The state of toxicities for immunotherapy for multiple myeloma

CAR T-cell therapies and bispecific antibodies have shown high response rates in patients with relapsed/refractory multiple myeloma. Dr Alfred Garfall (University of Pennsylvania, PA, USA) discussed efficacy, toxicities, and combination approaches of currently available CAR T-cell therapies and bispecific antibodies [1].

In terms of logistics and administration, CAR T-cell therapies require a dedicated cellular therapy centre, a manufacturing slot, and extended manufacturing time. Still, they are administered as easily as a one-time therapy. Bispecific antibodies are readily available off the shelf but require continuous subcutaneous dosing [1].

Each of these drug classes also has a particular set of toxicities. CAR T-cells lead to cytokine release syndrome and neurotoxicity, which are potentially severe, and cytopenia which are also potentially severe and might require stem cell rescue. BCMA-targeted bispecific antibodies, such as elranatamab and teclistamab, can lead to severe cytokine release syndrome, neurotoxicity, and cytopenia, with a potentially higher risk of infections compared with CAR T-cell therapies. The GPRC5D talquetamab has a particular set of toxicities characterised by oral, skin, and nail toxicities.

When comparing cytokine release syndrome and neurotoxicity for CAR T-cell therapies and bispecific antibodies, CAR T-cell therapies tend to lead to higher numbers of Grade 3/4 toxicities [1]. Furthermore, CAR T-cell toxicity seems to be associated with tumour burden as assessed by PET/CT. In a retrospective analysis, Grade 2 cytokine release syndrome (44% vs 12%; P=0.02) and any grade immune effector cell-associated neurotoxicity syndromes were more likely to occur in patients with high versus low metabolic tumour burden (27% vs 12%; P=0.1) [2]. Of note is late-onset Parkinsonism which, although rare, has been reported only with cilta-cel [3].

In terms of infections, although CAR T-cell therapies pose a risk for infections, phase 3 trial data with cilta-cel and ide-cel did not show higher rates of infections compared with their respective standard-of-care comparator arms [1]. In contrast, continuously dosed anti-BCMA therapies like teclistamab and elranatamab carry a significant infection risk [1]. Prophylaxis with IgG replacement therapy has shown benefit in the MajesTEC-1 trial and is a potential strategy to reduce severe infections due to anti-BCMA bispecific antibodies [4]. “In our practice, we give all of our patients IVIG prophylaxis even without prior evidence of infection,” said Dr Garfall. “We don’t wait for the infection to develop and it’s a little more aggressive [strategy] than with standard myeloma therapies”. On the other hand, non-BCMA bispecific antibodies tend to have lower risks of both Grade 3 or higher infections and neutropenia [5]. However, GPRC5D-targeted therapies were associated with skin and nail toxicities, rash, as well as oral toxicity, all of which require management [6].

What does the future look like for immunotherapies in multiple myeloma? Sequencing CAR T and bispecific antibodies is a topic of current debate. Repeating CAR T-cell dosing with the same therapy seems to be ineffective, while preliminary data with anti-BCMA bispecific antibodies prior to anti-BCMA CAR T-cell therapy has shown promising results. Furthermore, use of talquetamab following BCMA CAR-T cell therapy has also shown encouraging results [1].

Trials assessing combination approaches are currently ongoing. Teclistamab plus talquetamab is investigated in the RedirecTT-1 trial (NCT04586426), while other combinations include cevostamab plus elranatamab (NCT05927571), and bispecific antibodies either as bridging therapy to or consolidation therapy after CAR T-cell therapies (MonumenTAL-8; NCT05801939).

1. Garfall A. Immunotherapy for triple-class exposed MM. Session VII: Immunotherapy. EMN 2024, 18–20 April, Turin, Italy.
2. Villanueva R, et al. Blood. 2022;140(Supplement 1):10402-10404.
3. Cohen AD, et al. Blood Cancer J. 2022;12(2):32.
4. Nooka AK, et al. Cancer. 2024;130(6):886-900.
5. Mazahreh F, et al. Blood Adv. 2023;7(13):3069-3074.
6. Chari A, et al. N Engl J Med. 2022;387(24):2232-2244.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 23 April 202423 April 2024