A Randomized Comparison of Dexamethasone + Thalidomide (Dex/Thal) vs Dex + Placebo (Dex/P) in Patients (pts) with Relapsing Multiple Myeloma (MM).

We randomly compared a Dex/Thal and a Dex/placebo combination as treatment of MM pts in first or second relapse after high dose therapy (HDT) or conventional chemotherapy (CCT). 116 pts, aged 41 to 81 (med. 63 yrs), were enrolled between July 2001 and December 2004. Dex was given orally during 4 days at a dose of 40 mg/day every other week for 4 cycles and then monthly. Thal or placebo were given blindly at the initial dose of 100 mg, escalated up to 400 mg daily according to tolerance, and maintained for a maximum of 12 mths. In both arms, treatment initially included continuous infusions of Doxorubicin (9 mg/m²/d for 4 days 4–5 wk apart). In July 2002, because of a high incidence of thrombotic event (TE), the study was interrupted during a six-mth period, before restarting without Doxorubicin administration. Anticoagulation prophylaxis wasn’t systematically given at any time.

Main characteristics of pts included in both arms were similar, including age above 65 yrs (43% in the Dex/Thal arm, 44 % in the Dex/P arm), previous therapy (HDT 57% vs 56%), MM isotype (IgA: 26% vs 21%), serum β2m (≥3 mg/L, 48% vs 55%), serum creatinine (≤ 300 μmol/L in all pts) and albumin levels. Data were analyzed in an intent to treat basis, regarding EFS as the primary objective.

A partial response (defined by a 50% or more reduction of MM protein in serum) was achieved in 46% of all pts, in 65% of pts treated by Dex/Thal and in 28% of pts treated by Dex/P (p<.0001). At one year post randomization, 46.5% of pts in the Dex/Thal arm were alive and free of progression, compared to 31% in the Dex/P arm (p=.009). Death rates were 7% (n=4) and 5% (n=3), respectively.

Median dose of actually tolerated Thal was 150 mg daily. At least one ≥ grade II WHO adverse event was reported in 90% of pts who received Thal, as compared with 42% of pts who received the placebo (p<.0001). A TE was recorded in 12 (22%) of pts in the Dex/Thal arm, as compared to 4 (7%) of pts in the Dex/P arm (p= .02). Other frequent side effects were somnolence/mood changes (58% vs 21%), constipation/nausea (43% vs 11%), skin/mucosal dryness (26% vs 9%) and tremor (19% vs 4%). A symptomatic peripheral neuropathy was observed in 28% and 7% of pts, respectively. Besides the 25 pts who completed the trial (16 and 9 in both arms, respectively), toxicity was the main cause of treatment discontinuation in 21 (55%) pts of the Dex/Thal arm and in 3 (6%) pts of the Dex/P arm.

This randomized study demonstrates that the adjunction of Thal to Dex, although it increases toxicity, is a valuable therapeutic option for pts with relapsing MM since it produces higher response rate and longer remission duration than Dex alone.