Real-world safety and efficacy of BCMA bispecific antibodies in relapsed light chain amyloidosis Free

Light Chain (AL) Amyloidosis is a clonal plasma cell and protein processing disorder resulting in misfolded kappa or lambda light chains that deposit in key viscera leading to organ dysfunction. Amyloid production is shut down by achieving hematologic complete response (hCR) with anti-plasma cell therapy. With rapid hCR both overall survival (OS) and major organ deterioration progression free survival (MOD-PFS) improve. The current standard of care for newly diagnosed AL Amyloidosis is Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone with a hCR rate of 59.5% with median time to hCR of 67.5 days. There are three FDA approved B-cell maturation antigen (BCMA) bispecific antibodies (BSAbs) for the treatment of relapsed refractory multiple myeloma (RRMM) after 4+ lines of therapy, Teclistimab, Elranatamab and Linvoseltamab. All three products have impressive overall response rates (ORR) of 61-70% in heavily pre-treated MM. Studies are evaluating safety and efficacy in newly diagnosed MM (NDMM) in combinations with other myeloma drug classes and in a maintenance regimen after ASCT. However, there is limited safety and efficacy regarding BCMA BSAbs in AL Amyloidosis.

Our database combines two quaternary health care systems that identified 20 patients with relapsed AL Amyloidosis who received either Teclistimab or Elranatamab. We reviewed the charts for patient demographics, disease characteristics, treatment history and details regarding adverse events and response to BCMA BiAbs.

Of the 20 patients, median age 73 (60-83), 55% were female and the majority were caucasian 17 (85%). Patients received a median of 4 (3-10) prior lines of treatment. There were 14 patients with cardiac involvement with the following breakdown based on the 2004 Mayo Cardiac Staging: 3 with stage IIIB, 9 with stage IIIA, none with stage II and 2 with stage I. The average NTproBNP at the time of BCMA BsAb initiation was 8828 with a minimum of 284 and maximum of 70,000. Twelve patients had renal involvement. The median plasma cell bone marrow involvement at diagnosis was 10% (5-94%). There were two cases with dual diagnosis with myeloma. Eighteen of the 20 patients had cytogenetics performed; 6 had t(11;14) and 8 had high-risk FISH.

One patient was not included in the safety and efficacy analysis due to disease related death during step-up dosing. Based on the 19 patients included there was a 100% ORR, with 100% achieving a hCR. Median times to first hematologic response and to hCR were 0.5 (0.2-0.9) and 0.7 (0.2-1.9) months respectively. Eight of the 14 patients with cardiac amyloid had evidence of organ recovery with steady reduction in NT-pro-BNP. The data has not matured to determine DOR or survival analyses; however, multiple patients have a DOR in hCR for >20 months. Seventeen of 20 patients received PJP prophylaxis. Two reports of grade 3 neutropenia with upper respiratory infection, both supported with IVIG and G-CSF. Six patients discontinued therapy after achieving hCR and maintaining excellent disease control off treatment, with three patients ~12 months from the last BCMA BsAB dose.

In RR AL Amyloidosis we report an impressive ORR, hCR rate and time to hCR with a favorable safety profile. In AL Amyloidosis, there is an unmet need to improve both the hCR rate and time to hCR, especially those with advanced organ damage. Clinical trials to assess safety and efficacy for the use of BCMA BSAbs in AL Amyloidosis, specifically newly diagnosed, are essential in improving clinical outcomes. Studies will also need to address the optimal dose schedule and best approach regarding duration of therapy: a continuous or fixed course.