OPTIMUM Dose of Thalidomide for Relapsed Multiple Myeloma.

The OPTIMUM trial was designed to compare the efficacy of single-agent Thalidomide (THAL) with high-dose Dexamethasone (DEX) in patients with relapsed refractory (RR) multiple Myeloma (MM) and to determine the optimal dose of THAL in these patients.

Patients with RRMM who had progressed after 1-3 lines of prior therapy were eligible for this multinational, randomized, open label phase III study. Patients were randomized to either daily THAL 100mg (THAL 100), 200mg (THAL 200) or 400mg (THAL 400), or DEX (40mg daily on days 1-4, 9-12 and 17-20 of each 28 day cycle for four cycles. From cycle 5 onwards, the dosing schedule was reduced to 40mg daily on days 1-4 of each cycle). All patients received study medication until disease progression or for a maximum of 12 cycles. Anticoagulant prophylaxis was not given routinely. Stratification factors included number of prior lines of therapy (1 versus > 1), prior autologous stem cell transplantation (ASCT) and International Staging System (ISS) score (Stage I+II versus III). The primary endpoint was time-to-progression (TTP) validated by an Independent Review Committee (IRC). Secondary endpoints included response rate, clinical benefit, survival, quality of life and safety. Planned accrual was 496 patients in order to detect a significant difference of 3 months in median TTP between the arms with 82% power at a two-sided significance level of 0.05.

Between Apr 2006 and Feb 2008, 499 patients were randomized by 68 sites in 15 countries from Europe, Asia and South Africa. Median age was 64 years (range 33-86); 73% of patients had ISS Stage I+II; 56.7% had received one prior therapy, 29.7% had received 2 and 12.8% had received 3 prior lines; 14.4% of patients had received prior bortezomib. Patients who had received prior thalidomide or lenalidomide were not included in this trial. Based on IRC-confirmed disease progressions during the treatment phase of the study, median TTP in the THAL 400 and in the DEX groups were 9.9 versus 6.0 months (hazard ratio, 0.64; p=0.017). Median TTP of the THAL 100 and THAL 200 arms were 6.7 and 7.3 months, respectively. IRC-validated complete and partial response rates according to EBMT criteria were 20.7% with THAL 100, 18.0% with THAL 200, 21.5% with THAL 400, and 24.6% with DEX. However, duration of response (DOR) showed a clear benefit for patients responding to THAL in comparison to DEX (median DOR in months: THAL 100: 12.7, p=0.046; THAL 200: 13.1, p=0.005; THAL 400: 11.6, p=0.016; DEX: 6.5). There was no difference in one year overall survival between the groups (80%, 83%, 82% and 80% for THAL 100, THAL 200, THAL 400 and DEX, respectively). During the study treatment period, the median of average daily drug dose in the THAL 100, THAL 200, THAL 400 and DEX groups were 99.5 mg, 198.2 mg, 255.5 mg and 40 mg, and the median treatment duration was 185, 179, 195, and 144 days, respectively. 60.2% of patients treated with THAL 400 had at least one treatment emergent AE (TEAE) ≥ Grade 3 compared to 39.5% with DEX. Thalidomide caused more frequent nervous system events (16.4 versus 2.4%), ≥ Grade 3 blood and lymphatic system disorders (14.8 versus 4.8%) and general disorders (12.5 versus 8.1%). Infections ≥ Grade 3 were more frequent with DEX (10.5% versus 8.6%). However, since TEAE of Grade 4 or higher were similar between both groups (12.5 versus 11.3%), the higher number of grade 3/4 events in the THAL 400 arm is due to an increase in grade 3 but not grade 4 TEAE with THAL 400 versus DEX. Venous thromboembolic events were uncommon in both groups (1.6% with DEX versus none with THAL 400). Patients treated with lower doses of THAL showed a more favorable safety profile. TEAEs of grade 3 or higher occurred in only 38.2 and 32.0% of the patients treated in the THAL 200 and 100 arms, respectively.

This study is the first trial to evaluate the single agent activity of THAL in RRMM patients in a randomized controlled setting. Patients treated with THAL showed longer disease control in terms of TTP and DOR compared to high-dose DEX. The results confirm that THAL is a good treatment option for these patients with a dose dependent safety profile.

Kropff:Celgene, ORTHO BIOTECH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: In Europe, thalidomide is not approved for the treatment of relapsed multiple myeloma. . Robak:Celgene: Consultancy, Research Funding. Hajek:Janssen-Cilag: Honoraria. Liebisch:Celgene, ORTHO BIOTECH: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria. Caravita:Celgene: Honoraria. Pattou:Celgene: Employment. Lucy:Celgene: Employment, Equity Ownership. Kueenburg:Celgene: Employment. Glasmacher:Celgene: Employment, Equity Ownership. Zerbib:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.