The Year of the Bispecific

The year 2023 saw many advances in both the biologic understanding of multiple myeloma (MM) and clarity around frontline therapeutic approaches. The latter was quite evident with two phase III trials (PERSEUS¹ , ISKIA² ) just presented at #ASH2023 supporting the use of quadruplet induction therapy for transplant-eligible, newly diagnosed MM (TE-NDMM), which was previously shown in the GRIFFIN trial.³  However, the last 18 months have clearly belonged to the bispecific antibodies (BsAbs). Three new BsAbs (teclistamab, elranatamab, and talquetamab) have received accelerated FDA approval for the treatment of relapsed and/or refractory multiple myeloma (RRMM), and they are now being combined with drugs targeting other mechanisms of action in earlier lines of treatment.

Teclistamab (Tec) received an accelerated FDA approval based on the MajesTEC-1 trial data for patients with RRMM who had received four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.^{4, 5}  Tec is a CD3-engaging BsAb that simultaneously binds endogenous T cells and B-cell maturation antigen (BCMA)-expressing MM cells, leading to T-cell mediated lysis of MM cells. In August 2023, two additional CD3-engaging BsAbs received accelerated FDA approval for RRMM: elranatamab (Elra), which also targets BCMA, based on the MagnetisMM-3 trial⁶  and talquetamab (Talq), which targets GPRC5D (G protein-coupled receptor, class C, group 5), based on the MonumenTAL-1 trial.⁷ 

The overall response rates (ORRs) for subcutaneous administration at the recommended phase II doses were very impressive: 63%, 61%, and 68% for Tec, Elra, and Talq, respectively. The durations of response (DORs) were equally impressive: 18.4 months (median follow-up time: 14.1 months), not reached (median follow-up time: 14.7 months), and 7.8 to 10.2 months (median follow-up time: 7.7 months) for Tec, Elra, and Talq, respectively. While cases of cytokine release syndrome and neurologic side effects were mostly low grade when compared with those for approved CAR T-cell therapies, the most notable long-term side effects remain hypogammaglobulinemia and an increased risk of infections. Besides those examining the value of infection prophylaxis with intravenous immune globulin (IVIg) administration and antimicrobials, ongoing clinical investigations are working to de-escalate and/or define the duration of therapy for the approved BsAbs, as well as for other BsAbs that are still in clinical development (linvoseltamab, ABBV-383, alnuctamab, cevostamab, forimtamig, etc.).

While each of these nonrandomized clinical trials included a dose-escalation/dose-expansion cohort, there have been several efforts to identify mechanisms of resistance to BsAbs targeting BCMA and GPRC5D. Early data suggest that exposure to anti-BCMA therapies can result in deletions in TNFRSF17, the gene coding for BCMA.^{8, 9}  Beyond evaluations of target mutations in small BsAb-exposed retrospective datasets,¹⁰  there are no data to suggest that treatment with other T-cell redirecting strategies will be ineffective. In a recent retrospective study, patients with prior BsAb exposure who received alternate T-cell redirection therapies had an ORR greater than 50%.¹¹  One can thus hypothesize that not all emerging BCMA structural variants at the time of a single BsAb relapse preclude the future utility of other anti-BCMA BsAbs, as the BCMA binding affinity may remain despite those mutations and result in clinical efficacy. An important example here is the efficacy of ciltacabtagene autoleucel (cilta-cel) — a BCMA-directed CAR T-cell therapy — in a small subset of patients with RRMM who had prior exposure to anti-BCMA BsAb (n=7), among whom the ORR was 57%.¹²  Another important facet to the sequencing question will be the degree of T-cell anergy (reflected by a high TIGIT+ regulatory T-cell population) and immune paresis, which may influence the degree to which BsAbs exhibit clinical activity in MM.¹³  While the efficacy data for BsAbs are outstanding, much remains to be learned before they can best be integrated into earlier lines of treatment for MM.