ALBERT

Description: Background: Bortezomib (VELCADE®, Vel) and lenalidomide (Revlimid®, Rev) are both highly effective agents in multiple myeloma (MM). Preclinical studies show Rev sensitizes MM cells to Vel and dexamethasone (Dex), suggesting combination therapy may enhance clinical activity. This phase 1 dose-escalation study aimed to determine MTD and activity of Rev-Vel +/− Dex combination therapy in patients (pts) with relapsed and/or refractory MM. Methods: Eight cohorts (≥3 pts each) were planned, with dosing of Vel 1.0 or 1.3mg/m2 (d 1, 4, 8, 11) and Rev 5, 10, 15, or 20mg (d 1–14), in 21-d cycles. Dex 40mg (on day of and day after each Vel dose) could be added in pts with PD. NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) ≥3 non-hematologic toxicity, G4 neutropenia for ≥5 d and/or neutropenic fever, or platelets 1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Results: 28 pts were enrolled in cohorts 1–6 (Rev 5–15mg, Vel 1.0–1.3mg/m2) plus 10 additional pts at the MTD (Dose Level 5), including 12 with relapsed and 26 with relapsed and refractory MM (n=38). Among 25 men and 13 women, median age was 60yrs (range: 37–79), and median no. of prior therapies was 5 (range: 1–13), including 23 pts with prior SCT, 23 with prior Vel, 6 with prior Rev, and 36 with prior thalidomide (Thal). One DLT was observed in cohort 4 (Rev 10mg–Vel 1.3mg/m2; transient G3 hyponatremia). DLT was reached in cohort 6 (Rev 15mg–Vel 1.3mg/m2) with 1 episode of G3 HZV reactivation (successfully treated with acyclovir) and 1 G4 neutropenia (reversed with GCSF support and dose reduction). MTD was therefore declared at Rev 15mg–Vel 1.0mg/m2. In total, 5 pts had dose reductions for Vel, 6 pts for Rev, and 5 pts for both Rev and Vel. No significant (G≥3) fatigue or peripheral neuropathy has been seen. No anticoagulant prophylaxis was required and only 1 pt had DVT while on Rev alone. In 36 evaluable pts, the overall response rate (CR+PR+MR) is 58% (90% CI: 46%, 75%), including 6% CR/nCR (Table) after a median of 6 cycles (range: 4–17). Responses were durable (median 6 months, range: 1–26), and 11 pts remain on therapy beyond 1 year. Dex has been added in 14 pts with PD, resulting in PR/MR/SD in 10 (71%), with just 1 pt experiencing Dex-related G2 diarrhea and fatigue, which prompted discontinuation of therapy. Conclusions: Rev-Vel +/− Dex is well tolerated and very active with durable responses seen in pts with heavily pretreated relapsed and/or refractory MM, including pts who have had prior Rev, Vel, Thal and SCT. An MTD of Rev 15mg–Vel 1.0mg/m2 has been defined, with Phase 2 studies now ongoing in both newly diagnosed and relapsed/refractory MM. Best responses by Rev-Vel cohort (EBMT criteria) Cohort Rev-Vel dose Vel 1.0mg/m2 Vel 1.3mg/m2 1–2 Rev 5mg 2PR, 1MR 1CR, 2PR 3–4 Rev 10mg 1nCR, 2PR 2PR, 2MR, 1SD, 1PD 5–6 Rev 15mg 2PR, 4MR, 7SD, 1PD 2 PR, 5SD