Week 1, April 2026: Multiple Myeloma Antibody Treatments: A Field in Transition

More formats, more targets, more questions

Multiple myeloma (MM) treatment is increasingly shaped by antibody-based approaches, with monoclonal antibodies being redesigned, and newer formats (bispecifics, trispecifics, ADCs), expanding what antibodies can actually do in patients.

A few patterns seem to be taking shape:

• BCMA has become a central anchor, but not the only one anymore

• Immune redirection is now as important as direct tumor targeting

• Engineering (affinity, valency, dosing) is starting to matter as much as target choice

From early monoclonals to engineered specificity

Earlier antibody strategies in MM were largely about finding a target to hit, such as CD38, IL-6, CD40, and others, and then relying on mechanisms like ADCC or CDC. These approaches work, but can be inconsistent in the clinic, partly because target expression isn’t uniform and the bone marrow microenvironment is protective.

Nowadays, there is greater emphasis on plasma cell-restricted antigens (e.g., BCMA), less reliance on passive immune mechanisms, more on active immune engagement, and recognition that target selection alone isn’t enough.

Antibody-drug conjugates: lessons from belantamab mafodotin

The clinical trajectory of belantamab mafodotin highlights both the promise and challenges of ADCs in MM. The drug works through BCMA targeting with the microtubule-disrupting payload monomethyl auristatin F (MMAF), for targeted cytotoxic delivery. However, its withdrawal and subsequent reapproval highlight a broader trend in ADC development: the need to balance potency with manageable toxicity profiles, particularly ocular adverse events.

This has informed next-generation ADC design strategies, including optimization of linker stability, payload selection, and dosing regimens. ADCs are increasingly being reconsidered earlier in treatment if tolerability can be improved.

Bispecific antibodies: rapid expansion of off-the-shelf T-cell engagers

Bispecific antibodies are driving momentum in MM, as they simultaneously bind a tumor-associated antigen (e.g., BCMA, GPRC5D, FcRH5) and CD3 on T cells, resulting in immune synapse formation and cytotoxic activation.

A few trends within this space:

• BCMA remains the most validated target, but antigen escape is already a concern

• Expansion to alternative antigens such as GPRC5D (e.g., talquetamab) or FcRH5 (e.g., cevostamab)

• “Off-the-shelf” advantage as there is less manufacturing delay compared to CAR-T, and easier scalability in clinical practice

Trispecific antibodies: addressing resistance and enhancing immune engagement

Trispecific antibodies (e.g., targeting BCMA + CD38 + CD3) are still early in development, but they reflect where the field might be heading.

Preclinical and early clinical data suggest that trispecific formats may overcome key resistance mechanisms observed with bsAbs, including antigen loss and T-cell exhaustion. Furthermore, alternative designs incorporating co-stimulatory domains seek to augment T-cell persistence and functionality.

This modality reflects a growing recognition that single-antigen targeting may be insufficient in the context of clonal heterogeneity and dynamic tumor evolution in MM.

Resistance is shaping strategy

One consistent theme across studies is that resistance emerges through multiple routes:

• Antigen loss (e.g., BCMA alterations)

• T-cell exhaustion

• Microenvironmental suppression

Conclusion: toward multi-specific, immune-driven treatments

As resistance mechanisms become better understood and engineering technologies continue to advance, the future of MM therapy will likely be defined by:

• Earlier use of these agents, when immune function is less compromised

• More rational combinations, guided by antigen expression and prior exposure