Daratumumab Monotherapy Shows Durable Responses in Relapsed AL Amyloidosis

With a median follow-up of 26.9 months, the estimated median progression-free survival was 21.9 months and the median overall survival was 30.9 months. Treatment was generally well tolerated, with only three patients experiencing grade 3 to 4 hematologic adverse events and eight experiencing grade 3 to 4 non-hematologic adverse events. The authors report that deep hematologic responses and cardiac responses were each associated with significantly prolonged progression-free survival, and they conclude that daratumumab monotherapy provided rapid and durable responses in this heavily pretreated population.

Systemic light-chain AL amyloidosis is a rare clonal plasma cell disorder in which bone marrow plasma cells overproduce immunoglobulin light chains that misfold and form soluble toxic aggregates. These aggregates deposit as amyloid fibrils in multiple organs, causing organ dysfunction, organ failure, and ultimately death. Although novel sensitive biomarkers and advanced imaging technologies have been developed for amyloidosis detection, diagnosis is often delayed for more than a year because of nonspecific symptoms, a major reason why patients begin treatment at an advanced stage. Although treatment heavily borrows from multiple myeloma, patients with AL amyloidosis are often unable to tolerate therapies because of comorbid cardiac, renal, and neurological dysfunction, which makes treatment selection unusually difficult in this disease.

The primary goal of therapy is to prevent further organ damage through rapid and deep suppression of light-chain-producing plasma cells, so identifying the most effective yet safe treatment strategy is crucial. Because cardiac involvement is the major determinant of disease severity, it is incorporated into both staging systems and response criteria to better predict short- and long-term outcomes. Several agents widely used in multiple myeloma are poorly tolerated in patients with AL amyloidosis. Lenalidomide, for example, frequently causes fluid retention and cardiac and renal dysfunction that limit tolerability, and in a phase I study of carfilzomib plus dexamethasone in relapsed AL amyloidosis, significant fatigue, gastrointestinal toxicity, and cardiac events limited dose escalation to a maximum of 36 milligrams per square meter, considerably lower than the standard dose used in multiple myeloma. Agents that perform well in myeloma may therefore show a distinct safety profile in AL amyloidosis because of concomitant organ dysfunction.

Daratumumab is a monoclonal antibody that targets CD38 on the surface of plasma cells. Its efficacy in newly diagnosed AL amyloidosis was demonstrated in the ANDROMEDA trial, leading to approval by both the U.S. Food and Drug Administration and the European Medicines Agency. Because daratumumab itself rarely induces cardiac adverse events, monotherapy can be readily used in the relapsed setting, and its efficacy and safety in relapsed disease have been validated in two phase II trials and several retrospective studies. The research team behind the new analysis conducted this single-center retrospective study to contribute to the growing body of real-world evidence on daratumumab efficacy in relapsed disease.

The study drew on a prospective cohort that the center has maintained since 2012 using a multidisciplinary team approach. Patients with AL amyloidosis who received daratumumab monotherapy for relapsed disease and had measurable light chain disease were included, while patients whose bone marrow plasma cells exceeded 60 percent were excluded. Clinicopathological variables collected and analyzed included age, sex, cytogenetics, stage, prior treatment, hematologic and cardiac responses, and survival. Disease stages were categorized according to the Mayo 2012 guidelines, the Mayo 2004 staging system with European modification, and the Renal stage system. Daratumumab was administered either intravenously at 16 milligrams per kilogram or subcutaneously at 1,800 milligrams depending on patient circumstances, following a standard schedule of weekly doses for eight doses, then every two weeks for eight doses, then every four weeks until disease progression or unacceptable toxicity. All patients received oral acyclovir to prevent herpes zoster reactivation and oral trimethoprim/sulfamethoxazole to prevent pneumocystis reactivation.

A total of 40 patients treated between 2018 and 2025 were included. Twenty-four patients, or 60 percent, were male, and 29 patients, or 72.5 percent, had lambda light-chain disease. Among the 28 patients assessed for t(11;14) status, 6, or 21.4 percent, tested positive, and among the 32 assessed for gain(1q), 5, or 15.6 percent, tested positive. Before daratumumab monotherapy, patients had received a median of 3 prior lines of therapy, with a range of 1 to 6, including bortezomib in 97.5 percent, lenalidomide in 75.0 percent, pomalidomide in 42.5 percent, cyclophosphamide in 37.5 percent, and melphalan in 32.5 percent. None had received prior daratumumab, and 12 patients, or 30 percent, had undergone prior autologous stem cell transplantation. At the time daratumumab was started, the median age was 67 years, with a range of 48 to 83, and treatment began a median of 42.3 months after the initial diagnosis. Thirty-one patients, or 77.5 percent, were classified as stage III/IV by Mayo 2012 guidelines, and 32 patients, or 80 percent, were classified as stage IIIa/IIIb by the Euro stage guidelines. Cardiac involvement, defined by NT-proBNP above 332 picograms per milliliter, was present in 37 patients, or 92.5 percent, while 8 patients, or 20.0 percent, were classified as renal stage III, and renal involvement, defined by 24-hour urine protein above 500 milligrams, was observed in 22 patients, or 55.0 percent.

