Introduction: Multi-organ dysfunction remains a major cause of morbidity and mortality with light chain amyloidosis (AL) especially for patients not achieving hematologic complete response. Approval of daratumumab (DARA) has revolutionized the care of multiple myeloma and its therapeutic implications have shown to be safe and highly effective in relapsed/refractory AL amyloidosis. This analysis demonstrates the activity of the combination of DARA, bortezomib, and dexamethasone in AL amyloidosis patients somewhat refractory to cyclophosphamide, bortezomib, and dexamethasone (CyBorD).
Methods: Patients (pts) were identified via our IRB-approved plasma cell disorder registry. Pt selection included those who did not achieve at least a hematologic VGPR with first line treatment and who went on to receive a DARA containing second-line treatment for AL amyloidosis.
Results: Since the approval of DARA for multiple myeloma, we have seen 159 pts with newly diagnosed AL amyloidosis, of which we identified 10 pts who failed to achieve a VGPR with initial treatment (CyBorD). The median age of our cohort was 67 (range, 38-75), with 80% males. At the time of diagnosis, 50% of the pts had more than one organ involvement (cardiac, renal, GI, lung, and/or bone marrow). All pts were initially treated with CyBorD with average of 4 cycles (range, 2-6), of which 60% achieved a PR and 40% had stable disease. The most common second line regimen was DARA, bortezomib, and dexamethasone (70%) followed by DARA monotherapy. The median number of cycles was 5 (range 1-9) with 50% of pts still undergoing treatment at the time of analysis. The median time to first response was 1.5 cycles (range, 1-3), with 50% achieving a PR, 30% VGPR, 10% CR and the other 10% with stable disease. The overall hematologic response rate was 90% (5 pts achieved at least a VGPR and 2 pts achieved a CR). Organ response was noted in 70% of pts by average of 2 cycles (range, 1-5). Five pts had a cardiac response by NT-proBNP criteria and 2 pts had renal response with 50% reduction in 24 hour urine protein. Toxicity included 40% of pts with a grade 2 infusion reaction with first dose DARA, grade 1-2 fatigue in 60% of pts, and there were no hospitalizations and/or deaths attributed to therapy. Notably, our institutional policy in amyloidosis pts has been to eliminate dexamethasone as a premedication after 3 DARA doses to minimize the risk of volume overload. Six out of 10 pts had dexamethasone discontinued before the end of cycle 2, and of those, half had dexamethasone stopped after the third DARA dose. One additional pt had dexamethasone stopped after the third cycle. No pts had infusion reactions after the discontinuation of dexamethasone. Of the 10 pts, only 2 pts had disease progression. Notably, 1 of the 2 patient's progressed while off therapy, but within 1 additional cycle of DARA monotherapy hematologic CR was achieved.
Conclusion: Daratumumab is safe and highly effective in patients with AL amyloidosis who failed to achieve a deep hematological response with CyBorD. From our clinical experience, we have noted that DARA can induce rapid hematologic and organ responses which is critical to prevent irreversible organ damage. Monotherapy with DARA or in combination is well tolerated. Ongoing studies are investigating CyBorD with or without DARA in newly diagnosed patients. An unanswered question is whether or not CyBorD is needed at all when DARA is used in newly diagnosed patients. Exploring the molecular heterogeneity of these patients may also help identify a subset of patients that will benefit from DARA monotherapy upfront.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.