Elranatamab Shows Efficacy of BCMA-Targeted Therapy in Multiple Myeloma

Mansi R. Shah, MD

Assistant Professor of Medicine

Rutgers Robert Wood Johnson Medical School

New Brunswick, NJ

[Read Part 1]

Targeted Oncology: What trials investigated elranatamab (Elrexfio), and how did they compare with the trial of teclistamab (Tecvayli) in patients with relapsed/refractory multiple myeloma?

SHAH: The MagnetisMM-1 trial [NCT03269136] is for elranatamab, which was the second B-cell maturation antigen [BCMA] bispecific approved in August [2023].¹ This was the phase 1 dose-finding study, with very similar baseline patient characteristics [to MajesTEC-1 (NCT04557098)], but importantly 29% of patients had high-risk cytogenetics, and a median of 5 prior lines of therapy, and 90% of them were triple-class refractory compared with about 78% [in MajesTEC-1].^2,3 This trial included prior BCMA-directed therapy. Most of this was with an antibody-drug conjugate, but there were CAR [chimeric antigen receptor] T-cell therapy–exposed patients in this trial as well. The high-risk cytogenetics are anything with an immunoglobulin heavy chain: the translocations in 4;14, 14;20, and 14;16, deletion 17p, or TP53. There was a small number of patients who had prior BCMA exposure. Across the board, they still responded to another BCMA-targeted therapy. [The overall response rate (ORR) was 64%].² The duration of response was approximately 17 months, very similar to the MajesTEC-1 trial, with approximately 12 months’ median progression-free survival, and median overall survival of about 21 months.

Why is repeat BCMA-targeted therapy effective despite mechanisms of resistance?

That is an ongoing area of research. It could be that there’s a heterozygous mutation, there’s lack of expression, or there’s over expression that saturates the receptors. We know that increased BCMA exposure portends a poor outcome compared with lower BCMA exposure. They are looking into that and trying to understand if patients just stop making BCMA. It’s not as simple as that. There are a multitude of mutations that can happen in the BCMA pathway that can lead to resistance.

If patients had a prior BCMA CAR T-cell therapy and they are responding to the BCMA-targeted bispecific, will they respond to another bispecific?

I think we’re going to have to find out. I just continue to highlight that prior BCMA-exposed patients also had more subdued response, but about 54% of patients responded [vs 66.7% in those without prior BCMA therapy]. Even high-risk patients had a great ORR of approximately 50%, lower than those with the standard-risk cytogenetics [65.7%], but still a great response. This is traditionally a very hard-to-treat patient population. I’m very impressed by those with extramedullary disease who had an approximately 60% ORR, which again is a very hard-to-treat patient population.

What was the significance of the phase 2 MagnetisMM-3 trial (NCT04649359)?

This is the trial that led to the approval of elranatamab. In MagnetisMM-3, [cohort A] was not BCMA exposed. It was given subcutaneously. The time to response was 1.2 months and median time to best response was approximately 6 months.⁴ Across the board, the ORR was in the low 60s, [and overall] it was 61% [95% CI, 51.8-69.6%]. The swimmers’ plot showed the patients who responded continue to respond and the responses degrade over time.

During this study, the PFS was not reached but estimated 15-month PFS rate was [50.9%]…. I hope that this plateau continues for the patients who respond and maybe we can borrow from our lymphoma colleagues and finally achieve some kind of plateau with ongoing therapy.

What is important to know about the treatment-emergent adverse events seen on this trial?

The adverse events are similar; the incidence of cytokine release syndrome [CRS] was about 71%; importantly, there was no grade 3 or 4 CRS. [Although] 29% of patients required dose reduction and 77% required some kind of interruption in ongoing therapy, what’s important to remember is despite dose interruption, it does not impact efficacy. That’s what I counseled my patients; it’s OK that they’re not getting the drug today. We want to make sure that it’s safe to give it to them later.

This trial used mitigating strategies. One of the most important mitigating strategies was using this drug every 2 weeks once a patient achieved at least some kind of response. [Looking at] before the every-2-weeks switch vs after, toxicities diminish across the board. That was an important mitigating strategy, and they used upfront or earlier CRS mitigating strategies like tocilizumab [Actemra] or steroids.

How does the mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) algorithm help with management of CRS and neurotoxicity?

The mSMART criteria are from the Mayo Clinic.⁵ They have published these criteria for the management of CRS and neurotoxicity. Neurotoxicity is not that common with the bispecifics, but CRS is, and it [occurs] early—even grade 1 CRS, which is a fever without any hemodynamic instability. They’re using tocilizumab or dexamethasone quickly, with the hope that it doesn’t interrupt further dosing, and that we can get ahead of the CRS.

[The mSMART] algorithm for immune effector cell–associated neurotoxicity syndrome is for the neurotoxicity. If it’s grade 1, the patient has no motor deficits and no cerebral edema. That’s good. If they have grade 2 to 4, intervening early [with steroids] so that it doesn’t escalate is important.

_References:

_{1. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed January 17, 2023. https://tinyurl.com/38t58tx3}

_{2. Bahlis NJ, Costello CL, Raje NS, et al. Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. Nat Med. 2023;29(10):2570-2576. doi:10.1038/s41591-023-02589-w}

_{3. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478}

_{4. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9}

_{5. Mayo Stratification for Myeloma And Risk-adapted Therapy: Management of Teclistamab Cytokine Release Syndrome (CRS) and Immune Cell Associated Neurotoxicity Syndrome (ICANS). Mayo Clinic. Updated January 2023. Accessed January 17, 2023. http://tinyurl.com/bpbyex3f}