Final Analysis of HOVON-50 Randomized Phase III Study on the Effect of Thalidomide Combined with Adriamycine, Dexamethasone (AD) and High Dose Melphalan (HDM) in Patients with Multiple Myeloma (MM)

The randomised, open-label, phase III trial HOVON-50 was designed to evaluate whether the addition of Thalidomide to AD and HDM would prolong event-free survival (EFS) in patients with newly diagnosed MM. Patients with Salmon & Durie stage II or III, age 18–65 years inclusive were randomly assigned to arm A: 3 cycles of VAD or to arm B, the same regimen but with Thalidomide 200 orally, days 1–28 instead of Vincristine (TAD). Thalidomide was started at day 1 of the first TAD cycle and was stopped 2 weeks before stem cell mobilization was started. Patients in arm B received thrombosis prophylaxis consisting of subcutaneously Low Molecular Weight Heparin (LMWH). Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy all patients were to receive 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with ƒÑ-Interferon (3 „e 106 IU, thrice weekly, arm A) or Thalidomide 50 mg daily (arm B). Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 18 patients were not eligible, while from 2 patients data were incomplete. EFS was defined as time from randomisation to induction failure, progression, or death from any cause. Patients (n=109) who received a non-myeloablative allogeneic transplant after HDM 1 before progression, were censored at the date of allo-SCT; those patients were usually entered into the HOVON-54 trial. Both arms were comparable with regard to age, myeloma stage and prognostic factors. Best responses achieved on protocol were significantly higher in the patients randomized to thalidomide: Minimal PR rates were 87% and 79 % (p<0.01), VGPR 65 % and 54% (p<0.01), CR% 30% and 21 % (p=0.03), respectively. Thalidomide also significantly improved EFS from median 22 months to 33 months (p<0.001) and PFS from median 25 to 33 months (p<0.001). Overall survival however in both arms was comparable, 62 months in arm A and 59 months in arm B (P=0.96). LDH>ULN at diagnosis and higher ISS were identified as adverse prognostic factors for response and survival endpoints. Abnormalities of chromosome 13 as determined by FISH or conventional karyotyping had no prognostic impact. 96 patients (18%) went off protocol treatment without receiving HDM, mainly due to excessive toxicity (5 %), intercurrent death (4%) or ineligibility for further treatment (3%) comparable in both arms. IFN maintenance in 34% of patients of which 23 % stopped due to toxicity. Thalidomide maintenance started in 57% of patients in arm B of which 63% stopped due to toxicity Thalidomide resulted in significantly higher response rates and improved EFS and PFS. However, this did not translate into better overall survival