Risk-adapted dosing of melphalan (MEL) has been proposed as a means of reducing treatment-related mortality (TRM) in patients with AL undergoing SCT but recent retrospective studies show poorer response rates in patients receiving < 200mg/m2 of MEL (

Ann Intern Med 2004;140
;
BMT 2004;34
). We have prospectively studied a combined approach using risk-adapted MEL followed by adjuvant D ± T with the goals of achieving low TRM and optimal hematologic and organ response rates. To be eligible, patients with systemic AL with ≤ 2 organ systems involved and no advanced cardiac disease had to be untreated and diagnosed within 12 months of enrollment. Patients received MEL200, 140, or 100 mg/m2 with autologous SCT based on age, renal function, and cardiac involvement (
Blood 2002;99
). Those not achieving a hematologic complete response (CR) at 3 months post-SCT were treated with 9 months of D (20mg/m2, 1–3 pulses monthly) + T (50–200mg nightly), or only D if they had prior DVT or neuropathy. Forty-five patients (51% men) enrolled, a median of 57 years old (range 34–73) and 2 months from diagnosis. Dominant organ involvement was renal in 58% (n=26), cardiac in 24% (n=11), and liver/GI or peripheral nervous system in 18% (n=8). A third (n=15) had 2 organ systems involved. Twenty-one percent (8/38) had elevated serum troponin I levels (>0.06ng/ml) and 53% (19/36) had elevated serum brain natriuretic peptide levels (>100pg/ml) at baseline. Dose-assignments were MEL200 (n=15), MEL140 (n=24) and MEL100 (n=6). TRM was 4.4% (2/45), with 6 patients out of hospital and well < 100 days post-SCT. At 3 months post-SCT, 63% of patients had hematologic responses (8 CR, 15 PR). Persistent clonal plasma cell disease was found in 29 patients; 1 refused and 2 were too ill for D+T, 17 received D+T and 9 D. Ten completed 9 months of adjuvant therapy, with 13 discontinuing and 3 still on therapy. Reasons for discontinuation were progressive disease (n=4), DVT/PE (n=2), RSV pneumonia (n=2), femoral avascular necrosis (n=1), anxiety (n=1) and intolerance (n=3). Thirty-five percent (9/26) on adjuvant therapy had improvements in hematologic response at 12 mos post-SCT, including 4 PR to CR (2 D+T, 2 D) and 5 stable disease (SD) to PR (3 D+T, 2 D). The hematologic response rate at 12 months was 79% (22/28; 9 CR, 13 PR) with no significant difference based on dose of MEL. Forty-six percent (13/28) had organ responses at 12 months, while 32% had stable and 21% worsened organ function. Only patients who achieved a hematologic response at 12 months had organ responses (59% (13/22) of PR/CR patients vs. 0% (0/6) with stable or progressive disease, p=0.01). With a median follow-up of 18 months (range 1–33), overall survival is 76% and median survival is not yet reached. In summary, risk-adapted MEL has a low TRM and adjuvant D±T can improve hematologic response in a third of patients with persistent clonal plasma cell disease post-SCT, albeit with moderate toxicity. Further study of such combined approaches in AL SCT patients is warranted.

Topics:
autologous stem cell transplant, dexamethasone, immunoglobulin deposition disease, immunologic adjuvants, melphalan, pharmaceutical adjuvants, primary amyloidosis, thalidomide, adjuvant therapy, deep vein thrombosis

Author notes

Corresponding author

2005, The American Society of Hematology
2005
Sign in via your Institution