Long term outcome of patients treated on clinical trials of immunomodulatory agents for the treatment of Immunoglobulin light chain (AL) amyloidosis: A pooled analysis
Authors: Vaishali Sanchorawala, Gheorghe Doros, Anthony C. Shelton
Journal: American Journal of Hematology (2019)

Novel agents like proteasome inhibitors and immunomodulatory agents have changed the therapeutic landscape of multiple myeloma. These agents have also been studied as single agent and in combination with other agents in the treatment of AL amyloidosis.1 Systemic immunoglobulin light chain (AL) amyloidosis is a plasma cell dyscrasia leading to amyloid fibril deposition in various organs and tissues causing organ dysfunction, failure, and death. Treatment of AL amyloidosis is directed toward the plasma cell dyscrasia and is usually derived from the experience in myeloma. The aims of therapy are rapid elimination of the precursor protein, that is, plasma cell dyscrasia, and improved reabsorption of amyloid deposits to rapidly ameliorate organ function to improve patients' quality of life and survival. Ultimately, the types of therapy used depend on a fine balance of treatment toxicities and the patient's risk classification. A major breakthrough for patients with systemic AL amyloidosis was the introduction and incorporation of regimens using bortezomib (a proteasome inhibitor) and immunomodulatory agents. Bortezomib based regimens are now considered standard for the treatment of patients with AL amyloidosis who are not eligible to receive high dose melphalan and stem cell transplantation (HDM/SCT).2 Immunomodulatory agents (IMiDs) have been studied in multiple phase I/II clinical trials in the treatment of AL amyloidosis. We, at Boston University Amyloidosis Center, conducted three clinical trials of IMiDs in the treatment of AL amyloidosis. These clinical trials were designed to assess tolerability, safety, maximum tolerated dose, hematologic responses, and organ responses with these agents. However, there are limited data documenting long-term outcomes with respect to overall survival (OS) and progression free survival (PFS) for those who are treated with IMiDs. We report on patients with AL amyloidosis, pooled from the previously reported three clinical trials of IMiDs to review long-term survival data of this unique patient population. The primary objectives of this analysis were to evaluate hematologic response with IMiDs. Secondary objectives included evaluating PFS and OS of patients treated with IMiDs in AL amyloidosis. All three clinical trials were approved by the Institutional Review Board of Boston Medical Center in accordance with federal regulations and the Declaration of Helsinki. Pooled analysis of the three clinical trials was performed. The first clinical trial was of lenalidomide and dexamethasone (Len/dex) for the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00091260) which enrolled 82 patients with AL amyloidosis between 2004 and 2011.3 The next clinical trial was of a combination regimen of melphalan, lenalidomide, and dexamethasone (MLd) in AL amyloidosis (ClinicalTrials.gov: NCT00679367) in which 16 patients were enrolled from 2008 to 2011.4 This was then followed by a phase I/II clinical trial of pomalidomide and dexamethasone (Pom/dex) (ClinicalTrials.gov: NCT01570387) and 27 patients with AL amyloidosis were enrolled from 2012 to 2015.5 The response criteria for hematologic and clinical/organ response used were standards defined by the consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis and the updated version.6 A hematologic complete response (CR) was defined as absence of monoclonal protein in serum and urine by immunofixation electrophoresis, and a normal immunoglobulin free light chain ratio. Hematologic response were assessed after completion of three cycles of IMiDs and every three cycles thereafter. Time to progression (defined as the time from treatment initiation to first documented disease progression, or the time to first alternative treatment initiation or deaths prior to subsequent therapy were considered events), and OS were evaluated. Kaplan-Meier methodology was used for time-to-event analyses. Due to the limited sample size and the noncomparative nature of the study, all efficacy analyses were exploratory and descriptive. No statistical comparisons between treatment groups were conducted. A total of 125 patients with AL amyloidosis were enrolled on three separate clinical trials of IMiDs from 2004 to 2015. Patient characteristics are shown in Table 1. The distribution of organ involvement was typical for AL amyloidosis across all trials with 50% to 67% with cardiac involvement. Number of patients with cardiac involvement increased across the trials, with 50% in the first trial of len/dex and 67% in the last trial of pom/dex. This may suggest either the referral bias or identification of cardiac involvement based on sensitive criteria of cardiac biomarkers and not only echocardiographic features in the latter trial. Time to enrollment from diagnosis reflects eligibility criteria of the three clinical trials with MLd enrolling more newly diagnosed patients and therefore median time to enrollment shorter at 5 months compared to ~2 years for the other trials. Majority of patients had received prior treatment before enrollment on these trials, except for MLd trial in which 69% of patients were newly diagnosed without prior treatment. Prior treatments and prior treatment with bortezomib also different across trials based on time period when trial was initiated and availability of bortezomib and demonstration of its efficacy in AL amyloidosis; 5% of patients were treated with bortezomib on len/dex trial compared to 78% on pom/dex trial. Median number of treatment cycles were 9.5 for len/dex and 6 for MLd and pom/dex. Although overall hematologic response rate was similar on these trials of 50% to 60%, hematologic CR rates were higher in pom/dex clinical trial at 33% compared to 16% and 7% with len/dex and MLd, respectively. With a median follow-up of 8.4 years of surviving patients (range, 3.4-14.5), 78% of patients have died and 22% are alive to date. Median OS is 4.3 years (95% confidence interval, 3.0-5.6) and median PFS is 2.1 years (95% confidence interval, 1.6-2.6), as shown in Figure S1A. Median OS and PFS of each trial are demonstrated in Figure S1B,C,D. The occurrence of invasive second primary malignancy (SPM) was observed in all three clinical trials; four cases in len/dex trial, one in MLd trial, and two in pom/dex trial. There were two hematologic SPM (chronic myelogenous leukemia and myelodysplastic syndrome) and five solid tumor (lung cancer, prostate cancer, breast cancer, ovarian cancer, and squamous cell head and neck cancer) SPM. Therefore, the incidence of SPM was 5.6% in this post hoc pooled analysis. The incidence rates of hematologic and solid tumor SPMs with lenalidomide maintenance before progressive disease are 5.3% and 5.8%, respectively, in a meta-analysis of lenalidomide maintenance therapy in myeloma.7 In summary, these three phase I/II studies demonstrate that IMiDs have activity and efficacy in patients with AL amyloidosis, in inducing hematologic responses even among patients who had progressed after initial therapy. IMiDs also led to prolonged PFS and OS in patients who had relapsed after initial therapy. There should not be any conclusion made about superiority of one regimen over another due to heterogeneity in the eligibility criteria and this being a post hoc pooled analysis. Although immunomodulatory drugs are less often considered as the first choice for patients with newly diagnosed disease, they are often the backbone of treatment of patients with relapsed disease. One must note that these agents can lead to paradoxical increase in cardiac biomarkers, especially BNP,8 and also worsen renal failure.9 Organ responses following therapies with IMiDs may be difficult to assess due to these considerations. Moreover, 65% of patients had received prior therapy with HDM/SCT and therefore were good-risk patients enrolling on these three clinical trials.10 Future studies are required to understand how to better incorporate IMiDs into common practice, but long term results are remarkably encouraging and research for further improving outcomes is needed. These clinical trials were partly funded by Celgene Corporation. The authors declare no financial conflicts. V.S. designed research, performed research, analyzed data, wrote the manuscript, G.D. performed statistical analysis, A.C.S. collected data. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.