A RANDOMIZED PHASE II STUDY (GISL - MM03 TRIAL) WITH ORAL MELPHALAN+ PREDNISONE (MP) VERSUS MELPHALAN, + PREDNISONE + THALIDOMIDE (MPT) FOR NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA

Background. Several papers showed that MPT compared with MP improved response and survival outcomes. However, side effects increase and toxicity, as neutropenia, neuropathy, deep-vein thrombosis, depression and constipation reduce patients compliance. Thus, several patients have to discontinue or reduce the dose of Thalidomide. Aims. Aim of our research is to verify these results in a group of 128 patients not eligible for high dose treatment with stem cells support. Patients and Methods. The MM03 trial was approved by Ethical Committee of Modena and registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali at the end 2004. A total of 128 patients were enrolled between January 2005 to October 2008: 53% entered MPT arm. Median age of patients were 75 years (range: 63-88 yrs), 50% were female, 55% had Durie and Salmon stage II and 45% had stage III. Distribution of M spike were: 67%, 22% and 11% for IgG, IgA and urine light chains. Univariate analysis of variables at baseline did not show any difference between the two arms. In arm A Melphalan was given at a dose of 0.25 mg/kg and Prednisone 60 mg/m2 for 4 days every 28 days; in arm B Thalidomide was added at a dose of 100 mg every day; a maximum of ten cycles was planned. At the end of induction therapy, 26 patients who had obtained Complete Response, Partial Response, Minimal Response or Stable disease were randomized for maintenance with Dexamethasone 20 mg, day 1-4 every 28 days or Dexamethasone at the same dose plus Thalidomide 100 mg/day every day. Only 14 patients follow this indication and assumed maintenance treatment for 6-12 months; no differences were observed between the 2 arm of maintenance. The use of growth factors, was at treating physicians discretion. Starting from May 2005 enoxiparin was recommended during the first 4 cycles of MPT arm. Results. Of 128 patients, 91 patients are evaluable for response while 20 are still on treatment. The response, including MR among all patients who entered protocol were 76%, while 9% had SD and 15% presented PD. Considering separately the two arm, we observed in arm A 12% CR, 43% PR, 9% MR, 3% SD and 23% PD and in arm B 18% CR, 57% PR, 11% MR, 5% SD and 9% PD. A comparison between 55% of CR plus PR in arm A with 75% in arm B shows a p=0.049, showing an advantage for MPT arm. After a median follow up of 14 months, median Overall Survival at 24 months are not still reached. During treatment or progression 24 patients died. Grade III/IV adverse events were: 6 deep-vein thrombosis, all in MPT arm, 1 during enoxaparin prophylaxis, 1 pneumonitis, 6 neutropenia, 3 neurotoxicities, 3 constipation. Conclusions. Our results show that the addition of Thalidomide to MP improve number and quality of response. We are still collecting data for a better definition of OS, FFS and toxicity in arm A in comparison with arm B, and they will be presented during the meeting