Risk-Adapted Dosing of Melphalan for Systemic AL Amyloidosis (AL) Lowers Treatment-Related Mortality: Early Death but Not Post-3 Month Survival Is Linked to Cardiac Involvement.

Autologous stem cell transplant (SCT) with high-dose melphalan is a standard therapy for selected patients with AL. Treatment-related mortality (TRM), however, remains 10% to 15%. Risk-adapted melphalan (MEL) aims to reduce TRM (Blood 2002;99). Over the past 6 years we have used risk-adapted MEL at 200, 140 and 100 mg/m2. Dosing was based on age (MEL200 if ≤ 60, MEL140 if 61 to 71, MEL100 if > 71) for patients with no cardiac involvement, involvement of 1 or 2 major organ systems (of kidneys, liver/GI tract and peripheral nervous system) and creatinine clearance (CrCl) ≥ 51ml/min. Similarly, with cardiac involvement and/or CrCl < 51, MEL140 was used for those < 61 and MEL100 for those 61 to 71. Patients < 41 were treated with MEL200 as a rule. Patients with advanced involvement of the heart or ≥3 organ systems, or with cardiac involvement and age ≥ 71, were not SCT candidates. We followed TRM, defined as death during G-CSF mobilization or within 100 days of SCT, and also asked if survival at 3 months post-SCT was affected by achievement of complete hematologic response (CR) or by clonal Ig V L germline gene use. Of the 303 amyloid patients seen in that period, 94 were mobilized with G-CSF for SCT, 50M/44W with a median age of 57 (range, 32–73) at a median of 3 months from diagnosis (1–43). None had prior SCT and 71% (n=67) were untreated for plasma cell disease, including 45 who entered a clinical study employing adjuvant oral therapy after SCT. Fifty percent had dominant renal amyloid, 28% (n=27) cardiac, and 71% (n=67) single organ involvement. Clonal lambda disease was present in 83% (n=78) and serum free light-chain abnormalities in 95% (57/60). Patients were assigned to MEL200 (n=35), MEL140 (n=42) or MEL100 (n=17). There were 8 early deaths, 4 related to treatment (RTT), 1 in mobilization and 3 in SCT, and 4 related to progression of disease before SCT. All were associated with cardiac amyloid. Seven of the 8 were in the MEL100 group (RTT=3) and 1 was MEL140 (RTT=1). Overall TRM was 4.3% (4/94) with 3 in the MEL100 group. With a median follow-up of 22 months (1–77), survival is 81% and median survival has not been reached. From mobilization, non-cardiac patients had significantly better survival [88% (59/67) vs 63% (17/27), p<0.01] but from 3 months post-SCT they survived no better than those with cardiac amyloid (p=0.29). Median survival for the MEL100 group is 47 months (vs MEL 200, p=0.02) while median survivals for the others are not yet reached. At 3 months post-SCT, CR neither differed by dose [MEL200 34% (11/32), MEL140 29% (11/38), MEL100 50% (5/10)] nor significantly affected survival [CR 93% (25/27) versus non-CR 88% (45/53), p=0.22]. Clonal Ig V L germline donors were identified in 81 cases [common: 6a =23, 2a2 =15, 3r =9, DPK1 =5] but did not affect survival. In sum, risk-adapted dosing of melphalan has a low TRM. Patients with cardiac involvement are at risk of early death but by 3 months post-SCT their survival is not significantly different than non-cardiac patients. These results highlight the need for new approaches to improve survival of AL cardiac patients during SCT with risk-adapted melphalan.