Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. 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 report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma.

Pts received Bz 1.0–1.3 mg/m² on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm³ on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts 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, completed 8 cycles of therapy.

26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone.

CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m², DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting.

Alsina:Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.