Updated Results of Phase II Study of Cyclophosphamide(Cy), Bortezomib(Bz), Pegylated Doxorubicin(DOX), and Dexamethasone(dex), (CVDD), in Patients with Newly Diagnosed Myeloma:an Effective Induction Regimen for High Risk Disease

The VDD treatment regimen has been shown to be effective as initial therapy for multiple myeloma, as demonstrated by a Phase II trial with overall response rates of 89% and VGPR + CR rates of 53%. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We previously reported the results of a Phase I study of VDD with escalating doses of cyclophosphamide and reached the maximum planned dose (MPD) of the regimen without dose limiting toxicities. We now report updated results from the Phase II trial of CVDD in patients with newly diagnosed myeloma.

Patients were treated at the MPD defined by the phase I study, and received Cy 750 mg/m2 IV on day 1, Bz 1.3 mg/m² IV on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, a Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 for up to eight 21-day cycles. Patients with Gr ≥ 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Patients were stratified in 2 cohorts by risk. Patients with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t(4;14, t(14;16) or deletion of 17 p by FISH, were included in the high risk cohort (HR) and all others in the standard risk cohort (SR). Patients with at least partial response (≥PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after ≥6 cycles. Responsive patients with high risk cytogenetics completed 8 cycles of therapy.

Forty nine pts were treated in study and forty eight patients are evaluable for response. Median age was 57 yrs, 59% male. Twenty five % of forty nine patients had high risk myeloma. The median number of cycles completed by patients is 6 in the SR cohort and 8 in the HR cohort. The overall response rate (ORR; ≥PR) is 89% for the SR cohort and 100 % for the HR cohort. The rate of ≥VGPR was 69% and similar in both cohorts. However the rate of CR/sCR was higher in the HR cohort compared to the SR cohort at 50% and 25%, respectively. 62% patients proceeded to transplant and all had successful stem cell mobilization with G-CSF alone. At a median follow up of 24 months the median PFS or OS has not been reached, and the 2 year OS is 89.19 % for the standard risk group and 100% for the high risk group. Most common ≥ grade 3 toxicities events related to protocol treatment were myelosupression (48%), dizziness (7.7%), fatigue (6.5%), and PNY (6.5%).

CVDD produces high quality responses and is well tolerated in newly diagnosed MM patients, regardless of their cytogenetic status. Stem cell mobilization has been successful in all patients, with transplant course in patients otherwise unremarkable. The high rate of CR rates and OS in high risk patients warrants further evaluation of this regimen in that patient population.

Alsina:Millenium: Consultancy, Research Funding; Ortho Biotech: Research Funding. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding.