Combination of Talquetamab and Pomalidomide in relapse-refractory high-risk Multiple Myeloma, including refractoriness to Mezigdomide

Ultra-high-risk multiple myeloma (MM) patients present a very aggressive disease course and are often associated with early relapse and dismal outcomes. Here, we present a complex of ultra-high-risk myeloma where the patient exhausted all possible combinations, responding well to Talqeutamab and Pomalidomide despite relapsing on single-agent Talqeutamab alone and cereblon E3 ubiquitin ligase modulator.

She is a 55-year-old African American female, ECOG 1, who presented with aggressive IgG Kappa MM with 3% circulating plasma cells, multiple lytic lesions, 80% clonal plasma cells, TP53 deletion, and gain of 1q FISH results. She initially received the RVd regimen and had a partial response to the treatment. After 5 cycles, she underwent Autologous stem cell transplantation (ASCT). However, on day 60 post-ASCT, she had biochemical relapse. She then received Bortezomib, Mezigdomide, and dexamethasone, but had a poor response to the regimen and progressed within 2 months. Subsequently, she received Daratumumab, Carfilzomib, Dexamethasone (PFS 1 month) and then Carfilzomib, Cyclophosphamide, Dexamethasone (PFS 2 months), BCMA CAR-T (PFS 5 months), Allo-BCMA CAR-T (PFS 2 months). She then started talquetamab; however, she progressed again within 2 months, with a rapid rise in kappa light chains. At that time, pomalidomide 2mg was added to Talquetamab, which led to a dramatic drop in light chains. She is now VGPR, after 5 months on Talquetamab and pomalidomide, and doing well.

Given the immunomodulatory drug (IMiD) resistance in MM, the identification of biomarkers that can accurately predict drug responses is of high importance to discover novel therapeutic combinations. Our case highlights two important points. First, this case concurs with prior experimental findings that pomalidomide can be effective despite resistance to a cereblon E3 ubiquitin ligase modulator(mezigdomide). Second, despite multiple lines of therapy and refractory disease to Talquetamab, pomalidomide can be effective in combination with Talquetamab. The Phase 1b MonumenTAL-2 trial has reinforced this initial efficacy with overall response rates exceeding 84% while demonstrating a tolerable side effect profile, which necessitates further investigation of this regimen, particularly in cases where patients have been tried on more than 2 prior lines of treatment. Future studies should focus on incorporating this novel strategy in high-risk MM despite prior use of IMiD and cereblon E3 ubiquitin ligase modulator.