Autologous SCT with Mel 200 mg/m2 conditioning is considered standard consolidation treatment for MM pts. However, Mel 200 results in response rates of 20–40%, with nearly all pts ultimately relapsing. A double alkylating regimen of IV Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. The IV formulation of Bu has less pharmacokinetic variability, and results in less toxicity, specifically less hepatic and mucosal toxicity.

Patients and Methods: The conditioning regimen consists of IV Bu 130 mg/m2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of IV Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. After the four daily Bu doses, there is a rest day, followed by two daily doses of Mel at 70mg/m2. Stem cells are infused the following day. Dilantin is administered for seizure prophylaxis.

Results: 25 pts (16 M/9 F) with median age 53 years (range 31–64) have been treated. Salmon-Durie stage at diagnosis was I (n=6), II (n=11), and III (n=8); B2M at diagnosis was available for 16 pts, median 2.8 (range 1.4–5.2). The median number of prior chemotherapy regimens was 2 (range 1–5). At time of study entry, 20 pts were in partial remission, and 5 had refractory disease. The median CD34+ cell dose infused was 5.00 × 106/kg (range 2.5–7.7). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8–13) and 9 (7–23), respectively. Eighteen pts had IV Bu delivered per test dose guidance, with a median first dose systemic Bu exposure of 4606 μMol-min (range 4008–5601), necessitating a secondary adjustment to achieve an average daily AUC of 5000 μMol-min +/−12% in 6 pts. Median Bu clearance was 94 ml/min/m2 (range 83–113). Seven pts received fixed dose Bu at 130 mg/m2. With median follow-up time of 3 months, 17 pts are evaluable for response based on EORTC consensus criteria that mandate a response maintained for at least 6 weeks (

BJH
1998
,
102
:
1115
): 1 complete response, 6 partial response, 1 minor response, 7 stable disease, and 2 progressive disease. The treatment was well tolerated, with grade II or III diarrhea (n=6), mucositis (n=7), and nausea (n=9) being the most common regimen-related toxicities. Transient ascites concurrent with chemotherapy administration in a pt with refractory disease and high tumor mass was the only noted possible hepatic toxicity. Carbon monoxide diffusion capacity (DLCO) was measured to evaluate for pulmonary toxicity in 16 pts. At 3 months post study, asymptomatic grade II and III pulmonary toxicity was noted in 2 and 1 pts, respectively; 1 pt was not evaluable due to concurrent pneumonia. No grade IV toxicities or deaths have been observed.

Conclusion: Intravenous Bu-Mel is well tolerated, and individualized PK-directed dosing of IV Bu likely contributes to the low toxicity profile of this regimen. Although the final best response may be too early to evaluate, the preliminary response data in this group of poor prognosis MM pts suggest it is an effective conditioning regimen.

Topics:
autologous stem cell transplant, brachial plexus neuritis, busulfan, conditioning (psychology), melphalan, multiple myeloma, toxic effect, chemotherapy regimen, partial response, pulmonary toxicity

Disclosures: Have given educational talks regarding the the use of busulfan-based transplant regimens.

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2006, The American Society of Hematology
2006
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