The overall hematologic response rate was 72.5 percent, or 29 of 40 patients, including 9 very good partial responses and 15 complete responses, with a median time to response of 29 days and a range of 13 to 117 days. Patients with Euro stage I/II/IIIa disease had a significantly higher likelihood of achieving a complete or very good partial response compared with those at stage IIIb, at 20 of 27 patients, or 74.1 percent, versus 4 of 13 patients, or 30.8 percent, with a p value of 0.009. A similar comparison between Mayo 2012 stage I/II/III and stage IV showed a trend that did not reach statistical significance, at 68.0 percent versus 46.7 percent. Among 33 patients with measurable cardiac disease, defined as NT-proBNP above 650 picograms per milliliter, the overall cardiac response rate was 42.4 percent, or 14 patients, including 4 very good partial responses and 2 complete responses, with a median time to cardiac response of 92 days and a range of 27 to 887 days. Among 22 patients with renal involvement, 9 patients, or 40.9 percent, demonstrated a renal response. Patients who achieved a deep hematologic response were far more likely to achieve a cardiac response, at 13 of 18 hematologic responders, or 72.2 percent, versus 1 of 15 non-responders, or 6.7 percent, with a p value below 0.001, although deep hematologic response was not associated with renal response.

The final data cutoff date was November 30, 2025, and the median follow-up was 26.9 months. The estimated median progression-free survival was 21.9 months, with a 95 percent confidence interval of 10.0 to 33.8 months. Patients with deep hematologic responses had significantly prolonged progression-free survival compared with those with partial or no response, at 30.5 months versus 3.9 months, with a p value below 0.001. Median progression-free survival was 21.9 months for patients achieving very good partial response and 30.5 months for those achieving complete response, a difference that was not statistically significant, possibly due to the small sample size. Patients with a cardiac response had markedly longer progression-free survival than non-responders, at 38.8 months versus 5.3 months, with a p value of 0.001. None of the staging systems at the time of daratumumab initiation, including Mayo 2012, Euro, or renal staging, were predictive of prolonged progression-free survival, although numerically longer survival was observed in patients with early-stage disease. The median durations of hematologic and cardiac response were 26.2 months and 27.8 months, respectively. Seventeen deaths were recorded: 9 due to worsening amyloidosis, 2 due to septic shock, 1 unrelated to treatment, and 5 due to unknown causes among follow-up losses. Among the 10 patients who died within 6 months of treatment initiation, all had Mayo stage III/IV disease, 9 had Euro stage IIIa/IIIb disease, and none demonstrated a hematologic or cardiac response. The median overall survival for the entire cohort was 30.9 months, with a 95 percent confidence interval of 11.9 to 49.9 months, and the 3-year overall survival rate was 46.0 percent. For patients whose disease progressed on daratumumab, median overall survival was only 5.9 months. No significant differences were observed in response rates, progression-free survival, or overall survival according to abnormal cytogenetics including t(11;14) and gain(1q).

Safety findings supported the tolerability profile. Three patients experienced grade 3 to 4 hematologic adverse events, specifically two cases of thrombocytopenia and one of neutropenia, and one patient, who had undergone autologous stem cell transplantation four years before starting daratumumab, developed acute myeloid leukemia. Eight patients experienced grade 3 to 4 non-hematologic adverse events: two cases of pneumonia, two cases of COVID-19 pneumonia, one cholangitis, one gastrointestinal bleeding event, one acute kidney injury, and one case of liver enzyme elevation. The gastrointestinal bleeding, acute kidney injury, and liver enzyme elevation were likely attributable to AL amyloidosis itself. These adverse events led to treatment delays in 11 patients, and one patient permanently discontinued treatment because of acute kidney injury that developed after a single administration of daratumumab monotherapy.

The authors acknowledge limitations related to the relatively small number of patients, the single-center setting, and the retrospective nature of the study, while noting that a key strength was the inclusion of patients who received uniform treatment and supportive care and were followed over a relatively long duration. They also observe that although early death within 6 months was frequent, this likely reflected a higher proportion of advanced-stage disease in their cohort compared with previous studies, consistent with findings reported in frontline trials. Taken together, the findings suggest that daratumumab monotherapy provides rapid and durable responses and is generally well tolerated in patients with relapsed AL amyloidosis, but patients with advanced-stage disease experienced inferior outcomes and frequent early mortality, highlighting a significant unmet medical need in this subgroup.

Subject of Research: Retrospective analysis of daratumumab monotherapy in relapsed AL amyloidosis

Article Title: Daratumumab monotherapy for relapsed AL amyloidosis: a single center retrospective analysis

Article References: Yi, J. H., Yoon, S. E., Kim, S. J., Kim, D., Choi, J.-O., Min, J.-H., Kim, B. J., Kim, J.-S., Lee, J. E., Jeon, J., Choi, J. Y., & Kim, K. (2026). Daratumumab monotherapy for relapsed AL amyloidosis: a single center retrospective analysis. Blood Research, 61(1), Article 52. https://doi.org/10.1007/s44313-026-00174-x

Image Credits: AI Generated

DOI: 10.1007/s44313-026-00174-x

Keywords: AL amyloidosis, daratumumab, relapsed disease, monotherapy, retrospective study, hematologic response, cardiac response, progression-free survival, overall survival, CD38, plasma cell disorder, drug safety