Tandem Transplantation in Multiple Myeloma (MM) Patients With <12 Months of Prior Treatment

• To determine whether, in comparison to TT II, the median EFS can be increased from 4.8 years to 6.2 years, which represents an increase in median EFS of approximately 30% [ Time Frame: After enrollment of 204 subjects is completed ] [ Designated as safety issue: No ]
  
• In assessing patient safety, we will examine treatment toxicity related mortality and SAEs. Historical study results indicate that a mortality rate of greater than 10% is not acceptable in this population, nor is an SAE rate of greater than 15%. [ Time Frame: Interim analyses for safety will be performed after 20, 100, 200, and 300 patients have been enrolled. ] [ Designated as safety issue: Yes ]
  

• Overall survival will be compared to a historical control (UARK 98-026, TT2)as a secondary outcome. [ Time Frame: After 204 patients have been enrolled ] [ Designated as safety issue: No ]
  

Other: tandem autologous transplantation

DPACE: dexamethasone 20 mg days 1-4 and 8-11, cisplatin 10 mg/m2 days 1-4, Adriamycin 10 mg/m2 days 1-4, cyclophosphamide 400 mg/m2 days 1-4, etoposide 40 mg/m2 days 1-4.

Transplant 1: Dexamethasone 20 mg days -4 to -1 and +2 to +5. Velcade 1mg/m2 on days -4,-1, +2, and +5. Thalidomide 100mg on day -4 to day +5. Melphalan, 100 mg/m2 on days -4 and -1.

Transplant 2: Dexamethasone 20 mg on days -4 to -1 and +2 to +5. BCNU 300mg/m2 on day -4. Melphalan 140 mg/m2 on day -1. Velcade 1mg/m2 on days -4, -1, +2, +5. Gemcitabine 1000 mg/m2 on days -4 + -1.

Maintenance year 1: Bortezomib 1.0 mg/m2 on days 1, 4, 15,18 every cycle. Thalidomide, 100 mg . Dexamethasone,20 mg,on days 1-4 & 15-18 every cycle.

Maintenance year 2: Dexamethasone, 20 mg,days 1-4 every cycle.

This study is targeted towards patients who have been diagnosed with Multiple Myeloma and have had no prior autologous or allogeneic transplant. Furthermore, only up to 12 months of prior treatment are allowed in this patient population. The study schema consists of one round of induction chemotherapy, two transplants, one round of consolidation chemotherapy, and two years of maintenance treatment. This study design differs from its historical predecessors in the following manner:

• In contrast to Total Therapy II and III, which only allow enrollment of patients with at most one cycle or one month of treatment prior to enrollment, the proposed study allows enrollment of patients with up to 12 months of prior treatment. No statistically significant difference in outcome between patients with one or no cycle of preceding therapy and those with up to 12 months of prior therapy. This should allow enrollment of significantly more myeloma patients.
• Induction therapy has been reduced to a single cycle.
• Bortezomib and thalidomide have been added to the transplant regimen.
• BCNU is added to the second transplant to high dose melphalan.
• Gemcitabine is added to the second transplant regimen.
• Consolidation treatment has been reduced to a single cycle.
• The first year of maintenance is with bortezomib, thalidomide and dexamethasone, and the second year of maintenance therapy consists of dexamethasone only.
• The novel agents thalidomide and bortezomib are not introduced upfront, but only with transplantation and maintenance.