Velcade (V)-Thalidomide (T)-Dexamethasone (D) for Advanced and Refractory Multiple Myeloma (MM): Long-Term Follow-Up of Phase I–II Trial UARK 2001-37: Superior Outcome in Patients with Normal Cytogenetics and No Prior T.

INTRODUCTION: A 2-arm Phase I/II trial was initiated to determine activity and toxicities of the VTD combination in patients with advanced and refractory MM.

METHODOLOGY: Of 85 patients enrolled, 63 (74%) had abnormal cytogenetics (CA) including 40 patients with deletion of chromosome 13; 71 (84%) had received 1 prior autotransplant, including 56 (66%) with 2 prior autotransplants; 73% had previously received T; none had received prior V. V was given at a starting dose of 1.0 mg/m² (group A) on days 1, 4, 8, and 11 every 21 days; T was added with the 2nd cycle at dose increments of 50, 100, 150, and 200 mg daily in cohorts of at least 10 patients. In the absence of grade > 2 peripheral neuropathy (PN) with V at 1.0 mg/m² plus T 200mg, V was then increased to 1.3 mg/m² (group B); T was added in the same incremental dosing schedule as in group A. D was added (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days) with cycle #4 if partial response (PR) or better was not achieved; 34 patients received D, 19 in group A and 15 in group B. PR was defined as ≥ 50% reduction in serum M-protein and/or ≥ 75% reduction of urine M-protein. Responses were computed on an intent-to-treat basis.

RESULTS: Median numbers of cycles in group A were 6, 10, 7, 2 per T cohort and 12, 6, 11, 3, respectively, in group B. PR was obtained in 55% of patients, including 16% who achieved ≥ n-CR; an additional 15% had ≥ 25% M-protein reduction. Median EFS/OS for all 85 patients were 9/22 mos. Compared to group A, group B had a superior 12-mo EFS (47% vs. 26%) and OS (79% vs. 57%) (p=0.008/p=0.06); however, the 2 groups were not well balanced with regard to recognized prognostic factors (group A contained more patients with a low albumin level, high B2M, abnormal cytogenetics [CA] and high bone marrow plasmacytosis). No T dose effect on EFS or OS was apparent (≤ 100 mg/d, n=42; > 100 mg/d, n=43). Both EFS (p=0.01) and OS (p=0.03) were shorter in the presence of CA. EFS was also inferior in case of prior T (26% vs. 63%, p=0.03). The most common grade 3 or 4 toxicity was myelosuppression (thrombocytopenia and neutropenia). The proportion of patients in group A with PN grade > 1 was 41% at study entry and only slightly increased to 50% after cycle 5, with no T dose effect; the corresponding values for group B were 51% at study entry and 56% after cycle 5, with PN reaching grade 3 in 2/6 patients in the T=200 mg cohort. Syncope was observed in 2/6 patients receiving T=200mg in group B. Thus, in group A no T-MTD was reached, whereas it was 150mg in group B.

CONCLUSION: VTD is well tolerated at V 1.0 + T 200mg and V 1.3 + T 150mg. Its overall remarkable activity in a high-risk patient population yielded superior EFS/OS in the absence of either CA or prior T. The imbalance of prognostically relevant features, however, precludes a final dose recommendation for V. VTD (V=1.0, T=200mg, D=40mg) has since been combined with PACE combination chemotherapy (VTD-PACE) in Total Therapy 3 (TT3), raising >=n-CR rates beyond 80% compared to 65% with TT2+T (ASCO 2005), permitting robust PBSC collection >20 million CD34 cells/kg in >90% of >150 patients enrolled, when performed after the first cycle of VDT-PACE.