Dose Reduction of Thalidomide in Multiple Myeloma: A Feasible Option without Reducing of Efficacy.
Authors: Haas Peter , Denz Ulrich , Ihorst Gabriele , Engelhardt Monika 
Published: April 2020

Abstract
The central goal in improving multiple myeloma (MM) treatment is the achievement of higher complete remission (CR) rates and prolonged progression free (PFS) and overall survival (OS). Maintenance treatment after high-dose regimens has been one approach to attain this goal. As one of these maintenance agents Thalidomide (Thal) is used, since it leads to the inhibition of fibroblast growth factor (bFGF) and monocyte-derived TNF-alpha, reduced vascularisation, immune response upregulation and others. Response rates with single Thal are 30% and can be increased up to 60–70% with combined Dexamethasone (Dex) use. Maintenance treatment has shown an improved 3-year PFS rate of 15% after tandem autologous stem cell transplantation (auto-SCT). Although Thal is well tolerated compared to regular cytotoxic drugs, side effects occur in about one third of patients (pts), most disturbing being fatigue, polyneuropathy and deep venous thrombosis. As these are dose dependent, a dose-reduction has evolved from 800mg to 200mg/day (d). In this study, we analyzed, whether the Thal dose of 100mg/d is feasible and effective: 38 consecutive MM pts received Thal at our center between 5/01 and 6/05. The time to treatment failure was calculated from treatment start to death, relapse or therapy modification due to side effects. The median age of all pts was 62.4 years; 27 were male and 11 female. All pts had stage II and III MM according the DurieIgG was the most frequent MM subtype in 23 pts. Twelve showed deletion 13q14. The median time from initial diagnosis to Thal therapy was 3.9 years (range; 0–18.7). Pts had received a median of 2 treatment lines (range 0–3), three pts had received Thal as first-line treatment. Twenty-six pts (68.4%) underwent SCT prior to Thal treatment (23 pts single auto-SCT, 1 pt tandem auto SCT, 1 pt sequential auto- and allo-SCT and 1 pt with 2 allo-SCT). The median Thal dose was 125mg/d (range 50–800mg/d), 22 pts received more than 200mg/d and 16 pts less. The median Thal duration was 7 months (range; 0.3–37.8). Nineteen pts received Thal as a single-agent, 16 pts in combination with Dex or melphalan (Alexanian). Remission before Thal was PD in 21 pts, SD in 9 pts, MR in 1 pt, PR in 4 pts and CR in 3 pts. Causes for treatment failure were side effects in 10 pts, relapse in 18 pts and death in 1 pt. The median time to treatment failure (TTF) was 7.6 months. Subgroup analyses showed an advantage for pts without deletion 13q14 (8.2 vs. 2.8 months; p=0.054) and for the combination therapy with Thal/Dex or Thal/Alexanian (8.7 vs. 4.5 months; p=0.0554). Other parameters tested in univariate analysis (age, stage, remission status, prior Tx) showed no difference in TTF. Of note was that different dose-levels (&lt;200 vs. ≥200mg/d) revealed no difference in TTF (7.5 vs. 8.2 months; p=0.087). We conclude that a Thal dose of 100/d is efficient, which can be increased with combined Dex or other effective anti-MM usage. This is of importance since side-effects show a dose-relation and often lead to treatment discontinuation. The strategy to lower the Thal dose with persistence of high efficacy rates is a promising approach to optimize MM-treatment and make it a feasible option for more pts.