Systemic light chain amyloidosis is a clonal plasma cell disorder that can lead to end-organ dysfunction, with no approved treatment in the relapsed/refractory setting. Given this challenging clinical situation, two studies of novel therapies for this disease reported at the 2026 ASCO Annual Meeting were met with particular enthusiasm.

Although the phase III CARES study of anselamimab, a first-in-class kappa light chain–directed anti-fibril antibody, did not meet its primary endpoint in the overall population, the drug reduced the risk of death by 62% (hazard ratio [HR] = 0.38, 95% confidence interval [CI] = 0.17, nominal P = .012) in patients with kappa free light chain (FLC) involvement.¹In a broader population, the bispecific antibody linvoseltamab-gcpt demonstrated meaningful clinical activity as a single agent in a phase I/II trial, producing a hematologic very good partial response or better in 100% of patients.²

Ashutosh D. Wechalekar, MD, MBBS, FRCP, FRCPath, DM

Hans C. Lee, MD

Ashutosh D. Wechalekar, MD, MBBS, FRCP, FRCPath, DM, of the National Amyloidosis Centre and University College London Hospitals in the United Kingdom, was the lead author of both studies. The linvoseltamab findings were presented by co-investigator Hans C. Lee, MD, of Sarah Cannon Research Institute in Nashville.

Anselamimab: First-in-Class Anti-Fibril Antibody

In AL amyloidosis, light chains produced by abnormal plasma cells misfold and aggregate because of their instability. The resulting amyloid fibrils are deposited in tissues throughout the body, and their accumulation in organs—most commonly the heart and kidneys—drives organ dysfunction and damage. Standard treatment consists of regimens targeting the underlying plasma cell dyscrasia, such as daratumumab with CyBorD (cyclophosphamide, bortezomib, dexamethasone). However, treatments that reduce amyloid burden in organs and tissues are needed, especially for patients with advanced cardiac involvement, who have markedly reduced survival.

“For a very long time, the treatment of amyloidosis has been the treatment of plasma cell dyscrasia—kill the plasma cells, reduce the monoclonal protein, and then hope that the body does the rest to get rid of the end-organ damage, which is the major problem and is our unmet need. We have nothing to treat the end-organ dysfunction. I hope we now have data that might change that,” Dr. Wechalekar said.

Anselamimab is an anti-fibril monoclonal antibody that binds to toxic amyloid fibrils and induces their removal through phagocytosis. It has been shown to reduce or eliminate human light chain–derived lambda or kappa amyloidosis in mice.

About the CARES Trial

The CARES studies are multicenter, double-blind, randomized, placebo-controlled trials in which participants receive appropriate first-line treatment for plasma cell dyscrasia (PCD) plus either anselamimab at 1,000 mg/m² weekly for 4 weeks and then every 2 weeks thereafter or placebo. In the current study, 406 patients were randomly assigned 2:1 to anselamimab plus anti-PCD therapy or placebo plus anti-PCD therapy. All patients could receive anselamimab plus anti-PCD therapy during an open-label extension period.

The primary endpoint was a hierarchical composite of time to all-cause mortality and frequency of cardiovascular-related hospitalizations. A prespecified subgroup analysis evaluated the primary and secondary endpoints according to light chain isotype (kappa or lambda).

Key Findings

“Treatment with anselamimab did not result in statistically significant improvement in the primary hierarchical composite endpoint of all-cause mortality and cardiovascular hospitalization. Even when they were analyzed separately, there remained the same statistical significance,” Dr. Wechalekar reported.

“However, when we switched over to the prespecified subgroup analysis of kappa versus lambda, things became a bit more interesting,” he said. “Anselamimab improved survival by 62% and reduced the frequency of cardiovascular hospitalization by 71% in patients with the kappa isotype.”

In the overall population, the win ratio for the two components of the primary endpoint was 1.11 (P = .332), the HR for all-cause mortality was 0.80 (P = 0.290), and the incidence rate ratio for cardiovascular hospitalization was 0.67 (P = .145). In patients with kappa FLC involvement, however, treatment with anselamimab resulted in nominally statistically significant improvements in both all-cause mortality (HR = 0.38, P = .012) and cardiovascular hospitalization (HR = 0.29, P = .028). No benefit was observed in patients with the lambda isotype.

