Figure 2.
Treatment strategy for patients with newly diagnosed AL amyloidosis. The design of the treatment strategy requires accurate risk stratification. In the past, transplant-related mortality related to advanced amyloid organ involvement was very high. Refinement of selection criteria with the inclusion of cardiac biomarkers resulted in a significant improvement in tolerability of ASCT. Subjects who are not transplantation eligible at diagnosis, may become suitable transplantation candidates if they attain organ response after up-front therapy. Melphalan dose adjustment to extend ASCT eligibility does not decrease toxicity but negatively impacts response rate and should be discouraged. Pretransplant therapy with bortezomib-based regimens is beneficial in patients with a bone marrow PC infiltrate >10% but can be considered in all patients to attain rapid reduction of the amyloid light chain, if harvesting procedures and ASCT scheduling can result in a relevant delay. Moreover, recent data indicate that induction therapy independently increases PFS. Importantly, bortezomib-based therapy alone can grant satisfactory (CR and/or organ response) and durable response in some patients who may then not proceed to ASCT. Posttransplantation therapy with bortezomib-based regimens increases CR rate and extends PFS in patients who attain less than VGPR after ASCT. Amyloidogenic PCs depend on proteasomes to survive the stress caused by toxic LCs, resulting in particular sensitivity to proteasome inhibition, and bortezomib is also the cornerstone of treatment of patients who are not eligible for ASCT. Combination of bortezomib-based regimens with daratumumab will most likely become novel standards of care based on the results of recent clinical trials. In current clinical practice, daratumumab is still not widely accessible, and CyBorD is preferred over BMDex in patients with renal failure and in those who may later become eligible for ASCT, whereas BMDex may overcome the negative effects of both t(11;14) and gain 1q21. Venetoclax is also an appealing option for patients with t(11;14), but few data are available so far. Relevant comorbidities include potential contraindications to bortezomib, such as peripheral neuropathy and pulmonary fibrosis. Oral MDex or immunomodulatory drug (IMiD)-based regimens are valuable alternatives for subjects with contraindications to bortezomib. Carfilzomib can also be considered in patients with peripheral neuropathy, carefully balancing potential cardiac toxicity. Patients with non-PC clones should be treated with regimens specifically targeting the underlying amyloid clone.

Treatment strategy for patients with newly diagnosed AL amyloidosis. The design of the treatment strategy requires accurate risk stratification. In the past, transplant-related mortality related to advanced amyloid organ involvement was very high. Refinement of selection criteria with the inclusion of cardiac biomarkers resulted in a significant improvement in tolerability of ASCT. Subjects who are not transplantation eligible at diagnosis, may become suitable transplantation candidates if they attain organ response after up-front therapy. Melphalan dose adjustment to extend ASCT eligibility does not decrease toxicity but negatively impacts response rate and should be discouraged. Pretransplant therapy with bortezomib-based regimens is beneficial in patients with a bone marrow PC infiltrate >10% but can be considered in all patients to attain rapid reduction of the amyloid light chain, if harvesting procedures and ASCT scheduling can result in a relevant delay. Moreover, recent data indicate that induction therapy independently increases PFS. Importantly, bortezomib-based therapy alone can grant satisfactory (CR and/or organ response) and durable response in some patients who may then not proceed to ASCT. Posttransplantation therapy with bortezomib-based regimens increases CR rate and extends PFS in patients who attain less than VGPR after ASCT. Amyloidogenic PCs depend on proteasomes to survive the stress caused by toxic LCs, resulting in particular sensitivity to proteasome inhibition, and bortezomib is also the cornerstone of treatment of patients who are not eligible for ASCT. Combination of bortezomib-based regimens with daratumumab will most likely become novel standards of care based on the results of recent clinical trials. In current clinical practice, daratumumab is still not widely accessible, and CyBorD is preferred over BMDex in patients with renal failure and in those who may later become eligible for ASCT, whereas BMDex may overcome the negative effects of both t(11;14) and gain 1q21. Venetoclax is also an appealing option for patients with t(11;14), but few data are available so far. Relevant comorbidities include potential contraindications to bortezomib, such as peripheral neuropathy and pulmonary fibrosis. Oral MDex or immunomodulatory drug (IMiD)-based regimens are valuable alternatives for subjects with contraindications to bortezomib. Carfilzomib can also be considered in patients with peripheral neuropathy, carefully balancing potential cardiac toxicity. Patients with non-PC clones should be treated with regimens specifically targeting the underlying amyloid clone.

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