This a heavily pretreated patient population. The overall survival [OS] outcomes [have been] very dismal within this population, with OS [generally] less than a year. If you look at these 97 patients, the ORR was [57.7%], and the duration of response at the end of 6 months was [90.4%]. By the 9-month mark, it was [82.3%].

These were impressive results. The drug was effective and safe, and [patients were able to] sustain responses, even with the tapering of dosages. After the first 6 months, patients could [transition] to every-other-week [dosing], and responses continued to be maintained.

How effective was elranatamab in patients who had previously received a BCMA-targeted therapy?

There was a pooled analysis that was presented at the 2023 ASCO Annual Meeting, where [data from] 4 different trials were combined: [the phase 1 MagnetisMM-1 (NCT03269136), phase 1 MagnetisMM-2 (NCT04798586), MagnetisMM-3, and phase 2 MagnetisMM-9 (NCT05014412) trials].3 [This analysis included 87] patients who had previously received BCMA-targeted therapies, including antibody-drug conjugates [ADCs], CAR T-cell therapies, or other BCMA-directed bispecific antibodies.

The 2 primary cohorts evaluated consisted of patients who had previously received BCMA-directed CAR T-cell therapy or BCMA-directed ADC therapy. If you look at the responses to alternate BCMA-targeted therapy strategies, among approved agents, we probably have the best responses with the GPRC5D-targeted bispecific antibody [talquetamab-tgvs (Talvey)] that was approved [in August 2023]. However, without that, by repurposing a BCMA-targeted bispecific antibody for a patient who has [previously] seen a BCMA[-targeted therapy], we were able to see responses in [46%] of patients. That is not a bad number, and if you look at the past, approved agents were able to deliver us close to 30% response rates [in this patient population]. In that setting, [these improved responses] are a huge win for us.

What is the safety profile of elranatamab, as seen in the MagnetisMM-3 trial?

We must take [data] with a grain of salt when we look at safety profiles. These were heavily refractory patients who had seen 6 prior lines of therapy. In these patients, the major toxicity that was seen was hematological toxicity, [specifically] neutropenia, anemia, and thrombocytopenia, in close to half of patients. We also see that infection risk is higher using [bispecific antibodies].

[With elranatamab], there are specific AEs of interest, including CRS, which is a response by the immune system to myeloma cells killed by these T cell–redirecting therapies. If you look at the overall incidence of CRS [in patients receiving T cell–redirecting therapies], you are able to see that in [approximately] 75% of patients across all the BCMA-specific agents. In this cohort of MagnetisMM-3, the [any-grade] CRS rate was [58%]. However, higher-grade CRS was not as common. Grade 3 or higher CRS was seen in only 0.5% of patients. CRS happens, and in my opinion, it's a predictor of response. CRS can be mitigated by using appropriate strategies, including using tocilizumab [Actemra] or steroids.

Another AE is neurotoxicity. Neurotoxicity is a big umbrella, which can be seen in 50% to 60% of patients, and this could range from a simple headache to seizures. However, immune effector cell–associated neurotoxicity syndrome was seen in only 3.4% of patients.

Overall, the AE profile is manageable and predictable. We have gotten used to [managing] CRS and neurotoxicity with prior experiences with CAR T-cell therapies and previously approved bispecific antibodies. We’re in great shape at this point to manage these AEs.

However, one aspect I would highlight is the risk of infections [associated with] BCMA-directed bispecific antibodies. Patients need proper monitoring with a proper plan for IVIg administration and having all vaccinations in place. That approach increases the layers of security, where patients can continue to receive the benefit of elranatamab and not its toxicities.

With this approval, where do you see elranatamab fitting into the multiple myeloma treatment landscape, given the other T cell–redirecting therapies available in later lines of treatment?

The BCMA space is the previous CD38 space. There are a lot of patients who are available after receiving the CD38 monoclonal antibodies who have met the criteria of having seen more than 4 prior lines of therapy. Here, we get an option of whether a patient should go to a BCMA-directed CAR T-cell therapy, a BCMA-directed bispecific antibody, or a GPRC5D-directed bispecific antibody, which was recently approved as well.

