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BsAbs Updates for R/R MM
Latest Research and Clinical Development With Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma

Released: May 20, 2025

Expiration: May 19, 2026

Noopur Raje
Noopur Raje, MD
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Key Takeaways
  • Clinical trials of approved bispecific antibodies (BsAbs) (eg, elranatamab, teclistamab, and talquetamab) in combination with standard-of-care therapies have demonstrated encouraging efficacy for patients with relapsed/refractory multiple myeloma.
  • Other promising BsAbs in development include linvoseltamab, etentamig, and cevostamab.
  • Ongoing BsAbs trials are evaluating fewer frequent dosing schedules to help mitigate class-related cytokine syndrome and neurotoxicity.


Introduction
Bispecific antibodies (BsAbs) are one of the newest classes of therapy approved for patients with relapsed/refractory (R/R) multiple myeloma (MM). BsAbs are off-the-shelf antibodies that target a tumor antigen of interest and a cell-surface protein on T-cells. These therapies aid recruitment of T‑cells to tumor cells, facilitating tumor-cell targeting/apoptosis by the patient’s own immune system. Currently there are 3 FDA-approved BsAbs, including elranatamab; and teclistamab, targeting both CD3 and BCMA; and talquetamab, which targets both CD3 and GPRC5D. All 3 BsAbs are approved as single-agent therapy for patients with R/R MM after ≥4 previous lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. Because BsAbs have demonstrated safety and efficacy as single-agent treatment for R/R MM, they are now being explored in earlier settings and as part of novel combination regimens.

Ongoing Trials and Promising Combination Strategies With Approved BsAbs
Current studies are focused on combining BsAbs with backbone therapies that have long defined MM treatment, such as CD38-targeted antibodies (daratumumab or isatuximab), IMiDs (lenalidomide or pomalidomide), and/or PIs (bortezomib or carfilzomib). These combinations are not only logical from a mechanistic standpoint, but also practical, as they aim to build on familiar regimens with proven efficacy and manageable toxicity profiles.

Elranatamab
MagnetisMM-5 is a phase III ongoing confirmatory trial comparing elranatamab as monotherapy or in combination with daratumumab vs daratumumab plus pomalidomide plus dexamethasone in patients with R/R MM who have received prior therapy, including lenalidomide and a PI (NCT05020236). In the preliminary results from the safety lead-in cohort of the MagnetisMM-5 study, elranatamab in combination with daratumumab has an overall response rate (ORR) of 70.6%.

In the phase Ib MagnetisMM-20 study part 1, patients with R/R MM and 1-3 prior lines of therapy and no prior BCMA-directed therapy were treated with elranatamab plus carfilzomib plus dexamethasone (NCT05675449). In the 12 patients included in this analysis, the ORR with this combination was 100% (complete response or better in 75%), suggesting that this combination approach results in impressive response rates.

Another noteworthy phase III trial with elranatamab is MagnetisMM-6, which is comparing elranatamab plus daratumumab plus lenalidomide (EDR) vs daratumumab plus lenalidomide plus dexamethasone (DRd) in patients with newly diagnosed MM (NCT05623020). This study includes 2 parts: Part 1 will help determine the safety and recommended phase III dosing for EDR in patients with either newly diagnosed MM who are ineligible for autologous stem cell transplant (ASCT) or with R/R MM after 1-2 prior therapies including ≥1 IMiD and ≥1 PI. Part 2 will randomize patients to either EDR or DRd and include only patients with newly diagnosed MM who are transplant ineligible.

Teclistamab
The ongoing confirmatory phase III trial for teclistamab is MajesTEC-3, which is exploring teclistamab plus daratumumab vs daratumumab plus pomalidomide plus dexamethasone or daratumumab plus bortezomib plus dexamethasone in patients with R/R MM after 1-3 prior lines of therapy, including a PI and lenalidomide (NCT05083169). In addition, the phase III MajesTEC-9 trial is comparing teclistamab monotherapy vs investigator’s choice of either pomalidomide plus bortezomib plus dexamethasone or carfilzomib plus dexamethasone in patients with R/R MM after 1-3 prior therapies including an anti-CD38 monoclonal antibody and lenalidomide (NCT05572515). Results of these phase III trials will help guide healthcare professionals on the optimal use of teclistamab in clinical practice.

There are also multiple earlier phase studies with preliminary results for teclistamab combinations. A pooled analysis of the phase Ib trials, MajesTEC-2 (in patients with R/R MM after 1-3 previous therapies, including a PI and lenalidomide) and TRIMM-2 (in patients with R/R MM after ≥3 previous therapies, including a PI and IMiD) reported an ORR of 88.5% with the combination of pomalidomide plus daratumumab plus teclistamab in 27 patients after a median follow-up of 25.8 months. The phase Ib/II RedirecTT-1 study assessed the combination of teclistamab plus talquetamab in patients with R/R MM and prior therapy with a PI, IMiD, and anti-CD38 therapy and reported an ORR of 79.5% with teclistamab plus talquetamab in the overall patient population and 61.1% in patients with extramedullary disease.

Finally, preliminary data from the phase II MajesTEC-5 and the phase III MajesTEC-4/EMN30 trials suggest that teclistamab combinations may have a role in patients with newly diagnosed MM, either as a part of induction or maintenance therapy.  

Talquetamab
Like the combination studies with the BCMA-targeted BsAbs, ongoing trials are also assessing talquetamab in various combinations. The phase III MonumenTAL-3 is ongoing, with talquetamab plus daratumumab with or without pomalidomide vs daratumumab plus pomalidomide plus dexamethasone in patients with R/R MM after ≥1 prior therapies including a PI and lenalidomide (NCT05455320).

