Background: Light chain amyloidosis (AL) is a disorder characterized by protein deposition on various organs resulting in multi-organ failure and death. Treatment traditionally has been aimed at the underlying clonal plasma cell to stop production of amyloid fibrils. As in multiple myeloma, alkylators, autologous stem cell transplant, proteasome inhibitors and immunomodulating drugs (IMiDs) like Lenalidomide (Len), and Pomalidomide (Pom) have provided benefit. Due to the rarity of AL, studies are few and usually have small sample sizes. We have pooled results from 3 IMiD-based phase II studies conducted in AL in an attempt to learn more about the long term outcomes and toxicity.
Methods: Pooled analysis of 3 phase II studies of AL amyloid was performed. The Len-Dex (yrs: 2004-2006) and the cyclophosphamide+Len Dex (CRD) (yrs: 2007-2008) trials enrolled patients with newly diagnosed or relapsed disease, and the Pom-Dex (yrs: 2008-2010) trial was for relapsed or refractory patients only. The primary endpoint of all the studies was hematologic response: complete response, very good partial response, or partial response. Safety and toxicity was assessed every four weeks using Common Terminology Criteria for Adverse Effects (CTCAE) version 3. Overall survival (OS) was calculated from time of registration to death and progression free survival (PFS) were calculated from trial to progression or death. One hundred and six patients were enrolled in these studies but only 101 were evaluated for this analysis (Len-Dex: N=37, CRD: N=35, Pom-Dex: N=29). Four patients were excluded from Pom-Dex since they had participated in one of the other two trials, and 1 patient was excluded from Len-Dex as they withdrew consent prior to receiving any study drug.
Results: The median age for the entire cohort was 65, with 61% male study participants. Fifteen percent were cardiac stage I, 48% stage II, 20% stage IIIa, and 17% stage IIIb. The median follow up for surviving patients was 101.2 months (range 16.7 - 149.7), and 78% of patients have died. The OS and PFS for pooled patients was 31.1 months (95%CI: 17.6-43.8) and 14.8 months (95%CI: 10.8-29.7) respectively. On univariate analysis, only cardiac stage was prognostic for OS. Prior treatment, previous IMiD, or months from diagnosis to registration were not prognostic. As shown in Table, 5-year PFS and OS for CRD was 33% and 45%, respectively. Respective rates for Len-Dex were 24% and 32%, and for Pom-Dex, 11% and 28%. Most common grade >=3 toxicities attributed to study drug were neutropenia, thrombocytopenia, fatigue, rash, and edema, all of which were similar among studies, except there were no cases of rash associated with Pom-Dex. There also appeared to be less cardiac toxicity and less hypotension and syncope with Pom-Dex.
Conclusion: These analyses demonstrate that IMiDs can result in long progression-free intervals and survival rates among patients with AL amyloidosis.
Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Gertz: Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Dingli: Takeda: Consultancy; Millenium: Consultancy; Karyopharm Therapeutics: Research Funding; Alexion Pharmaceuticals: Consultancy; Janssen: Consultancy. Kapoor: Takeda, Celgene and Amgen: Research Funding. Russell: Imanis Life Sciences: Equity Ownership; Vyriad: Equity Ownership. Dispenzieri: Celgene, Millenium, Pfizer, Janssen: Research Funding.
Asterisk with author names denotes non-ASH members.