Results of the ANDROMEDA Study: Bortezomib, Cyclophosphamide, and Dexamethasone with or without Daratumumab in Newly Diagnosed AL Amyloidosis

The accumulation of insoluble amyloid fibrils generated by light chains produced by clonal CD38+ plasma cells is one characteristic of systemic light chain amyloidosis (AL). Previous research has shown that patients with AL can achieve significantly improved outcomes with treatment that combines daratumumab with bortezomib, cyclophosphamide, and dexamethasone (VCd). Researchers are taking new approaches to the classification of hematologic complete response (CR) in this disease; there is a growing recognition that absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are meaningful end points.

Raymond Comenzo, MD, of the Division of Hematology and Oncology, John C. Davis Myeloma and Amyloid Program, at Tufts Medical Center, in Boston, MA, and colleagues presented results from the ANDROMEDA study. Their intent was to demonstrate the effect of attaining deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS).

For the study, inclusion criteria included newly diagnosed AL with hematologic disease (measurable serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 organs involved, estimated glomerular filtration rate ≥20 mL/min, cardiac stage I-IIIA, as well as no current or past history of symptomatic multiple myeloma.

Researchers randomized patients (1:1) to receive daratumumab-VCd or VCd alone. All participants received bortezomib (weekly subcutaneous [SC] 1.3 mg/m2), cyclophosphamide (weekly oral [PO] or intravenous [IV] 300 mg/m2), and dexamethasone (weekly PO or IV 20-40 mg) for six 28-day cycles. In cycles 1 and 2, every other week in cycles 3 to 6, and every 4 weeks thereafter for up to 24 cycles, daratumumab SC was administered by injection. In cycles 1 to 6, clinical evaluation of health and disease occurred every 4 weeks, and after cycle 7 clinical evaluation occurred every 8 weeks until major organ deterioration, end of study, withdrawal, or death. Overall hematologic CR rate was the primary end point; this was defined as regulation of FLC levels and ratio (FLCr) combined with negative urine and serum immunofixation, confirmed subsequently at another visit.

There were 2 criteria for deep hematologic response used in this study: iFLC ≤20 mg/L regardless of FLCr and dFLC <10 regardless of FLCr. Deep hematologic response analyses were completed on the intent-to-treat group; participants without baseline or post-baseline data were considered nonresponders. The composite end point of MOD-PFS was defined as whichever of the following events occurred first: cardiac deterioration (requiring cardiac transplant, left ventricular assist device, or intra-aortic balloon pump), end-stage renal disease (requiring hemodialysis or renal transplant), hematologic progression per consensus guidelines, or death.

Patients (N = 388) were randomized; 195 received daratumumab-VCd and 193 received VCd alone. Between treatment groups, baseline characteristics were well-balanced. The median age was 64 years, and 65% of patients had ≥2 organs involved. The researchers reported that 71% of patients had heart involvement and 59% had kidney involvement, and that 23% of patients had cardiac stage I, 40% had stage II, and 37% had stage IIIA.

Median follow-up was 11.4 months. For daratumumab-VCd, the median duration of treatment was 9.6 months compared with 5.3 months for VCd. By all criteria, the rates of deep hematologic responses sharply favored the daratumumab-VCd cohort, and there was longer MOD-PFS in patients who achieved deep hematologic responses. Regardless of the hematologic response criteria used, MOD-PFS was comparable.

Combining daratumumab with VCd increased deep hematologic response rates in patients with newly diagnosed AL irrespective of criteria used, resulting in prolonged MOD-PFS. In this patient population, these data support the benefit of daratumumab.

Reference

Comenzo R, Kastritis E, Palladini G, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from Andromeda. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 552.

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