What we don't understand at this point is the mechanism of resistance when patients relapse or progress. This is currently in the process further exploration, because if you really have this understanding [of why patients experience relapse or progression], we can easily sequence agents and [determine] which [sequence] gives us the most [benefit]. However, in the absence of that, we have been used to making a class switch. If a patient progressed on an IMiD, you put them on a PI.

Here, we're talking about something slightly different: a target switch. If a patient is progressing on a BCMA-directed CAR T-cell therapy, you can put them on a GPRC5D-directed bispecific antibody. Once a patient progresses on GPRC5D-directed bispecific antibody, you have an option of using at BCMA-directed bispecific antibody. [Alternatively], you start with a BCMA-directed bispecific antibody, then you have an option of a GPRC5D-directed bispecific antibody, then a BCMA-directed CAR T-cell therapy.

Unfortunately, there is no cookie cutter approach on who is the right patient to go for each approach. What we really want to understand is, if I use one treatment option, will it [affect] any of my future treatment options? If the answer is no, we should be ready to proceed with the option using a BCMA-targeted bispecific antibody.

This is a great time for us. We have 2 CD38 monoclonal antibodies, 2 BCMA-directed CAR T-cell therapies, 2 BCMA-directed bispecific antibodies, and 1 GPRC5D-directed bispecific antibody. Having more allows us to explore combinations, and this could allow us to get a preliminary idea of what specific combinations could [lead to] future drug development.

Where do these agents fit in? Can they be combined with other agents in a safe way? Can they be used as maintenance therapies? This is all up to exploration. I'm excited to see these agents earlier in the early relapse or newly diagnosed settings so we can have the best benefit of these agents in the long run.

What is the rationale and design of the phase 3 MagnetisMM-5 trial (NCT05020236)?

MagnetisMM-5 is randomized control trial evaluating elranatamab and daratumumab [Darzalex] vs daratumumab, pomalidomide [Pomalyst], and dexamethasone. Why was this control arm chosen? [This triplet] was shown to be superior to pomalidomide and dexamethasone alone in the [phase 3] APOLLO trial [NCT03180736].

If you have an accelerated approval [such as elranatamab], you need a confirmatory trial to show the benefit of this drug in a randomized phase 3 [setting]. This is one of the trials in the pipeline that is evaluating the benefit of elranatamab in combination with daratumumab vs the daratumumab, pomalidomide, and dexamethasone combination.

What advice would you give for a physician prescribing elranatamab to a patient?

Right now may not be a good timeframe to deliver this drug [only] in the community, but it [would be beneficial to have] an academic and a community partnership, where the first cycle or so can be given in the hospital, where the risks are all minimized, and the patients could then receive the drugs in the community.

In the future, this may not be the case. Once we get a good handle on how to manage CRS and neurotoxicity, and how to give this drug in a safer way, this could easily be given in the community. That’s why I call this a revolutionary treatment option that would give a benefit [in access] to approximately 60% of patients.

The long-term AEs are what we need watch out for. We should not forget that these drugs can increase the risk of infections. Having a good plan [is important]. When do we start antibiotics? What is the threshold for the lymphopenia? Do patients need to go on prophylaxis? Does every patient need IVIg? All these things need to be incorporated and delved into detail before administering the drug so patients can get the benefit of the treatment while toxicities are constantly monitored.

References

1. Pfizer's Elrexfio receives US FDA accelerated approval for relapsed or refractory multiple myeloma. News release. Pfizer. August 14, 2023. Accessed October 5, 2023. https://investors.pfizer.com/Investors/News/news-details/2023/Pfizers-ELREXFIO-Receives-U.S.-FDA-Accelerated-Approval-for-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
2. Elranatamab-bcmm (Elrexfio) Prescribing Information. Pfizer; August 2023. Accessed October 5, 2023. https://labeling.pfizer.com/ShowLabeling.aspx?id=19669
3. Nooka AK, Lesokhin AM, Mohty M, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B-cell maturation antigen (BCMA)-directed therapies: A pooled analysis from MagnetisMM studies. J Clin Oncol. 2023;41(suppl 16):8008. doi:10.1200/JCO.2023.41.16_suppl.8008