Combination Therapy with Velcade, Doxil, and Dexamethasone (VDD) for Patients with Relapsed/Refractory Multiple Myeloma (MM).
Authors: Jakubowiak Andrzej J. , Brackett Lindsey , Kendall Tara , Friedman Judah , Kaminski Mark S. 
Published: April 2020

Background: Combination regimens with Velcade demonstrate high activity in both relapsed/refractory and newly diagnosed MM, including higher than previously observed rates of complete responses (CR) and near complete responses (nCR). In this study, we evaluated the activity of a combination of Velcade, Doxil, and Dexamethasone (VDD) in relapsed/refractory MM. The rationale for combining these 3 agents was provided in pre-clinical studies which showed that Velcade can synergize with DNA-damaging agents via caspase-8 pathway and with Dexamethasone via caspase-9 pathway. In addition, prior clinical studies showed that combinations of Velcade with either Doxil or dexamethasone are well tolerated and more active than Velcade alone. The primary objective of the study was to assess the overall response to VDD and to estimate whether this combination can improve the rate of CR and nCR.

Methods: The trial opened in November 2004 with target accrual of 30 patients. EBMT criteria were used for evaluation of response and nCR was defined as M-protein reduced to a level detectable by only immunofixation. The regimen in both relapsed/refractory and frontline trials was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg orally on days 1–4. VDD was repeated every 3 weeks for a total of 6 cycles. After the completion of 6 cycles, patients in the relapsed/refractory trial were maintained on Velcade weekly and Dexamethasone on days 1–4 in 5-week cycles.

Results: To date, 20 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 3.6 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 62 (range 39–78), 1–5 prior lines of therapy, single autologous stem cell transplant in 14 patients, tandem transplant in 1 patient, allogeneic transplant in 1 patient, chromosome 13 deletion in 5 patients. Complete or near complete responses (CR + nCR) have been observed in 6 patients (33%), very good partial response and partial response (VGPR + PR) in 4 patients (22%) and minor response in 5 patients (28%) for an overall response (CR, nCR, VGPR, PR, MR) of 83%. One patient achieved stable disease and two progressed (11%). Of the 14 patients who achieved response, 8 continue treatment, 3 are in remission off therapy (2 in nCR and 1 in PR), 2 relapsed, and 1 died of pneumonitis during therapy. Grade 3 and 4 toxicities were mostly related to cytopenias (thrombocytopenia in 7 patients, neutropenia in 7 patients, pneumonitis in 5 patients) and occurred among patients who had baseline cytopenia at study entry. The most common grade 1 and 2 toxicities included fatigue, neuropathy, diarrhea, neutropenia, and thrombocytopenia.

Conclusion: VDD combination shows promising overall activity and rate of CR and nCR and appears well tolerated. Based on these preliminary results, we have activated frontline VDD trial with 6 patients enrolled to date.