Teclistamab Induces Rapid Responses in Patients with Relapsed/Refractory AL Amyloidosis

Introduction

Systemic light chain (AL) amyloidosis is a rare disorder characterized by tissue deposition of amyloid fibrils derived from immunoglobulin free light chains. While daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) is the standard for upfront treatment of AL, management of relapsed/refractory (R/R) disease is often challenging, particularly in context of multiorgan dysfunction. Teclistamab was recently approved for treatment of R/R multiple myeloma (MM) and showed an overall response rate (ORR) of 63% (N Engl J Med 2022;387:495). Notable adverse effects (AEs) included cytokine release syndrome (CRS), neurologic, renal and hematologic toxicities, and infections. Efficacy of teclistamab in AL has not been previously reported. Here, we present a series of three patients who received treatment with teclistamab for R/R AL and MM.

Methods

In this retrospective study, we included all patients with R/R AL and MM who received teclistamab at two US academic centers between October 2022 and July 2023. We recorded all standard metrics, including serologic and biomarker data. Hematologic and organ responses were evaluated based on standard consensus criteria. Toxicity assessment was performed in accordance with the NCI CTCAE v5.0, except for CRS and neurotoxicity, which were graded according to the 2019 ASTCT criteria (BBMT 2019;25:625).

Results

We identified 3 patients; baseline characteristics are provided in Table 1 and treatment data in Table 2. Median age was 67 years (range, 54-70). All patients were male, and 2 had AL λ-type. At the time of teclistamab initiation, the median number of prior therapies was 7 (5-10), with all patients being refractory to a bortezomib, lenalidomide and daratumumab. Median iFLC was 228 mg/L (45.5-1272) with 10% median bone marrow (BM) plasmacytosis. In one patient with rapidly progressive multiple myeloma, BM FISH showed high-risk cytogenetic changes, including gain 1q, del 1p and del 17p.

All patients were hospitalized for treatment initiation and received escalating doses of 0.06 mg/kg, 0.3 mg/kg and 1.5 mg/kg during the ramp-up phase. Subsequent treatment with target dose of 1.5 mg/kg was continued in the outpatient setting on a weekly basis. Monitoring for cytokine release syndrome (CRS) and neurologic toxicity was performed in accordance with institutional protocols.

At a median follow-up of 49 days (44-58), 2 patients achieved hematologic responses (HR), with 1 complete hematologic response (CR) and 1 low dFLC PR. Both hematologic responses occurred promptly within 3 weeks of treatment initiation, were deep with iFLC <10 mg/L, and were ongoing at the last follow-up. One patient with rapid renal progression prior to teclistamab also enjoyed a renal response by day 42. The most common toxicity was hematologic, with 1 patient experiencing grade 4 lymphopenia, grade 2 thrombocytopenia and hypogammaglobulinemia. There were no infectious complications or instances of febrile neutropenia, CRS or neurologic AEs. All patients received routine prophylaxis against VZV and PJP, as well as prophylactic IVIg. One patient with heavily pre-treated, high-risk MM had an aggressive clinical relapse with widespread osseous involvement within 6 months of an autologous stem cell transplant (ASCT) and experienced progressive disease as best response to teclistamab, necessitating discontinuation after 29 days in favor of cytotoxic chemotherapy.

Conclusion

In this series of 3 patients with heavily pre-treated, R/R AL and MM, teclistamab showed an impressive hematologic response rate of 67%. These responses were deep and occurred rapidly within 3 weeks of treatment initiation. One patient also enjoyed a renal response, whereas cardiac responses were non-evaluable in 2 patients. While the most common treatment-related toxicity was hematologic in nature, infections or febrile neutropenia were not observed, likely due to the institution of aggressive prophylactic measures. Importantly, no new safety signals were identified in AL patients. To our knowledge, this is the first report providing preliminary evidence for efficacy of teclistamab in R/R AL, highlighting the need to investigate this strategy in clinical trials.