Salvage Therapy with Lenalidomide and Dexamethasone (LDex) In Patients with Advanced AL Amyloidosis Refractory to Both Melphalan and Bortezomib

Abstract 3062

In the last few years the therapeutic armamentarium for AL amyloidosis has substantially increased with the introduction of new agents, such as bortezomib and immunomodulatory drugs. Although the probability of responding to the potent first line regimens also increased, still several patients are refractory to 2 or more agents, including new drugs. These patients often develop severe cardiac involvement, which further reduces the therapeutic options and portends a dismal prognosis. Given its toxicity profile, lenalidomide is an appealing therapeutic option for subjects with advanced disease. The efficacy of lenalidomide in AL amyloidosis has been reported by the Mayo Clinic (Dispenzieri et al, Blood 2007; 109: 465-70) and Boston (Sanchorawala et al, Blood 2007; 109: 492-96) groups. Overall, 56 patients were reported in these studies, 44 of whom were previously treated. However, prior exposure to bortezomib was not reported, and the median number of previous regimens was 1. In the present study we describe the outcome of 24 patients with advanced AL amyloidosis, refractory to both melphalan and bortezomib, who were treated with the combination of lenalidomide and dexamethasone (LDex).

The patients received lenalidomide (15 mg on days 1–21 with dose reductions for renal failure) and dexamethasone (dex, 20 mg on days 1, 8, 15 and 22) in 28 days cycles, between July 2007 and July 2009. Prophylactic aspirin and omeprazole were also administered. Response was assessed after 2 cycles according to the 2005 International Society of Amyloidosis criteria (Gertz et al, Am J Hematol 2005; 79: 319-28).

All the patients were refractory to prior melphalan (autologous stem cell transplant in 7 cases and oral melphalan plus dex in 17) and bortezomib plus dex. Moreover, 19 patients (79%) were also refractory to thalidomide (administered in association with cyclophosphamide and dex in 10 subjects and with dex alone in 9). The median number of prior treatments was 3 (range 2–5). Sixteen patients (67%) had heart involvement as assessed by echocardiography. According to the cardiac staging system based on NT-proBNP (cutoff 332 ng/L) and troponin I (cutoff 100 ng/L), 6 patients (25%) were stage 1 (both markers below the cutoff), 3 (13%) were stage 2 (only 1 marker elevated), and 15 (62%) were stage 3 (both markers elevated). Six patients (25%) had glomerular filtration rate <30 mL/min, 3 of whom were on dialysis. The patients received a median of 4 cycles of LDex (range: 1–14). Eleven subjects (46%) experienced severe (grade 3 or 4), though not fatal adverse events (thrombocytopenia in 4, neutropenia in 3, renal failure in 2 and skin rash in 2), that required treatment discontinuation during cycle 1 in 2 cases (thrombocytopenia and rash). Three patients (13%) died on treatment due to progressive disease. Nine (41%) of the 22 patients who completed at least 2 cycles of LDex achieved a partial hematologic response. There were no complete remissions and 1 subject achieved an organ (cardiac) response. After cycle 2, we observed NT-proBNP stability in patients who attained hematologic response (median change 15%) and increase in non-responders (median change 183%). Overall, 13 patients (54%) died and median survival was 19.7 months. Response to LDex significantly prolonged survival (median 10 months vs. not reached, p=0.005).

Our results indicate that treatment can be continued in patients with advanced AL amyloidosis refractory to 2 or more prior regimens and that LDex is a valuable option in this setting.