Elranatamab in Patients with Daratumumab Relapsed and/or Refractory Light Chain Amyloidosis
Authors: Vianna Pedro G , Hossain Shahrier , Miller Shannon , Rossi Annemarie , Cuddy Sarah AM , Falk Rodney H , Laubach Jacob P. , Bianchi Giada 
Published: December 2024

Background:
Immunoglobulin light chain (AL) amyloidosis patients benefit from anti-plasma cell therapies effective in multiple myeloma (MM). However, significant cardiovascular and/or renal involvement poses additional safety concerns. Rapid and deep normalization of involved immunoglobulin free light chains (iFLCs) is necessary to halt progressive organ dysfunction and maximize survival. There are no FDA-approved treatments for AL amyloidosis patients with relapsed and/or refractory (RR) disease following frontline Daratumumab-containing regimens. Effective and tolerable therapies for this high-risk population remains a critical unmet need. B-cell maturation antigen (BCMA)-targeting bispecific T-cell engagers (BiTEs), Teclistimab and Elranatamab have shown rapid and durable responses in RRMM with a lower incidence and severity of cytokine release syndrome (CRS) compared to chimeric antigen receptor T-cell therapies. Two retrospective case series of RRAL patients treated with Teclistimab showed 88-100% very-good partial response or better (≥VGPR) with acceptable side effects. There are no published data on Elranatamab in AL. Herein, we report safety and efficacy data on three consecutive, Daratumumab-refractory AL amyloidosis patients treated with Elranatamab in a real-life setting.
Methods:
We retrospectively identified three AL amyloidosis patients who were refractory to Daratumumab-based therapy, defined as failure to achieve a ≥VGPR after two cycles and/or progressive disease while on therapy, and who had received at least one full dose between February-June 2024 at our center. All patients received anti-viral and anti-Pneumocystis prophylaxis, and monthly intravenous immunoglobulins. All patients gave informed consent. The revised 2004 Mayo Clinic criteria with European modifications were used for cardiac staging. Hematological and organ responses were assessed according to consensus criteria.
Results:
The median age was 64 years (range 46-68). All patients had advanced stage cardiac involvement: Two were Mayo stage 3A and one Mayo stage 3B. Baseline NT-proBNP was 2,164 pg/mL (range 2031-26,684). All were transplant ineligible, BCMA-naïve, had received a median of two lines of prior therapy, and were refractory to their immediate prior line of treatment. Two patients were negative for the presence of a t(11;14). No patients met criteria for MM based on CRAB criteria or bone marrow plasmacytosis, but two patients had a FLC ratio &gt;100. The mean difference between iFLC and uninvolved FLC (dFLC) was 192.4 mg/L (range 48.2-641.8) prior to Elranatamab initiation. At a median follow up of 141 days (range 140-178), patients had received an average of 11 doses of Elranatamab (range 8-19). We observed a 100% hematological complete response (hCR) with all patients achieving a dFLC &lt;10 mg/L at the end of the first cycle. Median time to hCR was 14 days (range 11-14). Minimal residual disease (MRD) could be assessed in two patients via Clonoseq at 10-6 and both were MRD-negative after 3-5 cycles. Two patients evaluable for a cardiac response achieved a cardiacVGPR after three cycles. All patients are alive and in an ongoing hCR at the time of this report. Two patients developed CRS, and all were grade 2. CRS occurred within 24 hours of the first priming dose, lasted two days, and resolved with IV fluids, tocilizumab, and dexamethasone without recurrence. We did not observe immune effector cell-associate neurotoxicity syndrome (ICANS), acute heart failure decompensation, or admission to the intensive care unit. Treatment-related cytopenia were seen in two patients during the first cycle, one grade 2 neutropenia and one grade 1 thrombocytopenia. There were no infectious complications.
Conclusion:
In this case series of heavily pre-treated Daratumumab relapsed/ refractory AL amyloidosis patients with advanced cardiac involvement, Elranatamab elicited rapid and deep hematological responses with all patients achieving a hematological complete response with deep suppression of iFLC within two weeks of treatment initiation, including MRD negative disease and cardiac responses in all tested patients after 3-5 cycles. Elranatamab was well-tolerated with no added toxicity and acceptable safety profile. These data support Elranatamab's use in relapsed/refractory AL amyloidosis and prospective studies using BCMA-targeting BiTEs in this high-risk, high-need population.