Looking specifically at all-cause mortality, no significant difference was observed between the treatment arms in the overall population (HR = 0.80, P = .290), whereas patients with the kappa isotype had a 62% lower risk of death with anselamimab (HR = 0.38, P = .012). No difference was observed among patients with the lambda isotype (HR = 1.02, P = .647). The effect of anselamimab in patients with the kappa isotype was observed across disease stages. Although the effect was greater in patients with Mayo stage IIIa disease (HR = 0.25, P = .021) than in those with stage IIIb disease (HR = 0.52, P = .238), an improvement in the survival curve was seen “even in patients with advanced-stage cardiac disease,” Dr. Wechalekar noted.

“Key secondary endpoints at 50 weeks also showed improvements in the kappa isotype population. In particular, the KCCQ-OS, a cardiac-directed quality-of-life score, increased by 10 points in the anselamimab arm. It is generally accepted that a KCCQ increase of 5 points is clinically meaningful. There was also some increase in the 6-minute walk test.”

Why Greater Efficacy in Kappa Light Chain Amyloidosis?

The greater efficacy observed in patients with the kappa isotype might be attributable to anselamimab binding more strongly to kappa fibrils than to lambda fibrils, Dr. Wechalekar proposed. He acknowledged that kappa amyloidosis “is a rare disease,” noting that only 17% of enrolled patients had kappa light chain amyloidosis. Conducting a study solely in this subset would be very challenging, he added.

During the discussion, Dr. Wechalekar noted that within the kappa subset, patients in the anselamimab arm were actually a “sicker” group, with more patients having stage IIIb disease, than those in the placebo arm. He suggested that this imbalance made the efficacy findings more compelling.

“But even within the small population, there was a very clear impact on patients with kappa light chain disease,” he emphasized. “Overall, the results to me are very convincing. It looks like this drug does work in kappa light chain patients. It’s biologically plausible. It’s a clinically detectable subgroup, so we know which patients we can easily treat. It’s very well tolerated in this population, and it has immediate benefits for a patient population for which we have no treatments. I would like to get this drug into patients and collect more data to confirm these findings.”

Safety Profile of Anselamimab

“This was a patient population with stage III cardiac amyloidosis—an advanced group of patients—and as expected, we saw quite a lot of adverse events,” he said. Nevertheless, the overall safety profiles were comparable between the anselamimab and placebo arms, with no safety signals specifically associated with anselamimab, he noted.

Overall, about 75% of patients in each arm experienced a serious adverse event. Grade ≥ 3 adverse events were reported in 80% of those in the anselamimab arm and 84% of those in the placebo arm. The most common were gastrointestinal toxicities and peripheral edema and were mostly attributable to the underlying amyloidosis or complications of chemotherapy.

Phase I/II Study of Linvoseltamab

Linvoseltamab is a B-cell maturation antigen (BMCA) × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma and considered a potential therapeutic option for AL amyloidosis. The hope is that it may induce rapid, deep, and durable hematologic responses, preserve or restore organ function, and prolong survival, Dr. Lee said. Moreover, he noted that with upfront standard-of-care treatment in newly diagnosed AL amyloidosis, fewer than 50% of patients achieve a hematologic complete response, which has been associated with overall survival, and therefore also remains an unmet need.

Linvoseltamab induces T-cell–mediated depletion of the clonal plasma cells. This reduces the production and deposition of amyloidogenic light chains and may allow for the preservation or recovery of organ function, he explained.

LINKER-AL2 is an ongoing, open-label, phase I/II study evaluating linvoseltamab monotherapy in 200 patients with relapsed/refractory systemic AL amyloidosis. Dr. Lee reported findings for the first 20 patients, who received either 80 mg (low dose) or 240 mg (high dose) of linvoseltamab.

Key Findings of LINKER-AL2

At a median follow-up of 9.5 months, the following findings were reported with linvoseltamab monotherapy:

• Deep hematologic responses were observed, with 100% of patients achieving a very good partial response or better and 90% achieving a complete response.
• Involved free light chain levels normalized rapidly by a median time of 2.1 weeks across both doses.
• No hematologic disease progression was observed, and 17 of 20 patients remained on study.
• Cardiac and renal responses were observed in 50% and 73% of patients, respectively, despite the short treatment duration.
• Responses deepened over time and appeared durable.

