Combination Melphalan and Bortezomib Conditioning with Autologous Hematopoietic Stem Cell Support in Patients with Advanced Multiple Myeloma. A Phase I/II Study.

Abstract 1214

Poster Board I-236

Bortezomib is an active agent in the treatment of multiple myeloma (MM) and shows additive or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan with autologous peripheral blood stem cell transplantation (PBSCT) in patients (pts) with disease progression or less than partial response after a prior PBSCT (tandem transplant). Primary exclusion criteria are active infection at time of PBSCT, cardiac amyloid deposition, and creatinine clearance of <20 ml/min. Peripheral neuropathy of less than grade 4 is not an exclusion. Bortezomib is given on days -4 and -1 with melphalan 200 mg/m2 (actual weight) given on day -2 before PBSCT. All pts are given oral ice during the melphalan infusion to prevent oral mucositis. For the phase I study, bortezomib was given at rising doses of 1.0, 1.3, and 1.6 mg/m2. Three pts were to be enrolled at each dose level, with an additional 3 pts enrolled in case of a serious toxicity event at any level. An additional 20 pts are being enrolled in the phase II portion of the study.

Twelve pts (median age, 59 yrs) were treated in the phase I study with 6 pts treated at the 1.0 mg/m2 level after 1 pt experienced an SAE of prolonged diarrhea, and 3 pts treated at each of the subsequent levels. Eleven pts had 1 prior and 1 pt tandem prior cycles of dose-intense melphalan with PBSCT. All pts experienced the expected pancytopenia requiring red cell and/or platelet support. Ten pts had febrile neutropenia with bacteremia identified in 3 pts. One pt had mild tumor lysis. Mucositis was minimal and comparable to PBSCT with melphalan alone. All pts engrafted at a median time to ANC>500/uL of 11 days (range, 9-19) and plt>20,000/uL of 14 days (range, 11-27). No other SAEs occurred in the phase I study beyond the usual events of high-dose therapy. No neurological SAEs, including severe peripheral neuropathies, were observed. A bortezomib dose of 1.6 mg/m2 was chosen for the phase II study.

Eleven pts (median age, 57 yrs) are now treated in the phase II study. Three pts had disease progression and 8 pts had less than PR after a prior PBSCT. All pts experienced pancytopenia and 10 engrafted with median time to ANC>500/uL of 10 days (range, 8-13) and plt>20,000 11 days (range, 9-65). Seven pts had febrile neutropenia with 3 pts with positive blood cultures and 1 pt with RSV bronchitis. Three SAEs are reported in the phase II portion: 1 pt expired of complications of Candida krusei infection and 1 of MRSA sepsis (before ANC recovery). A third pt developed tumor lysis requiring dialysis. One pt had a dysphoric reaction to anti-emetics and did not receive the 2^nd bortezomib dose. No neurological SAEs attributable to this regimen were observed in this population.

Pts underwent restaging studies at monthly intervals after transplantation with marrow examination at 3 and 12 months (mos). Response classification is in accordance to standard definitions. Three pts underwent subsequent allogeneic PBSC and 2 pts died of transplant-related complications and are not evaluable for response. Two pts succumbed to progressive disease. The remaining 16 pts are in ongoing follow-up. Eight pts including 6 of 11 pts with stable disease or minimal response after prior dose-intense melphalan achieved a CR. Six pts remain in continuous CR at 11+ to 23+ mos (median, 15+ mos) after PBSCT with 2 pts having disease progression at 12 and 26 mo after PBSCT.

These data indicate that bortezomib can be added to dose-intense melphalan in this schedule with acceptable toxicities. Strikingly, 8 of 20 pts achieved CR after minimal response to dose-intense melphalan alone or disease progression after a prior PBSCT, and 2 pts showed tumor lysis, indicating a synergistic effect of adding bortezomib to dose-intense melphalan. This regimen will now be studied in a larger cross-over study of tandem PBSCT to assess relative response to the two regimens.