This trial is supported by data from the phase Ib TRIMM-2 study, which included an evaluation of talquetamab plus daratumumab plus pomalidomide in patients with R/R MM after ≥3 previous lines of therapy, including a PI and an IMiD, or those who were refractory to both a PI and an IMiD and had not yet received a CD38-targeted therapy. Data from TRIMM-2 showed an ORR of 82% with this combination, even in patients who had received prior BsAbs, and a median progression-free survival (PFS) of up to 20 months.

In addition, the phase Ib MonumenTAL-2 study included talquetamab in combination with different backbones in various cohorts of patients with MM (NCT05050097). In a cohort of patients with R/R MM after ≥2 previous lines of therapy, including a PI and lenalidomide, the combination of talquetamab plus pomalidomide showed an ORR of 88.6%. In a cohort of patients with newly diagnosed MM who were not eligible for ASCT, the combination of talquetamab plus daratumumab plus lenalidomide reported an ORR of 100% with every-2-week talquetamab and 96.2% with every-4-week talquetamab and a 6-month PFS of 100% with the every-2-week talquetamab and 95.8% with every-4-week talquetamab.  

Additional phase III studies include MonumenTAL-6, which is assessing talquetamab plus pomalidomide plus dexamethasone or talquetamab plus teclistamab plus dexamethasone vs pomalidomide plus elotuzumab plus dexamethasone or pomalidomide plus bortezomib plus dexamethasone in patients with R/R MM after 1-4 previous lines of treatment, including an CD38-targeted antibody and lenalidomide (NCT06208150).

Finally, the phase III MajesTEC-7 trial is assessing teclistamab and talquetamab combinations in patients with newly diagnosed MM who are not candidates for ASCT (NCT05552222). This study is comparing the efficacy and safety of teclistamab plus daratumumab plus lenalidomide (Tec-DR) and talquetamab plus daratumumab plus lenalidomide (Tal-DR) vs standard treatment with daratumumab plus lenalidomide plus dexamethasone (DRd). Results from the safety run-in cohort with Tec-DR reported an ORR of 92.3% with a 12-month PFS rate of 96.2%.

Novel BsAbs in Clinical Development
There are several other BsAbs in clinical development that are building upon our current knowledge. Linvoseltamab is a BsAbs targeting BCMA and is currently under review by the FDA for patients with R/R MM after ≥4 prior lines of therapy or after 3 prior lines of therapy for those who are refractory to their last line of therapy, based on the phase I/II LINKER-MM1 trial. Linvoseltamab administration is unique in that it is given by weekly intravenous infusion and does not require the step-up dosing needed to mitigate cytokine release syndrome (CRS) with other BsAbs like elranatamab, teclistamab, or talquetamab. Of importance, linvoseltamab is associated with a lower incidence of CRS and neurotoxicity.

Linvoseltamab is currently being evaluated in 2 ongoing phase III trials. The confirmatory trial LINKER-MM3 in patients with R/R MM after 1-4 prior lines of therapy, including lenalidomide and a PI, is assessing efficacy and safety of linvoseltamab vs elotuzumab plus pomalidomide plus dexamethasone (NCT05730036). The EMN39 trial is exploring the use of linvoseltamab as maintenance therapy after induction with daratumumab plus lenalidomide plus dexamethasone vs continued daratumumab plus lenalidomide plus dexamethasone in adults with newly diagnosed MM who are ineligible for ASCT (NCT06932562). Like the approved BCMA-targeted BsAbs, linvoseltamab is also being assessed in various combinations, including in a multicohort phase I study with many of the standard antimyeloma back-bone regimens (NCT05137054).

Etentamig is another BCMA-targeted BsAb in development. Similar to linvoseltamab, it is administered by intravenous infusion. Etentamig monotherapy is being studied against standard-of-care therapies (carfilzomib plus dexamethasone; elotuzumab plus pomalidomide plus dexamethasone; or selinexor plus bortezomib plus dexamethasone) in adults with R/R MM (≥2 prior therapies, including a PI, IMiD, and an anti-CD38 monoclonal antibody) in a phase III trial (NCT06158841).

Cevostamab is a BsAb that targets a very different antigen FcRH5, which is another target present on multiple myeloma cells. The function of FcRH5 is still unknown; however, we do know that targeting against FcRH5 with cevostamab leads to high response rates in the context of MM. Specifically, updated results from an ongoing phase I study of cevostamab in patients with heavily pretreated R/R MM showed an ORR of 43.1% in patients receiving the 160 mg target dose (NCT03275103).

Future Strategies to Mitigate BsAb Adverse Events 
Common adverse events (AEs) associated with BsAbs (either BCMA-targeted or GPRC5D-targeted agents) include CRS and ICANS. However, we now have more experience in the management of CRS and ICANS extrapolated from the use of CAR T-cell therapies for patients with R/R MM, as well as with the clinical use of currently approved BsAbs. Unique AEs associated with GPRC5D-targeted BsAb, talquetamab are skin, nail, hair, and oral toxicity. Many nonpharmacologic strategies exist to manage these toxicities (eg, skin emollients, nail hardeners).

Alternative dosing schedules are being explored with the current BsAb armamentarium to better mitigate these and other AEs. At this time, the available BsAbs elranatamab, teclistamab, and talquetamab are used either weekly or every other week, but there are clinical trials underway (NCT06421675, NCT05932680) that are looking at the BsAbs with alternate dosing schedules, whether it be monthly or even less frequently. Over the next year or so, we will have a better understanding of what the ideal dosing of these BsAbs should be.

Your Thoughts
Which developments with the BsAbs for your patients with R/R MM excite you the most? Join the discussion by leaving a comment below. Download the slides, listen to a podcast, and access our Interactive Decision Support Tool to learn from the experts on R/R MM management and BsAb-related AEs.

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