Lenalidomide, Bortezomib, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Encouraging Efficacy in High Risk Groups with Updated Results of a Phase I/II Study

Background: Bortezomib (VELCADE^®, Bz) is approved for the treatment of patients (pts) with multiple myeloma (MM). Lenalidomide (Revlimid^®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥1 prior therapy. Len/Bz±Dex is active and well tolerated in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in front-line MM. The aims of this phase l/ll study were to determine the maximum tolerated dose of Len/Bz/Dex (RVD) and to assess safety and efficacy in previously untreated MM pts.

Methods: Pts received Len 15–25 mg on days 1–14, Bz 1.0–1.3 mg/m² on days 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on days 1, 2, 4, 5, 8, 9, 11, 12, for up to eight 21-day cycles, initially at four planned dose levels (Len/Bz: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs; Grade (G) ≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm³ on >1 occasion despite transfusion support; G4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Based on safety data, dose level 4M (Len/Bz 25/1.3) was added with a reduced Dex (20/10 mg) starting dose. Pts with G≥2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts with at least partial response (≥PR) could proceed to autologous stem cell transplant (ASCT) after ≥4 cycles.

Results: 68 pts have been enrolled to date: 33 in phase l, including 17 pts at the maximum planned dose (MPD, dose level 4M) and 35 in phase ll (at MPD). Data are available for 66 pts (median age 58 yrs, 55% men, 67% IgG MM, 50% with ISS stage II/III). Pts have received a median of 10 cycles; 46 have completed all 8 cycles, 39 have discontinued/completed therapy. Two DLTs of G3 hyperglycemia due to high-dose Dex were seen at dose level 4. Dose reductions in cycle 2 and beyond have occurred in overall/dose levels 1–4 for: Len 16/8 pts, Bz 23/8 pts, and Dex 19/15 pts. Toxicities to date have been manageable, including all G3/4 hematological toxicities (3–15%), G3 hypophosphatemia (8%) and deep vein thrombosis/pulmonary embolism (5%, with daily aspirin), with no G4 PNY, and no treatment-related mortality. The overall response rate (ORR; ≥ PR) is 98%, including 71% ≥ VGPR and 36% CR/nCR; at MPD, ORR is 100%. Efficacy was independent of baseline cytogenetics or ISS stage (Table). ORR and ≥ VGPR rates were similar regardless of the absence or presence of deletion 13q or translocation 4;14; ORR rates ranged from 86% to 100% and ≥ VGPR rates ranged from 57% to 75%. Pts from all three ISS categories achieved ORR ranging from 97% to 100% and ≥ VGPR ranging from 51% to 80%; of note, the 10 pts with ISS stage III disease had an ORR of 100% and ≥ VGPR rate of 80%. Median stem cell collection in 21/23 pts was 6.2 × 10⁶ CD34+ cells/kg after a median of 6 cycles of therapy; 15 pts have proceeded to ASCT, with the transplant course in each case reported as unremarkable. Two of 23 pts (9%) have had difficulty with mobilization. After a median follow-up of 8 months, median time to progression, progression-free survival, and overall survival have not been reached.

Conclusions: RVD 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 Len 25 mg, Bz 1.3 mg/m², and Dex 20 mg, with phase ll enrollment now complete and 100% ORR reported at the MPD. Stem cell mobilization has been successful in almost all pts, with transplant course in pts otherwise unremarkable. Updated efficacy and ASCT data will be presented at the meeting.

Responses by cytogenetic status (normal, abnormal [deletion 13q or t(4;14)]), and ISS stage