Bispecific antibodies (BsAbs) are the newest FDA approved class of therapy for patients with relapsed/refractory multiple myeloma whose disease has progressed through four prior lines of therapies, including immunomodulatory drugs (IMiDS), proteasome inhibitors, and anti-CD38 monoclonal antibodies. BsAbs have yielded impressive responses, even when given as single agents, in this late-relapsed disease setting (Table).1-4 This is an important advance given the broader accessibility of this treatment than chimeric antigen receptor (CAR) T-cell therapy.
FDA-approved Bispecific Antibodies
| . | Teclistamab MajesTEC-11 N=165 . | Elranatamab MagnetisMM-32 N=123 . | Talquetamab MonumenTAL-14,14 N=187 . |
|---|---|---|---|
| Dose Schedule | 1.5 mg/kg subQ weekly | 76 mg subQ weekly | 0.4 mg/kg subQ weekly OR 0.8 mg/kg subQ biweekly |
| Prior lines, median (range) | 5 (2-14) | 5 (2-22) | 5 (4-13) |
| Median follow-up | 14.1 months | 10.4 months | 13.8 months |
| ORR | 63.0% | 61% | Weekly: 73% Biweekly: 73.6% |
| sCR/CR, % | 39.4% | 35% | Weekly: 35%; Biweekly: 33% |
| Median PFS, months | 11.3 | Not reached | Not reached |
| . | Teclistamab MajesTEC-11 N=165 . | Elranatamab MagnetisMM-32 N=123 . | Talquetamab MonumenTAL-14,14 N=187 . |
|---|---|---|---|
| Dose Schedule | 1.5 mg/kg subQ weekly | 76 mg subQ weekly | 0.4 mg/kg subQ weekly OR 0.8 mg/kg subQ biweekly |
| Prior lines, median (range) | 5 (2-14) | 5 (2-22) | 5 (4-13) |
| Median follow-up | 14.1 months | 10.4 months | 13.8 months |
| ORR | 63.0% | 61% | Weekly: 73% Biweekly: 73.6% |
| sCR/CR, % | 39.4% | 35% | Weekly: 35%; Biweekly: 33% |
| Median PFS, months | 11.3 | Not reached | Not reached |
ORR: objective response rate; CR: complete response; sCR: stringent complete response; subQ: subcutaneous; PFS: progression-free survival
First, BsAbs are more readily accessible as off-the-shelf drugs for patients whose disease may progress too quickly for CAR-T manufacturing. Second, BsAbs are given without lymphodepletion chemotherapy, and the immediate toxicities of severe cytokine release syndrome and neurotoxicities are less frequent with step-up dosing. Thus, patients who may not be able to tolerate the toxicities of lymphodepletion chemotherapy and CAR-T could potentially receive BsAbs. In addition, broader oncology practices may make it easier to meet regulatory requirements when administering this therapy versus CAR-T. Finally, with the number of B-cell maturation antigen (BCMA)-targeting CAR-T and BsAb therapies available — and the emerging resistance to BCMA-targeted therapies — talquetamab has been developed as the first therapy in standard-of-care practice to target another novel antigen: GPRC5D. A BsAb targeting FcRH5, cevostamab, has yielded similarly impressive clinical responses and is anticipated to be reviewed for regulatory approval by the FDA this year.5
Given the transformative clinical activities of BsAbs, numerous clinical trials have investigated their use in earlier lines of therapy. Correlative analyses from the MajesTEC-1 study revealed that patients with clinical response to teclistamab had a higher number of baseline T cells, a higher percentage of naïve CD8+ T cells, and a lower percentage of regulatory T cells than non-responders.6 The use of BsAbs in earlier disease settings may lead to an improved clinical response given that the T cells may be more fit and that immune suppression induced by the disease/systemic therapy may be less profound.7 In addition, BsAbs can more readily combine with other active anti-myeloma agents, particularly those with favorable immune stimulatory effects, to yield deeper clinical responses.
Several ongoing combination trials and randomized phase III clinical trials have yielded promising results. Preliminary findings from MajesTEC-2 (NCT04722146) indicated that response rates were significantly higher for the combination of teclistamab, daratumumab, and lenalidomide in patients who had received one to three prior lines of therapy (n=32, overall response rate [ORR]: 93.5%, complete response [CR]/stringent CR [sCR]: 54.8%), including those patients with disease refractory to daratumumab and/or lenalidomide.8 Different combinations were also tested in other cohorts, including teclistamab with daratumumab and pomalidomide; teclistamab with daratumumab, lenalidomide, and bortezomib; and teclistamab with a gamma-secretase inhibitor. Similarly, in patients who had received two or more prior lines of therapy, an ORR of 80% (n=35) was observed among those treated with talquetamab and pomalidomide in MonumenTAL-2 (NCT05050097). MonumenTAL-2 also included cohorts treated with talquetamab in combination with carfilzomib or lenalidomide, with and without daratumumab.
Talquetamab is also being studied in the phase III MonumenTAL-3 trial (NCT05455320), which includes patients with first relapse, and in which patients will be randomized for treatment with talquetamab and daratumumab; talquetamab and daratumumab with pomalidomide; or daratumumab, pomalidomide, and dexamethasone (DEX). Elranatamab is being studied in the phase III MagnetisMM-5 trial (NCT05020236), where patients who have received at least one prior line of therapy will be randomized to treatment with elranatamab alone; elranatamab with daratumumab; or daratumumb, pomalidomide, and DEX. Safety lead-in cohort data have been encouraging.9 To date, the safety data for BsAb combinations have not identified any new adverse events beyond those observed with single agents. Both teclistamab (MajesTEC-7, NCT05552222) and elranatamab (MagnetisMM-6, NCT05623020) are being studied in combination with lenalidomide and DEX in randomized, phase III studies for patients with newly diagnosed multiple myeloma who are ineligible or not indicated for autologous stem cell transplant (ASCT).
Finally, the immune recovery state after ASCT may be favorable for BsAb engagement of T cells.10 To that end, ongoing randomized phase III study studies are investigating teclistamab and lenalidomide versus lenalidomide maintenance in patients with newly diagnosed myeloma after induction therapy and ASCT (MajesTEC-4, NCT05243797). Patients with newly diagnosed myeloma with measurable residual disease positivity (MRD+) after ASCT could also be considered for the phase III MagnestisMM-7 study (NCT05317416), where they would be randomized for treatment with either elranatamab or lenalidomide.
One of the most exciting combinations is being tested in the phase I RedirecTT-1 study (NCT04586426), in which patients receive both talquetamab and teclistamab.11 Among the 93 patients treated to date, the ORR was 96.3%, while the CR/sCR rate was 40.7%, including an ORR of 86% in patients with extramedullary disease. However, patients experienced unique toxicities related to talquetamab treatment with this combination, including dysgeusia (61.3%), skin/nail toxicities (>50%), and infections (grade 3: >60%; grade 4: 21%). This leads to an important consideration in optimizing the use of BsAb. Can the dosing frequency and duration of therapy be optimized to maintain clinical response without excessive immune exhaustion and increases in toxicity? Indeed, current clinical trials are examining different dosing schedules, including changes in the schedule after clinical response has been obtained.12 Data have also been presented for fixed-duration therapy with cevostamab.13
Looking ahead, the treatment landscape for multiple myeloma is bright. The question may not be whether to choose between CAR-T and BsAbs, but on how to best sequence and use each from the newly diagnosed to relapsed/refractory setting to obtain a “functional cure” for all patients (i.e., treatment-free period or treatment period without major side effects or evidence of disease).
Competing Interests
Dr. Lin indicated no relevant conflicts of interest.
