Optimal Therapy for Relapsed AL Amyloidosis Post Autologous Stem Cell Transplant
Authors: Sidiqi M Hasib , Al Saleh Abdullah S. S. , Vaxman Iuliana , Dispenzieri Angela , Buadi Francis K. , Muchtar Eli , Warsame Rahma M , Lacy Martha Q. , Dingli David , Leung Nelson , Gonsalves Wilson I , Kapoor Prashant , Kourelis Taxiarchis , Rajkumar S. Vincent , Kumar Shaji K. , Gertz Morie A 
Published: November 2019

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma.
Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included.
Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients were excluded from this analysis as they either proceeded directly to second ASCT (n=10) or received an atypical regimen not commonly considered for AL amyloidosis (n=24). Five categories of therapy regimens were identified, thalidomide based (n=110), melphalan plus steroids (n=31), 2nd generation immunomodulatory (IMiD) drug +/- alkylator (n=76), proteasome inhibitor (PI) +/- alkylator (n=116), PI plus IMiD (n=16), or daratumumab based (n=9). Disease and treatment characteristics for patients treated with these regimens are listed in Table 2. Patients treated with thalidomide had the shortest PFS1 (17.7 months) but PFS1 was similar for those treated with melphalan plus steroids, PI+IMiD and 2nd generation IMiDs (25.5, 24.3 and 25.6 months respectively). Patients treated with a PI +/- alkylator and daratumumab based regimen had the longest PFS1 (36.7 and 41.9 months respectively). The median duration of therapy was longer in patients treated with a 2nd generation IMiD or daratumumab based regimen (10.2, 12, 6.1, 5.5, 6.2 and 5.9 months for Dara based, 2nd generation IMiD, PI+/- alkylator, PI+IMiD, melphalan plus steroids and thalidomide based respectively).
Hematologic response rate was lowest in those treated with melphalan plus steroids or thalidomide based regimens (44% and 55% respectively) and highest for patients treated with a PI+/- alkylator, (Figure 1). Progression free survival from relapsed therapy (PFS2) was longest amongst patients treated with daratumumab based regimens, PI +/- alkylator and 2nd generation IMiDs (not reached, 29.9 and 26.7 months respectively), Figure 2A. Overall survival from time of relapsed therapy favored patients treated with daratumumab based regimens, 2nd generation IMiDs and PI +/- alkylator, Figure 2b).
Conclusion: A second generation IMiD based regimen or PI +/- alkylator produce high response rates and prolonged progression free and overall survival for relapsed AL amyloidosis. Patients treated with daratumumab based regimens and those treated with a PI plus IMiD also appear to do well, although numbers were low in our study. Patients treated with melphalan plus steroids or thalidomide based combinations have inferior outcomes and these regimens should be avoided.

Disclosures
Dispenzieri: Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Annexon: Consultancy.

OffLabel Disclosure:
Daratumumab off label use for AL amyloidosis.