Therapeutic innovations in MM

In this highlights video from IMS 2026 in Glasgow Dr Nicolas Kint, hematologist at Ghent University Hospital, reflects on key highlights from the meeting regarding innovative treatment strategies. Against a backdrop of increasingly deep and durable remissions three areas stood out during IMS: advancing T-cell redirection through multi-target approaches and novel combinations, shortening access to CAR T-cell therapy through in vivo generation, and improving the prevention of delayed CAR T-cell neurotoxicity.

T-cell redirection has transformed treatment options for heavily pretreated patients, but current bispecific antibodies remain limited by heterogeneous responses and eventual disease progression. One emerging strategy is therefore to target more than one myeloma antigen simultaneously. Experience combining separate BCMA- and GPRC5D-directed therapies has provided a rationale for trispecific T-cell engagers capable of incorporating both targets within a single construct. Updated results with such agents support this concept, showing deep and apparently durable responses in relapsed/refractory disease alongside manageable toxicity. Encouraging activity has also been observed in patients previously exposed to BCMA- or GPRC5D-directed treatment, suggesting that dual-antigen targeting could potentially address resistance and disease heterogeneity. A parallel approach is emerging with dual-targeting CAR T-cell products directed against both BCMA and GPRC5D, which have similarly demonstrated promising early activity.^1-3

Innovation in T-cell redirection does not depend exclusively on new constructs. Existing bispecific antibodies may also be enhanced through rational combinations with immunomodulatory agents or anti-CD38 antibodies, with the aim of strengthening the immune response and increasing the depth and durability of disease control. Early findings combining the BCMA-directed bispecific antibody etentamig with pomalidomide and dexamethasone provided further support for this strategy.⁴ Although these findings are hypothesis-generating rather than comparative evidence, they reinforce the potential of moving beyond bispecific monotherapy toward combinations that enhance T-cell redirection using established immunomodulatory mechanisms.

A second potentially disruptive development concerns the way CAR T cells are produced. Conventional autologous CAR T-cell therapy requires leukapheresis, ex vivo genetic modification and manufacturing, creating a waiting period during which patients frequently require bridging therapy. For those with highly refractory or rapidly progressive disease, this interval can be particularly challenging. In vivo CAR T-cell therapy seeks to circumvent this bottleneck by administering the vector directly to the patient and generating CAR T cells within the body. Early proof-of-concept studies indicate that this approach can enable rapid treatment delivery without leukapheresis or conventional lymphodepletion, while achieving CAR T-cell expansion and encouraging initial antimyeloma responses.^5,6

A third area discussed in the video concerns the important unresolved challenge of current CAR T-cell therapy: delayed, non-ICANS neurotoxicity. Although relatively uncommon, complications including parkinsonism, Guillain–Barré syndrome and cranial nerve palsies can result in substantial morbidity and, in some cases, mortality. One increasingly used preventive strategy is to intervene when marked lymphocyte expansion suggests pronounced CAR T-cell proliferation, for example with a short course of dexamethasone. However, whether this approach actually prevents delayed neurological complications has remained uncertain. Prospective evaluation of pre-emptive dexamethasone, alongside an alternative strategy using cyclophosphamide, did not demonstrate a clear reduction in the incidence of delayed neurotoxicity compared with historical experience. How best to predict, prevent and manage delayed neurotoxicity therefore remains an important unanswered question, emphasizing the need for more effective mitigation strategies as CAR T-cell therapy becomes increasingly integrated into multiple myeloma care.