Talquetamab induces deep responses in heavily pre-treated patients with systemic light-chain amyloidosis

Abstract Background: Treatment alternatives are scarce for patients with primary AL amyloidosis who have progressed following daratumumab- bortezomib cyclophosphamide and dexamethasone (VCD). Recent evidence supports the efficacy of B-cell maturation antigen (BCMA) -targeted agents, including chimeric antigen receptor T-cell therapy (CAR-T), antibody-drug conjugates and T-cell engagers. However, no data are available regarding treatment of AL amyloidosis patients with talquetamab (TAL), a T-cell engager targeting G protein–coupled receptor class C group 5 member D (GPRC5D) with proven efficacy in heavily pretreated multiple myeloma (MM) patients, but also with on target off-tumor toxicity, mainly dysgeusia and weight loss. Methods: A retrospective, multisite case series, evaluating safety and efficacy in relapsed or refractory (R/R) AL amyloidosis patients. All patients who received their first TAL dose escalation (“step-up”) for were included. Efficacy was assessed applying International Society of Amyloidosis (ISA) /European Hematology Association (EHA) consensus hematologic and organ response criteria. Minimal residual disease (MRD) was evaluated by multiparameter flow cytometry at a sensitivity threshold of 10^-5. Results: Patient characteristics: Six patients (five males), median age 63 years (range 53–74), were included. Two had concurrent MM. The heart and kidneys were the most commonly involved organs (five patients each). Three patients had ≥3 organs involved at baseline. At TAL initiation, three patients were Mayo stage 3 or 4. Median N-terminus-pro brain natriuretic protein (NT PROBNP) prior to TAL was 4, 000 pg/mL (range 570–10, 000). All patients had impaired renal function: one with mild (estimated glomerular filtration rate eGFR 50 mL/min/1. 73m²), one with moderate (eGFR 41), and four with severe impairment (eGFR 28, 15, 12, and 11), including two who were dialysis-dependent. Five patients had abnormal cytogenetics; three had 1q gain (one also with del17p), two had del13, and t (4;14) and t (11;14) were each detected in one patient. Patients had received a median of 7 (range 2–11) prior treatment lines. All were refractory to daratumumab, bortezomib, cyclophosphamide, and pomalidomide; four were refractory to lenalidomide and belantamab mafodotin; one patient with t (11;14) was refractory to venetoclax. Three relapsed after anti-BCMA academic CAR-T (HBI0101). Additional therapies included ixazomib (2), carfilzomib (1), elotuzumab (1), and melphalan (1). TAL was initiated for progressive disease (PD) in four patients and for insufficient response in two. Efficacy: Five patients (83%) achieved hematologic response, all of whom obtained complete remission (CR). MRD testing, performed in three patients, was negative in all. Among responders, three remain in CR at 19, 8, and 3 months of follow-up. At data cutoff, three patients were alive (all in hematologic CR), while three had died: one after discontinuing TAL while in CR, experienced clinical deterioration and later relapsed and died from sepsis; one from cardiac failure despite achieving CR ; and one who was primary refractory. Time from TAL initiation to death was 6 months, 6 weeks and 4 weeks, respectively. None of the patients received subsequent therapy. Cardiac response was assessed in two of five with cardiac involvement: one achieved complete cardiac response, while the refractory patient showed cardiac progression. Safety: Cytokine release syndrome (CRS) occurred in four patients (all grade 1–2). One patient developed grade 2 immune effector-cell–associated neurotoxicity syndrome (ICANS). Infectious complications included sepsis (one grade 3, one grade 5). Congestive heart failure exacerbation occurred in 2 (grades 3 and 4). Additional adverse events included: grade 1–2 dysgeusia, xerostomia, weight loss (two patients each) ; anemia (grade 3) and thrombocytopenia (grade 2, one each). Conclusions: Talquetamab produced deep and durable hematologic responses in heavily pretreated patients with R/R AL amyloidosis. Assessment of organ response potential was limited by irreversible organ dysfunction at baseline and short follow-up. Treatment was feasible, including in end-stage renal disease, and the safety profile was manageable without unexpected toxicities. These results support further investigation of talquetamab in this setting.