Suzanne Lentzsch

Immunomodulatory drugs (IMiDs) have fundamentally reshaped multiple myeloma therapy, extending survival and establishing durable backbones across induction, relapse, and maintenance. Cereblon's identification as a druggable E3 ligase substrate receptor created the mechanistic path to next-generation modulators, whereas widespread frontline lenalidomide exposure created the clinical need for scalable oral agents active in IMiD-refractory, triple-class–exposed disease. In this review, we link the clinical evolution of the IMiD class to its mechanistic foundation. We trace the path from thalidomide's serendipitous repurposing to lenalidomide's establishment of the Rd backbone and maintenance paradigm and to pomalidomide's ability to retain efficacy after lenalidomide failure. We integrate structural and biochemical insights showing how medicinal chemistry reshaped cereblon engagement and selective neosubstrate degradation, producing tumor-intrinsic and immune-mediated effects. We then focus on next-generation cereblon E3 ligase modulators (CELMoDs), including iberdomide and mezigdomide, designed to deepen cereblon modulation and overcome resistance. We summarize early clinical experience and ongoing randomized programs, discuss rational combinations with monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapies, and propose a pragmatic framework for positioning CELMoDs in an immunotherapy-rich treatment era.

1. Systemic amyloidosis refers to a group of protein-misfolding disorders, resulting in dysfunction and potentially organ failure if not treated properly [1–3]. Amyloid fibrils are formed by normal...

Light chain (AL) amyloidosis is a fatal plasma cell dyscrasia characterized by the overproduction of misfolded l or k immunoglobulin light chains (LCs) produced by clonal plasma cells, which aggregate into amyloid fibrils that deposit in tissues and cause progressive organ damage. While current anti-plasma cell therapies reduce the production of new amyloidogenic LCs, pre-existing fibrils persist and continue to drive organ damage. Amyloid-targeting monoclonal antibodies birtamimab and anselamimab were developed and tested for active AL amyloid clearance; however, they failed to meet the primary endpoint in Phase 3 trials, presumably due to insufficient binding affinity for l LC amyloid, which occurs in ~80% of patients. Here, we reported the development of 1F10, a novel high-affinity l subtype-specific amyloid-binding monoclonal antibody that does not cross-react with soluble native l or k LCs. 1F10 exhibits superior binding affinity to l AL amyloid fibrils and significantly enhances antibody-dependent phagocytosis (ADP) of l AL amyloid compared with birtamimab and anselamimab. Specific binding of 1F10 to l amyloid is confirmed by immunohistochemical staining of patient-derived tissue biopsies. Importantly, 1F10 demonstrates robust in vivo activity, significantly accelerating the resolution of l amyloid fibrils in an AL amyloidoma mouse model. Together, these findings establish 1F10 antibody as a promising subtype-specific immunotherapeutic candidate for targeting l LC amyloid, addressing a critical unmet need for the majority of patients with AL amyloidosis.

PURPOSE: In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS: Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS: Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION: Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

The B-cell maturation antigen (BCMA)–targeting bispecific T-cell engager pavurutamab (AMG 701) directs the cytotoxic T-cell response toward multiple myeloma (MM) cells. This phase 1/1b, open-label, dose-exploration and dose-expansion study evaluated the safety, tolerability, and efficacy of pavurutamab monotherapy in patients with triple-class relapsed/refractory MM (RRMM). Pavurutamab (5-18 000 μg) was administered IV weekly with step-up dosing in week 1. Overall, 172 patients received at least 1 dose of pavurutamab; 73 received the recommended phase 2 dose (RP2D; 18 000 μg), with 2 different step-up dosing regimens in phase 1b. Twelve patients had dose-limiting toxicities, which included cytokine release syndrome (CRS) and increased transaminases; none of which occurred at the RP2D. The most frequently reported treatment-emergent adverse events included CRS (74.4%), anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade ≥3 infections were noted in 60 patients (34.9%). The overall response rate (ORR) was 46.5% among all patients and 65.8% (very good partial response [VGPR] or better, 60.3%) among 73 patients treated at the RP2D. At median follow-up of 17.2 months, median duration of response (DOR) was 36.6 months (95% confidence interval [CI], 22.3 to not estimable). Median progression-free survival (PFS) for all patients was 5.5 months (95% CI, 2.8-10.1) and 16.8 months (95% CI, 5.0 to not estimable) with the RP2D. Pavurutamab exposure generally increased in a dose-proportional manner, with high soluble BCMA levels correlating with lower exposure level. The acceptable safety profile, pharmacokinetics, and preliminary efficacy of pavurutamab supports anti-BCMA T-cell engager therapy in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as NCT03287908.

Talquetamab is a first-in-class GPRC5DxCD3 bispecific antibody approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM), and this multicenter retrospective analysis of 114 RRMM patients treated between October 2023 and January 2025 demonstrated significant efficacy in a heavily pretreated population with median 6 prior therapies. All patients were triple-class refractory, 79% were penta-refractory, and 65% had received prior BCMA-targeted therapy. The overall response rate was 73%, including complete response in 26% and very good partial response in 26%, with six-month progression-free and overall survival rates of 56 and 86% respectively and median progression-free survival of 10 months. Common adverse events included cytokine release syndrome (CRS; 54% with grade ≥2 in 7.3%), infections (27%), and immune effector cell-associated neurotoxicity syndrome (9.8%). The 3-month cumulative infection incidence of 14% for both bacterial and viral infections, where 59% were viral and 41% bacterial, grade ≥3 infections occurred in 18%, and intravenous immunoglobulin was used in 61% of patients. Significant weight loss was observed, with a mean 8.8% decrease at 6 months. This real-world analysis confirms talquetamab’s efficacy in heavily pretreated RRMM while highlighting notable toxicities, including progressive weight loss and infections, which require rigorous monitoring and proactive supportive care.

Immunoglobulin light-chain (AL) amyloidosis is a plasma cell disorder characterized by progressive organ dysfunction secondary to deposition of organized immunoglobulin light-chain aggregates. Achievement of rapid and deep normalization of involved immunoglobulin free light chains is necessary to maximize chances of reversibility of organ dysfunction, which, in turn, results in improved quality and length of life. There are no US Food and Drug Administration (FDA)–approved therapies for patients with relapsed AL amyloidosis. B-cell maturation antigen–targeting (BCMA)-bispecific T-cell engagers teclistamab and elranatamab have shown high activity and acceptable safety profile in patients with relapsed and/or refractory multiple myeloma, leading to their FDA approval. Herein, we report on safety and efficacy of elranatamab for patients with relapsed and/or refractory AL amyloidosis. We treated 9 consecutive patients with advanced-stage AL amyloidosis with single-agent elranatamab, observing a 100% overall response and 67% complete response rate, including minimal residual disease negativity, with expected toxicities. Median time to hematological response was 9 days (range, 6-24), with deep suppression in involved free light chains observed within 1 cycle of therapy, translating in cardiac and renal responses at 3 to 6 months. These data support prospective studies exploring elranatamab for patients with relapsed AL amyloidosis.