AL AMYLOIDOSIS UPFRONT TREATMENT AND CURRENT AND FUTURE STUDIES

Abstract

The treatment of AL amyloidosis is based on the elimination of the plasma cell clone. Today, approved therapies include combinations of the anti-CD38 monoclonal antibody daratumumab with bortezomib, cyclophosphamide and dexamethasone (D-VCd); this combination is effective with about 50%-60% of the patients achieving complete hematologic response and about 80% achieving at least a very good partial hematologic response. However, there are still several unmet needs: patients with very advanced cardiac amyloidosis, such as those stage 3B disease, have been excluded from the clinical trials, and they still have a very poor outcome. Second, at least 50% of patients with AL amyloidosis still fails to achieve a clinically significant organ function improvement. Finally, for patients failing to achieve hematologic or organ response or those who relapse after initial response, there is a need for new treatments and novel strategies. Although most treatments for patients with AL amyloidosis come from the myeloma field, not every therapy given for myeloma is suitable for patients with AL amyloidosis. Targeted therapies, such as those targeting BCL2, can be quite effective, since about 50% of AL patients harbor t(11;14). Anti-BCMA targeting therapies are also promising but they need to be further explored in the setting of AL amyloidosis. Experience with cellular therapies and T-cell redirecting therapies is still limited in AL amyloidosis; such therapies could be quite effective in eliminating the small but toxic amyloidogenic plasma cell clone but their toxicity should be explored specifically in patients with AL amyloidosis. An urgent need remains for the treatment of patients with very advanced cardiac involvement, for which even a deep hematologic remission may not be enough. For these patients, regimens with low toxicity and high efficacy should be prioritized and combined with potentially active amyloid targeting therapies. Combinations of non-cardiotoxic, non-nephrotoxic and non-neurotoxic agents should be prioritized, preferably in fixed duration regimens.