Risk-Adapted Intravenous Melphalan Followed by Adjuvant Dexamethasone (D) and Thalidomide (T) for Newly Diagnosed Patients with Systemic AL Amyloidosis (AL): Interim Results of a Phase II Study.
Authors: Cohen Adam D. , Zhou Ping , Reich Lillian , Quinn Alice , Fircanis Sophia , Drake Lisa , Hedvat Cyrus , Teruya-Feldstein Julie , Filippa Daniel A. , Fleisher Martin , Comenzo Raymond L. 
Published: April 2020

Abstract
High-dose melphalan (M) with autologous stem cell transplant (ASCT) is an effective therapy for AL, but treatment-related mortality (TRM) remains high, and hematologic complete responses (CR) occur in a minority of patients. In this study, we asked whether a risk-adapted approach to IV M dosing could decrease TRM, and whether adjuvant D +/− T could improve hematologic and amyloid-involved organ response rates. Other objectives of the trial are to study prospectively the prognostic significance of the serum free light chain (FLC), troponin I, and brain natriuretic peptide (BNP) assays. Newly diagnosed untreated AL patients are risk-stratified upon enrollment. Low-risk patients (1 or 2 major organs involved, no advanced cardiac disease) receive M 100, 140, or 200 mg/m2 with ASCT based on age, presence of cardiac involvement, and renal function. High-risk patients (≥3 organs involved or advanced cardiac disease) receive 2 cycles of M 40 mg/m2 without ASCT. Patients with persistent clonal plasma cell disease at 3 months receive 9 months of adjuvant D+T or D alone (if history of deep venous thrombosis or neuropathy). Since 9/02, 38 patients (median age=57.5 (range 34–73), 68% males) have enrolled. Median time from diagnosis to enrollment is 1.5 months (range 0.5 – 7). Organ involvement includes 13 (34%) cardiac, 24 (63%) renal (12 with renal only), 13 (34%) liver/GI tract, and 10 (26%) peripheral nervous system. Thirty-two (84%) had baseline elevated serum FLC with abnormal κ:λ ratio. Thirty-four patients have been treated--3 high-risk and 31 low-risk (5 at M 100, 16 at 140 and 10 at 200 mg/m2). Treatment-related mortality is 7.4% (2/27) with an additional 7 patients alive &lt;100 days post-treatment. Six patients, including all 3 treated high-risk patients, have died of progressive disease (PD) a median of 5.5 months (range 4–17) after M. Of the 8 patients who died, 7 had symptomatic cardiac involvement. At 3 months, 22 low-risk patients are evaluable for hematologic response. Thirteen (59%) responded (4 CR, 9 PR) and 9 had stable disease. Of the 18 patients with persistent clonal disease, 9 began T (50 to 200 mg nightly) and D (1 to 3 four-day pulses monthly), 6 began D alone, and 3 had no adjuvant therapy (refused or too ill). Five patients completed 9 months of adjuvant therapy, and 2 remain on therapy, with 2 conversions from PR→CR (T+D, D), and 1 from SD→PR (D). Reasons for discontinuation were PD (n=4), pulmonary embolus (n=1), pneumonia (n=2), and intolerance (n=2). Eleven patients are evaluable at 12 months, with 10 (91%) responses (4 CR, 6 PR) and 1 PD (9%). Seven (77%) have objective improvement in amyloid-related organ function, 2 have stable and 2 worsened AL. Preliminary analysis of serum FLC data (n=23) shows an association between a persistently abnormal κ:λ ratio 3 months after treatment and an increased risk of death (RR=1.67, 95% CI=1.10–2.52, p=0.02). Analyses of the prognostic significance of serial troponin and BNP assays are ongoing. In conclusion, risk-adapted dosing of IV M in newly diagnosed AL patients has a low TRM. Adjuvant D +/− T is feasible, with toxicity leading to discontinuation in 33% (5/15) of patients, and with a benefit to date in 20% (3/15) of patients with persistent clonal plasma cell disease 3 months post ASCT, including induction of 2 hematologic CRs.