A Phase I/II Study of Bortezomib in Combination with Melphalan and Prednisolone in Japanese Patients with Newly Diagnosed Multiple Myeloma

Abstract 5132

BACKGROUND AND PURPOSE: Although bortezomib is widely used both in newly diagnosed and in relapsed/refractory multiple myeloma (MM) patients (pts), it is only approved for relapsed/refractory MM in Japan. To evaluate safety, pharmacokinetics (PK) and efficacy of bortezomib combined with melphalan and prednisolone (MPB) therapy, we conducted a phase I/II study in untreated Japanese MM pts who were ineligible for hematopoietic stem cell transplant (HSCT). METHODS: This was a dose-escalation study designed to determine the recommended dose (RD) of bortezomib in combination with melphalan and prednisolone by estimating the maximum tolerated dose based on dose-limiting toxicity (DLT) in the phase I portion, and to investigate the overall response rate (ORR; CR+PR) and safety of MPB therapy in the phase II portion. Particularly, a continuity of treatment was historically compared with a global phase III study (VISTA trial), and the incidence of interstitial lung disease was assessed. Pts were planned to receive 9 cycles (6-week/cycle) of bortezomib (days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1 to 4; and days 1, 8, 22, and 29 in cycles 5 to 9) plus melphalan (9 mg/m²) and prednisolone (60 mg/m²) administered on days 1 to 4 of each cycle. RESULTS: A total of 101 pts were enrolled and 99 received at least one dose of the study treatment. The median age was 72 years (range: 48–84), and 5 were under 65 years. The most common type of MM was IgG (66%), followed by IgA (25%). In the phase I portion, each 6 pts were assigned to receive 0.7 mg/m² and 1.0 mg/m², and no DLTs were observed in either dose level. In 1.3 mg/m² group, 2 events of DLTs (enterocolitis infections and ileus) occurred in 1 of the 6 pts. Therefore, 1.3 mg/m² was determined as RD for the subsequent phase II portion. In the phase I portion, PK parameters, C_max (120 ng/mL), t_max (0.078 h) and AUC₂₄ (74.1 ng·h/mL) in plasma bortezomib at RD, were similar to those in VISTA trial and no apparent drug-drug interaction was observed in the PK of bortezomib in the MPB therapy. The response was evaluated in 17 pts in the phase I portion, and in 86 pts in the phase II portion (including 5 pts receiving 1.3 mg/m² in the phase I portion). In the phase I portion, all 6 pts in 0.7 mg/m² achieved partial response (PR). In 1.0 mg/m², 3 pts achieved complete response (CR), and 2 pts achieved PR out of 6 pts. In 1.3 mg/m², 2 pts achieved CR, and 2 pts achieved PR out of 6 pts. In the phase II portion, 17 pts achieved CR, and 43 pts achieved PR. The ORR was 70% (60/86) with the two-sided 90% confidence interval of the ORR was 61% to 78%. This ORR (70%) was comparable with the ORR (71%) in the MPB group of VISTA trial. The median time to response was 51 days (range: 43–82). In the phase II portion, the frequent (≥50%) adverse events (AEs) were hematologic toxicities (neutropenia, lymphopenia, thrombocytopenia and anemia), diarrhea, nausea, constipation, rash, elevated c-reactive protein, elevated lactate dehydrogenase, weight loss, anorexia, hyponatremia, peripheral neuropathy, leukocytosis and hepatic dysfunction. The incidence of AEs was generally higher and AEs were generally more severe in this study compared with the MPB group of VISTA trial, but most of the AEs were clinically manageable. Incidence of interstitial lung disease (interstitial pneumonia, pneumonitis and hypoxia) was 10% (9/87) in the phase II portion (with chest X-ray and oximeter analysis periodically and arterial oxygen partial pressure and chest CT as needed) and 1% (4/340) in the MPB group of VISTA trial, respectively. There was no death due to lung disorder in this study. Only rare cases of grade 3 events (pneumonitis and hypoxia) or serious events were reported, and all of the events were clinically manageable. Whereas the incidence of peripheral neuropathy (grade 3 and 4), the median number of treatment cycles (range) and the median dose intensity for bortezomib in the first 4 cycles were 10% (9/87), 5 cycles (1–9) and 6.86 mg/m²/cycle in the phase II portion of this study, those in the MPB group of VISTA trial were 14% (46/340), 9 cycles (1–9) and 8.32 mg/m²/cycle, respectively. CONCLUSION: This phase I/II study in Japan suggests that the RD of bortezomib in MPB therapy is 1.3 mg/m² and MPB therapy in newly diagnosed Japanese MM pts ineligible for HSCT is effective as well as those in VISTA trial. Further investigation is needed to refine the administration schedule of this combination in Japanese pts.