Adding subcutaneous daratumumab to the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) resulted in deeper and more rapid hematologic responses and improved clinical outcomes, compared with CyBorD alone, in patients with newly diagnosed light chain amyloidosis, according to the results of the phase III ANDROMEDA study.
Systemic amyloid light chain (AL) amyloidosis is a rare disease with no approved therapies, explained Efstathios Kastritis, MD, of National and Kapodistrian University of Athens, in Greece, who presented results of the study as part of EHA25 Virtual, the 25th European Hematology Association Annual Congress. However, “outcomes have improved due to use of novel multiple myeloma drugs, in particular bortezomib-based therapies, but more effective therapies are still needed,” he said. Based on the results from ANDROMEDA, “daratumumab plus CyBorD significantly improves outcomes for patients with newly diagnosed AL amyloidosis and will become a new standard of care.”
The study randomized 388 patients to receive CyBorD alone (n=193) or with daratumumab (n=195). Participants had newly diagnosed AL amyloidosis and the median age at enrollment was 64 years. Most patients had heart and kidney involvement (71% in the daratumumab group and 59% in the CyBorD group), and 65% had involvement in at least two organs.
All patients received CyBorD for six 28-day cycles. Daratumumab was given once weekly in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks in cycles thereafter, for up to 24 cycles. The primary endpoint was overall complete hematologic response (CHR) rate.
At a median duration of follow-up of 11.4 months, the median duration of treatment was more than 4 months longer in patients assigned to the daratumumab group (9.6 vs. 5.3 months), suggesting that the four-drug combination is tolerable for most patients. Dr. Kastritis added that 72% of patients in the daratumumab group were continuing to receive study treatment at the time of data presentation.
While 19 patients assigned to daratumumab (10%) went on to receive subsequent therapy, 79 assigned to CyBorD (42%) went on to receive subsequent therapy. Of note, 48 of these eventually received daratumumab.
More than one-half of patients assigned to daratumumab achieved a CHR (53%) compared with only 18% of patients assigned to CyBorD (odds ratio [OR] = 5.1; p<0.0001).
Response with the daratumumab combination were deeper and achieved more rapidly, Dr. Kastritis commented. The median time to CR was 60 days in the daratumumab group, versus 85 days for CyBorD alone. The CHR rate at 6 months was 50% in the daratumumab group, versus 14% in the CyBorD group, which was consistent with the overall CHR rate (OR=6.1; p<.001).
In addition, treatment with daratumumab was associated with higher rates of overall hematologic response (92% vs. 77%) and very good partial response or better (79% vs. 49%; OR=3.8; p<0.0001). Median time to very good partial response or better was 17 days for daratumumab compared with 25 days for CyBorD.
The CHR rate was better with daratumumab and remained consistent across every subgroup, Dr. Kastritis added.
Major organ deterioration progression-free survival (MOD-PFS) – time free from hematologic progression, development of end-stage cardiac or renal disease, or death – was a secondary endpoint. At a median follow-up of 11.4 months, MOD-PFS favored treatment with daratumumab as well (hazard ratio = 0.58; p=0.0224).
The researchers also investigated organ response rates, which almost doubled with the addition of daratumumab. The 6-month cardiac response rate was 42% for the daratumumab combination compared with 22% for CyBorD alone (p=0.0029), and the 6-month renal response rates were 54% and 27%, respectively (p<0.0001).
In the first 6 months, 25 patients in the daratumumab arm and 20 in the CyBorD arm died. However, more than 90% of these deaths was related to underlying amyloidosis, rather than treatment toxicity, Dr. Kastritis said.
Common grade 3/4 adverse events (AEs) included lymphopenia, pneumonia, diarrhea, cardiac failure, neutropenia, syncope, and peripheral edema. The rate of infections was slightly higher with daratumumab (12% vs. 9%). However, treatment discontinuation due to AEs was low, at 4% in both arms. Overall, the safety profile of the four-drug regimen was consistent with the known profiles of each component.
Study authors report relationships with Janssen, which sponsored the trial.
Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyborD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 Andromeda study. Abstract LB2604. Presented as part of EHA25 Virtual, June 14, 2020.