What is on the horizon for BCMA-directed ADCs in MM?

The Multiple Myeloma Hub spoke with Marc Raab, Heidelberg University Hospital, DE. We asked, What is on the horizon for BCMA-directed antibody–drug conjugates in multiple myeloma. 

In this interview, Raab discusses the ongoing development of belantamab mafodotin in additional combination regimens and earlier lines of therapy, as well as investigational antibody–drug conjugates (ADCs) incorporating alternative cytotoxic payloads or targeting other antigens. Raab also explores the potential role of ADC-based regimens for patients who are ineligible for, or have previously received, chimeric antigen receptor (CAR) T-cell therapy or bispecific antibodies. 

Key points 

• ADCs deliver a cytotoxic payload to target-expressing myeloma cells and can be combined with established multiple myeloma (MM) treatments.¹ 
• Belantamab mafodotin, a B-cell maturation antigen (BCMA)-directed ADC, is approved in combination with bortezomib + dexamethasone (Vd) by the U.S. Food and Drug Administration (FDA) after two prior lines of therapy and in combination with Vd or pomalidomide + dexamethasone (Pd), by the European Medicines Agency (EMA) after one prior line of therapy in patients with relapsed/refractory MM (RRMM).² 
• Belantamab mafodotin is being investigated in new combination regimens, such as with standard-of-care therapies in earlier treatment settings, including frontline MM.² 
• In frontline MM, belantamab mafodotin-based combinations are being investigated in patients who are ineligible for transplant, including as an alternative to the anti-CD38 antibody component of standard-of-care bortezomib + lenalidomide + dexamethasone (VRd)-based regimens.² 
• Investigational BCMA-directed ADCs are also being evaluated, including HDP-101, which incorporates the cytotoxic payload amanitin, while belantamab mafodotin carries monomethyl auristatin F.^1,3  
• The HDP-101 payload inhibits RNA polymerase II, disrupting cellular transcription irrespective of cell proliferation status and potentially enabling activity against non-dividing myeloma cells.³ 
• ADCs targeting alternative antigens, including G protein-coupled receptor, class C, group 5, member D (GPRC5D), are also under investigation. These approaches may offer an alternative strategy when BCMA expression is lost or altered.^4,5 
• Ongoing ADC development in MM includes evaluating approved agents in earlier treatment settings and new combinations, alongside investigational ADCs incorporating alternative payloads and antigen targets.^1–4  

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