PK-Directed Intravenous Busulfan in Combination with High-Dose Melphalan and Bortezomib As Conditioning Regimen for Patients with Multiple Myeloma

Introduction:

High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The CR rate, an indicator for progression-free and overall survival (PFS; OS) observed after the most commonly used conditioning regimen Mel200 (Melphalan 200mg/m²) is between 10-35%. The objective of our trial is to assess whether conditioning with a combination of PK-directed Busulfan (Bu), Mel and Bortezomib (Btz) is safe and can improve CR rates in patients with MM.

Methods:

Patients aged 18-72 with MM, who had received less than one year of prior myeloma-directed therapy and were eligible for ASCT were assigned to receive PK-directed i.v. Bu, i.v. Mel and i.v. Btz as per Fig. 1. Subsequent consolidative or maintenance therapy was left to investigator's choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes are overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov (NCT01605032).

Results:

To date, 18 patients have been treated (median age 61 (range 44-70), 61% male, 17% with ISS stage 3; median number of prior regimens 1 (range 1-3); prior bortezomib 94%). For the 12 evaluable patients the median days to ANC >/=0.5 x 10⁹/L and platelet count >/=30 x 10⁹/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities (100%) were alopecia, oral mucositis (62% G3), dysphagia (85% G3), as well as electrolyte abnormalities (62% ≥G3). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 15% G3), while 84% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (15%; zoster & skin abscess, 1 each), other infections (31%), and engraftment syndrome (8%). No patient developed sinusoidal obstruction syndrome of the liver. Response assessment was available for 11 patients: 1 achieved a stringent CR (9.1%), 5 VGPR (45.5%), and 5 PR (45.5%), resulting in a 100% ORR.  After a median follow up of 5.2 months (range 1-18) all patients are alive and no patient has relapsed. The trial is ongoing.

Conclusion: PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with MM. Further evaluation is warranted.