Retrospective Analysis of Fractionated High-Dose Melphalan (F-MEL) and Bortezomib-Thalidomide-Dexamethasone (VTD) with Autotransplant (AT) Support for Advanced and Refractory Multiple Myeloma (AR-MM).

Background: MEL is an effective and safe AT regimen for MM, usually administered as a single dose at 200mg/m²; mucositis is dose-limiting. There is recent pre-clinical and clinical evidence of synergistic interaction of MEL with both immuno-modulatory agents (thalidomide, MPT [Palumbo, Lancet, 2006], lenalidomide, RMP [Palumbo, ASCO, 2006]) and with the first-in-class proteasome inhibitor, bortezomib (Velcade^R) (VMP, Mateos, ASCO, 2006). We previously reported on the marked activity of VTD in AR-MM, even in a setting of resistance to single agent thalidomide and bortezomib (Blood, January, 2004). In a clinical setting of AR-MM, we administered IV MEL after bortezomib (V) on days 1, 4, 7 +/− d 10, along with daily thalidomide (T) and dexamethasone (D), in order to achieve maximum pharmacological synergy of all 4 drugs.

Patients and Methods: A retrospective analysis was performed of 22 patients with AR-MM, who were treated with the F-MEL-VTD regimen with the following MEL fractions:

• 3-F at 50–80mg/m2 for total doses of 150–240 mg/m², 18 patients;

• 4-F at 50–60mg/m² for total doses of 200–240 mg/m², 4 patients;

• 5-F at 15–50 mg/m² for total doses of 150–250 mg/m², 2 patients.

V was given at doses of 1.0–1.3 mg/m2 immediately preceding each MEL fraction; T was dosed at 100–200 mg/d from day 1 until the last day of MEL; D was given at 20–40 mg on the day of and after V and MEL. Two patients received 2 cycles of F-MEL-VTD, so that 24 courses could be evaluated.

Results: Patient characteristics included a median age of 61yr (range, 46–75yr), median creatinine of 0.85mg/dL (range, 0.6–1.9mg/dL); abnormal cytogenetics (CA) were present in 15/22 (68%) - typifying the high-risk nature of their disease; the median number of prior regimens was 6 (range, 1–14); prior AT: 0 in 3 patients, 1 in 11, 2 in 8 and 3 in 1 patients. F-MEL-VTD was initiated in the outpatient setting in 15, only 3 of whom required subsequent hospital admission. Toxicities included grade 3–4 diarrhea mainly due to C. difficile in 8 (33%) and oral mucositis > grade 2 in only 1; grade 3 fever in 3 (12%) with Aspergillus pneumonia in 2 patients; no transplant-related mortality. Hematopoietic recovery was excellent with median times to ANC>500/microL of 10 days (range, 8–19d) and platelets > 50.000/microL of 17 days (range, 10–24d); 2 patients receiving 1.88 and 1.95 x 10⁶ CD34+ cells/kg failed to recover platelet counts to >50.000/microL. Response rates were measured at 6 weeks, using Blade criteria: CR, 11 (46%) with an additional 3 achieving near-CR (>=n-CR, 59%); PR, 4 (17%); the remainder 24% had transient or no response.

Conclusion: F-MEL-VTD was remarkably well tolerated, permitting total MEL dose escalation to > 200mg/m² in 13 of 22 patients, without incurring grade >2 stomatitis in the majority of patients. Due to the protracted administration involved in this regimen, the median duration of neutropenia was 10 d (range, 8 to 19d) with life-threatening infections observed in only 2 patients. These encouraging data form the basis for a randomized trial of VTD followed by standard 1-F MEL versus 3-F MEL with VTD preceding each MEL dose.