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Addition of Daratumumab to Standard Therapy Does Not Increase Cardiac Events in AL Amyloidosis

January 12, 2023

Mid-January 2023

Across all cardiac stages (I-IIA), patients with newly diagnosed light chain (AL) amyloidosis treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had better outcomes than those treated with VCd, according to Monique C. Minnema, MD, of UMC Utrecht Cancer Center in the Netherlands, and colleagues. The findings represent a post-hoc analysis of the phase III ANDROMEDA trial and support the use of D-VCd in patients with cardiac involvement, according to results published in JACC: CardioOncology.

The ANDROMEDA study included 388 patients with newly diagnosed AL amyloidosis and compared the standard chemotherapy treatment of VCd (n=193) with D-VCd (n=195). The primary study results, published in 2021, demonstrated the superiority of D-VCd over VCd alone in newly diagnosed AL amyloidosis. The study included high-risk patients with stage IIIA disease but excluded the highest risk group (stage IIIB). Baseline characteristics were balanced between the two treatment groups and across cardiac stages, with one main exception. Patients with stage IIIA cardiac disease had worse Eastern Cooperative Oncology Group performance status, more advanced renal dysfunction, and functionally worse heart failure.

Since the current analyses of the ANDROMEDA data were exploratory, the authors did not conduct a formal statistical comparison of the results. In the ANROMEDA study, patients had a median follow-up of 15.7 months, and the proportions of patients with stage I, II, and IIIA disease in the study were 23.2%, 40.2%, and 36.6%, respectively. Across all cardiac stages, the investigators found the daratumumab combination therapy was more effective for both hematologic and organ response rates as well as major organ deterioration-progression-free survival and -event-free survival than the standard therapy. The study did not document a reduction in the rate of early deaths with D-VCd.

When investigators analyzed data from patients who were cardiac-response evaluable, they found the rate of cardiac progression at six months was 13.6% in the D-VCd group (95% CI 8.0-21.1) versus 19.7% in the VCd group (95% CI 12.9-28.0). Likewise, in the intent-to-treat and cardiac response-evaluable patients, N-terminal pro-brain natriuretic peptide levels increased during the first treatment cycles and then declined over time, with the rate of decline being earlier and more pronounced in the D-VCd group versus the VCd group.

Researchers found the rates of serious adverse events (SAEs) were higher in patients with cardiac involvement and more advanced cardiac stage, regardless of treatment. They observed cardiac SAEs almost exclusively in patients who already had cardiac involvement. Moreover, most patients who experienced serious or fatal cardiac events had baseline cardiac stage II or IIIA or baseline New York Heart Association class II or IIIA. Because there was a difference in treatment duration between the D-VCd and VCd arms (13.4 vs. 5.3 months), investigators calculated an exposure-adjusted incidence rate for cardiac events and found that it was lower with D-VCd than VCd.

Daratumumab has U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for AL amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed patients.

“The ANDROMEDA trial led to the first registration of the therapy in AL amyloidosis patients in both Europe/E.U. and the U.S., and it is currently advised as a standard first-line therapy,” Dr. Minnema said.

While previous studies in patients with multiple myeloma have not indicated an association between daratumumab and serious cardiac toxicity, there has been some concern that the addition of daratumumab to the treatment regimen for AL amyloidosis would not be beneficial for patients with severe cardiac involvement.

“In this post-hoc analysis, we studied the outcome parameters per cardiac stage and provided the cardiac biomarkers as measured over time,” Dr. Minnema said. “We demonstrated the efficacy and safety of the combination regimen with daratumumab in all cardiac risk groups and found no enhanced cardiac risk with the use of daratumumab in patients with AL amyloidosis with cardiac involvement (stages I-II-IIIA). The results were no surprise to me because there is no pathophysiological rational for why daratumumab, an anti-CD38 antibody, would have any cardiac toxicity.”

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Minnema MC, Dispenzieri A, Merlini G, et al. Outcomes by cardiac stage in patients with newly diagnosed AL amyloidosis: Phase 3 ANDROMEDA trial. JACC: CardioOncology. 2022;4(4):474-487.

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