Dr. Raymond L. Comenzo is a Tufts Medical Center-affiliated oncologist in Boston, Massachusetts. He graduated from Boston University School of Medicine and has been practicing medicine for almost 20 years. In this video Dr. Comenzo discusses the Subcutaneous Daratumumab with Bortezomib, Cyclophosphamide, and Dexamethasone in Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: 18-Month Analysis of the Phase 3 ANDROMEDA Study
Link to Abstract-
https://ash.confex.com/ash/2021/webprogram/Paper146820.html
Introduction: Light chain (AL) amyloidosis is a plasma cell disease in which insoluble amyloid fibrils develop in tissues, causing organ failure and death. The ANDROMEDA trial (NCT03201965) found that adding SC daratumumab to the standard-of-care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone at 6 and 12 months, with greater rates of hematologic complete response (CR) and an acceptable safety profile. Daratumumab with VCd (D-VCd) was approved for newly diagnosed AL amyloidosis in January 2021 in the US and June 2021 in the EU based on these findings. We share data from the ANDROMEDA study’s 18-month analysis here.
Methods: ANDROMEDA is a phase 3 randomized, open-label, active-controlled study that enrolls patients with newly diagnosed AL amyloidosis who have demonstrable hematologic illness, 1 involved organ, cardiac stage I–IIIA, estimated glomerular filtration rate 20 mL/min, and no symptoms of multiple myeloma. For six 28-day cycles, patients were randomly assigned (1:1) to D-VCd or VCd. Weekly treatments included bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2 up to 500 mg per week), and dexamethasone (20–40 mg). In cycles 1 and 2, SC daratumumab (1800 mg co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was given once weekly, and every two weeks in cycles 3 to 6. After cycle 6, patients in the D-VCd arm got only SC daratumumab every four weeks (up to a total of 24 cycles from first dose). The primary endpoint was the overall (i.e., at any time) hematologic CR rate, which was defined as normalization of free light chain (FLC) levels and ratio (FLCr), as well as negative serum and urine immunofixation, which was confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if involved FLC was lower than the upper limit of normal. Major organ deterioration progression-free survival (PFS), organ response rate, duration to hematologic response, overall survival (OS), and safety were all secondary goals.
The patients were randomly assigned to receive D-VCd (N=195) or VCd alone (N=193). The median length of treatment for the D-VCd and VCd arms was 21.3 and 5.3 months, respectively, at the clinical cutoff in May 2021. After completing 6 cycles of D-VCd, 149 patients (77.2%) got daratumumab monotherapy in the D-VCd group, with 17 (11.4%) still receiving treatment. The D-VCd therapy arm had a higher rate of profound hematological responses (Table). The rate of hematologic CR was considerably greater in the D-VCd arm compared to the VCd arm at a median follow-up of 25.8 months (59.5 percent vs 19.2 percent; odds ratio [95 percent confidence interval (CI)], 6.03 [3.80–9.58]; P0.0001). Similarly, more patients (79.0 percent vs 50.3 percent; odds ratio [95 percent CI], 3.74 [2.39–5.86]; P0.0001) had a very good partial response or better (VGPR). The median time from randomization to VGPR was shorter in the D-VCd arm (0.56 months) than in the VCd arm among those who responded (0.82 months). When compared to the cardiac response study at 6 months (D-VCd vs VCd, 42 percent vs 22 percent), D-VCd achieved higher cardiac response rates at 18 months than VCd (53 percent vs 24 percent ). Similarly, at 18 months, D-VCd remained superior than VCd alone in terms of renal response rates (58 percent vs 26 percent compared with 6 months [54 percent vs 27 percent ]). There were 79 deaths in all (D-VCd, N=34; VCd, N=45). Over the course of 18 months vs. 12 months, only one additional grade 3/4 treatment-emergent adverse event occurred in the D-VCd arm (119 [61.7 percent] vs. 118 [61.1 percent] patients), and no additional infusion-related responses were observed. After approximately 200 events, the OS will be assessed, and the PFS for severe organ degradation will be revised.
Conclusions: These findings show that D-VCd vs VCd had long-term therapeutic benefits in terms of hematologic and organ responses, despite the fact that many patients in the D-VCd arm got daratumumab monotherapy after 6 cycles of D-VCd, whereas individuals in the VCd group ceased study treatment. Despite this, the study suggests that D-VCd should be used instead of VCd alone in patients with newly diagnosed AL amyloidosis. D-VCd is a novel SOC for patients with AL amyloidosis, following its recent approval.