Safety Profile

No dose-limiting toxicities were observed. Cytokine-release syndrome occurred in 50% of patients; all events were grade 1 or 2 and resolved within 48 hours. One patient (5%) experienced grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS), which resolved without treatment discontinuation. Infections occurred in 85% of patients and were grade ≥ 3 in 25%.

Two patients died from treatment-emergent adverse events, both of which were considered unrelated to linvoseltamab. Another patient discontinued treatment because of pneumonia after achieving a complete response and experiencing recurrent infections.

Discussion and Next Steps

In the discussion period, Dr. Lee commented that high organ response rates speak not only to the deep responses but the rapid hematologic responses seen with linvoseltamab and other bispecifics. The availability of agents capable of inducing rapid hematologic responses may shorten the expectation of time to organ response, he suggested.

“I think this is a paradigm shift for these patients,” he said. “This has historically been an orphan disease with unmet needs and patients have not done well, but I think with potentially available therapies, this hopefully will change.”

Based on the findings from phase I of LINKER-AL2, phase II is ongoing with potential registrational intent. 

DISCLOSURE: Dr. Wechalekar had personal financial disclosures for Alexion Pharmaceuticals, Janssen-Cilag, Prothena, ATTRALUS, GlaxoSmithKline, and AstraZeneca. Dr. Lee had personal financial disclosures for Alexion Pharmaceuticals, Allogene Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, Janssen Research & Development, Menarini Silicon Biosystems, Pfizer, Predicta, Regeneron, Sanofi, and Takeda.

REFERENCES

1. Wechalekar AD, Dispenzieri A, Sanchorawala V, et al: Phase 3 randomized trial to evaluate the impact of anselamimab on all-cause mortality in kappa light chain amyloidosis. 2026 ASCO Annual Meeting. Abstract 7501. Presented May 29, 2026.

2. Wechalekar A, Lee HC, Palladini G, et al: First results from the phase 1/2 LINKER-AL2 trial of linvoseltamab in patients with relapsed or refractory systemic light chain amyloidosis. 2026 ASCO Annual Meeting. Abstract 7502. Presented May 29, 2026.

EXPERT POINT OF VIEW

The management of patients with amyloidosis, particularly those with advanced cardiac involvement, remains challenging. “We clearly need better treatments for them,” said Rafat Abonour, MD, Professor of Medicine in the Division of Myeloma at Sylvester Comprehensive Cancer Center, University of Miami, who was invited by ASCO to discuss the two studies presented at the 2026 Annual Meeting.

He noted that the phase III CARES trial enrolled newly diagnosed patients at high risk, mainly those with stage IIIa and IIIb disease, the majority of whom had lambda light chain amyloidosis. The evaluation of the monoclonal antibody anselamimab in this population with a high unmet clinical need “ensures relevant clinical insights” from the study, Dr. Abonour said.

The study used a hierarchical composite primary endpoint of all-cause mortality and cardiovascular hospitalization. Patients were randomly assigned to receive anselamimab or placebo alongside CyBorD-based therapy, with daratumumab permitted as part of current standard therapy.

“The primary endpoint was not met; it was technically a negative trial, but there was a case-specific survival signal, and I think that is very important,” Dr. Abonour said. “Reducing mortality and cardiac hospitalization [in the kappa light chain group] is very important, and this is a credible finding as it comes not from a post-hoc analysis but one that was prespecified prior to the start of the study.”

Dr. Abonour considered the findings credible and suggested that, in very ill patients, treatment with anselamimab might “turn things around in 3 or 4 months.” However, he emphasized the need for future studies to confirm the findings reported at the ASCO Annual Meeting.

In the LINKER-AL2 study of the bispecific antibody linvoseltamab, all 20 patients with relapsed/refractory systemic AL amyloidosis achieved a very good partial response or better, and 90% achieved a complete response. Involved free light chain levels normalized rapidly, by day 15, and high organ response rates were observed, with no hematologic disease progression.

“This is a small trial, but treating 20 amyloidosis patients with a bispecific is a challenge, and I think these investigators met the challenge,” he commented. “They showed that at a median follow-up of 9.5 months, they got a high rate of eradication of the light chain—and in very sick patients.”

Within just 6 weeks, 50% of patients had a cardiac response and 73% had a renal response, defined as a ≥ 30% reduction in 24-hour protein.“These are great results,” he commented. 

DISCLOSURE: Dr. Abonour had personal disclosures for Johnson & Johnson/Janssen, Pfizer, Sanofi, and Takeda.