Discordant Biochemical and Clinical Response During Talquetamab Therapy in Multi-Refractory Myeloma

Introduction/Background/Significance: Patients with relapsed/refractory multiple myeloma (RRMM) often undergo numerous lines of therapy, including novel bispecific agents such as talquetamab. Data on the safety and efficacy of these agents in patients with end-stage renal disease (ESRD) remain limited. Moreover, biochemical markers—including serum free light chains and M-protein—may not reliably reflect true disease status, as extramedullary progression can occur despite apparent serologic response. We present a case of dialysis-dependent RRMM in which Talquetamab therapy led to marked biochemical improvement but was complicated by cytokine release syndrome (CRS) and clinically significant extramedullary progression.

Materials and Methods/Case Presentation/Objective: A 68-year-old Black male with IgG kappa RRMM, initially diagnosed in 2019 with light chain myeloma complicated by AKI and subsequent ESRD (myeloma kidney), was treated with multiple prior lines including CyBorD, autologous stem cell transplant (ASCT in 12/2019), and Revlimid maintenance, which he self-discontinued in 7/2022 due to intolerable muscle cramping. He maintained a complete response until mid-2023, when relapse occurred. After failing Elranatamab and Tecvayli, he initiated Talquetamab therapy with step-up dosing over a 6-day period. The treatment dose was deferred due to development of Grade 2 cytokine release syndrome (CRS), and the patient was discharged prior to receiving the planned full dose. He was readmitted on 5/11 with fever, hypotension, and pancytopenia. Blood cultures grew Staph epidermidis. He was treated with vancomycin, which was later discontinued when repeat cultures remained negative. He received dexamethasone for CRS. Talquetamab was held due to ongoing cytopenias and ultimately not resumed given the patient's clinical decline.

Results/Description/Main Outcome Measures: The patient showed a marked biochemical response to Talquetamab, with serum kappa free light chains declining from >64,000 to 5,535 mg/L and M-spike from 1.37 to 0.05 g/dL. However, he developed new right shoulder swelling; biopsy of the deltoid mass confirmed 72% plasma cell infiltration, indicating extramedullary progression. Despite negative repeat cultures and normal serum viscosity, the patient's bilirubin rose and respiratory status worsened. CT imaging revealed diffuse alveolar infiltrates. Bone marrow biopsy and bronchoscopy were offered but declined. The discordance between serologic improvement and clinical deterioration led to recognition of disease progression and a transition to inpatient hospice.

Conclusions: This case highlights that biochemical response to bispecific therapy may not reflect true disease status in relapsed/refractory multiple myeloma. Extramedullary progression can occur even as markers improve, emphasizing the importance of tissue confirmation when clinical status worsens. The experience underscores the need for vigilance in interpreting responses to novel therapies and illustrates the critical role of timely palliative care integration.