ALBERT

Description: High-dose therapy plus autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM) aged ≤65 years. Melphalan–prednisone (MP)-based therapy is the standard for non-ASCT candidates but is not typically used for transplant-eligible patients as prolonged therapy with melphalan can adversely affect stem cell collection. The phase 3 VISTA study demonstrated the superior efficacy of bortezomib plus MP (VMP) versus MP in previously untreated MM patients ineligible for ASCT. In this phase 2 study, we evaluated the efficacy of a shorter course of VMP on a different treatment schedule as induction therapy prior to ASCT or as frontline therapy in non- ASCT candidates. Patients aged ≥18 years with previously untreated MM received up to six 28-day cycles of bortezomib 1.3 mg/m2 IV, days 1, 4, 8, and 11, plus oral melphalan 6 mg/m2 and oral prednisone 60 mg/m2, days 1–7. After 2–6 cycles, ASCT-eligible patients could proceed to stem cell mobilization (G-CSF 10 mg/kg/day ± GM-CSF 250 mg/m2/ day or cyclophosphamide 4 g/m2 + GM-CSF) and conditioning with melphalan 200 mg/ m2 (140 mg/m2 if aged 〉65 years). Response was assessed every two cycles and post- ASCT by International Uniform Response Criteria. The primary end point was complete response (CR) rate to VMP. A total of 45 patients were enrolled; 27 were male. Median age was 63 years (range 33–75). MM subtype was 67% IgG, 16% IgA, and 9% each κ- and λ- light-chain; 37% of patients had ISS Stage III MM, 22% had ECOG performance status 〉1, and 70% had ≥40% plasma cells in bone marrow. In total, 20 patients proceeded to ASCT. Median duration of VMP was 4 cycles in both non-ASCT (range 1–6) and ASCT (range 2–6) patients. Response rate (best response) to VMP was 95% (42 of 44 evaluable patients), including 9% stringent CR (sCR), 9% CR (18% ≥CR [95% CI: 7%, 30%]), 27% very good partial response (VGPR), and 50% partial response (PR). Best response was achieved after cycle 2 in 10 patients, cycle 4 in 25 patients, and cycle 6 in 7 patients. All 20 ASCT patients had successful stem cell mobilization; median yield of CD34+ cells/ kg was 5.6 x 106 (range 2.3–12.2 x 106), in a median of 2 collection days. Post-transplant responses were 10% sCR, 20% CR, 55% VGPR, and 5% PR; the remaining 2 patients need further follow-up for response assessment. Response improved post-VMP to post-ASCT in 10 patients (6 PR to VGPR, 2 PR to CR, 2 VGPR to CR). After median follow-up of 14.0 months (range 7.4–47.7) and 14.6 months (range 8.2–42.9) in non-ASCT and ASCT patients, respectively, both median time to progression and progression-free survival were 19.8 months (95% CI: 14.3 months, not estimable [NE]) in non-ASCT patients and 27.9 months (95% CI: 14.6 months, NE) in ASCT patients. A total of 7 patients (5 non- ASCT, 2 ASCT) have died; 1-year survival rate was 82% (95% CI: 59%, 93%) in non- ASCT patients and 95% (95% CI: 69%, 99%) in ASCT patients. Most common grade 3/4 adverse events in all 45 patients during VMP therapy included peripheral neuropathy (24%), thrombocytopenia (20%), neutropenia (18%), and infection (9%). Only 1 patient had deep-vein thrombosis. In conclusion, VMP represents a highly effective therapy for previously untreated MM, with 45% of patients achieving VGPR or better, including 18% sCR/CR. Toxicities were predictable and generally manageable. Short-course VMP therapy did not negatively impact stem cell mobilization, supporting its use as induction therapy prior to ASCT. Very high post-transplant response rates were seen, with 85% of patients achieving ≥VGPR, including 30% sCR/CR. Since achievement of CR/VGPR is associated with improved long-term outcomes in MM, the preliminary outcome data presented here appear promising; however, longer follow-up is required.