Consolidation with bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in systemic AL amyloidosis

High-dose melphalan and autologous stem cell transplant (SCT) induce hematologic and clinical remissions in AL and results in prolonged survival. In a prior phase II study, we showed that post-SCT adjuvant thalidomide and dexamethasone improved hematologic responses in 42% of patients, resulting in a 39% strictly defined complete response (sCR) rate at 12 months post-SCT (Cohen et al., Br J Haematol 2007;139:224–233). With a median follow-up of 59 months, the overall survival of patients on that study is 69% (Comenzo, Blood 2009;114:3147–3157). We now report on a phase II trial in which we use bortezomib and dexamethasone (BD) following risk-adapted SCT in newly diagnosed patients with amyloidosis who had residual disease following SCT. We show that BD is welltolerated and effective for eradicating persistent clonal plasma cell disease. At 12 months post-SCT, consolidation with BD achieves high overall and unprecedented sCR rates with frequent organ improvement that continues to occur over time. Introduction: High-dose melphalan and autologous stem cell transplant (SCT) induce hematologic and clinical remissions in light chain amyloidosis (AL) and prolong survival when complete hematologic responses (CR) are achieved [1]. This approach has been limited by high treatment related mortality (TRM) rates, especially in older patients and those with advanced cardiac or multiorgan involvement [2]. Careful selection of patients and adjusted dosing of melphalan has improved the safety of this approach. In a prior phase II study, thalidomide and dexamethasone (TD) following melphalan SCT improved response rates in patients not achieving stringent complete hematologic responses (including normalization of the free light chain (FLC) ratio; sCR) [3]. We now report on a phase II trial using consolidation with bortezomib and dexamethasone (BD) after risk-adapted melphalan SCT. Methods: Patients with newly diagnosed AL involving 2 organs were assigned to melphalan 100, 140, or 200 mg/m based on age, renal, and cardiac status. Responses were assessed at 2–3 months following transplant. Patients with persistent clonal plasma cell disease began BD (for a planned 6 cycles, including two 21-day cycles of B 1.3 mg/m days 1, 4, 8, and 11, and four 35-day cycles of B 1.3 mg/m days 1, 8, 15, and 22; on all cycles with D 20 mg on the day of and after B). At 12and 24-months postSCT, we evaluated hematologic and organ responses as well as overall survival (OS). The primary end point was the improvement in response rate of plasma cell disease at 12 months post-SCT in the subset of patients receiving BD consolidation. OS was defined from treatment start until date of death or last follow-up and was estimated by the method of Kaplan–Meier. The association of brain natriuretic peptide (BNP) and troponin-I on OS was assessed using the Cox proportional hazards model. The logrank test was used to determine the association of heart involvement on OS. The safety and tolerability of BD administered post-SCT were also evaluated. Results and discussion: Thirty-seven patients have been enrolled with kidney (N1⁄4 25), heart (N1⁄4 16), liver/GI (N1⁄4 5), and peripheral nervous system (N1⁄4 6) involvement; 43% had two organs involved (Figure 1). Three patients were excluded prior to SCT and 33 have undergone SCT, with one patient not yet evaluable and one taken off study for progression of disease (PD) during SCT (Figure 1). SCT-related 100-day mortality was 11% (4/37), all in patients with advanced cardiac amyloid. At 2–3 months post-SCT, the overall response (OR) rate was 59% (17/29) with 28% (N1⁄4 8) achieving sCR (Figure 2). Nineteen patients received a median of 6 cycles of BD (range 1–6) for persistent clonal plasma cell disease; one patient who was eligible declined. Figure 1. Patient characteristics (N1⁄437) and patient flow. 135