Abstract
In 1995 HOVON started a prospective randomized multicenter trial to compare the efficacy of intensified treatment followed by myelo-ablative therapy and stem cell transplantation (PBSCT) with intensified treatment alone in patients with myeloma. We now report the results of a second analysis in 441 eligible patients with stage II (22%) and III (78%) disease. The median age was 55 years. Remission induction consisted of 3 courses of VAD. 63 patients with an HLA identical sibling were candidates for an allogeneic transplantation. After VAD, patients without donor were randomized to melphalan 140 mg/m2 divided in 2 doses of 70 mg/m2 (IDM) without PBSCT (arm A) or this regimen followed by myelo-ablation with cyclophosphamide (120 mg/kg) and TBI with PBSCT (arm B). Peripheral stem cells were mobilized by cyclophosphamide and G-CSF after VAD. Interferon-a -2a was given as maintenance therapy in both arms.
Of 441 patients, 303 were eligible for randomization. Patient characteristics were not significantly different between the two arms. The median follow-up from randomization was 56 months. 81% of patients received both cycles of IDM (79% in arm A and 83% in arm B) and 79% of patients received myeloablative therapy followed by autologous PBSCT in arm B. The median duration of maintenance treatment was 12 (arm A) vs 7 months (arm B). The CR rate was better in Arm B (28% vs 13% , p=0.002), while overall response rate (PR + CR) was not different (90% vs 86% , p=0.23). Median event-free survival (EFS) from randomization was 22 (arm B) vs 20 months (arm A) (logrank p=0.016). Median progression-free survival (PFS) was significantly better in patients treated with double intensification (24 vs 23 months, logrank p=0.036). Time to Progression (TTP) was significantly worse in arm A (median 25 vs 33 months, logrank p=0.001). The difference for EFS, PFS and TTP became only evident after at least 4 years of follow-up. Overall survival (OS) was not different (55 months in arm A vs 50 in arm B, logrank p=0.38). Multivariate analysis showed that treatment arm A, higher age, hemoglobin < 6.21 mmol/l, stage 3 and elevated serum LDH were significant adverse prognostic factors for EFS. Cytogenetic analysis, available in 151 registered patients was abnormal in 37% (45% del 13/13q-, 51% abnormal 1p/q, 33% del 6q, 89% complex abnormalities). Cox regression analysis showed that 1p/q was an independent unfavourable prognostic factor for OS, EFS, PFS and TTP (p<0.001), calculated from start VAD. Del 13/13q- was highly correlated with 1p/q abnormalities. By combining B2M > 3 mg/L with del13/13q- and 1p/q, prognostic groups could be defined with a significant impact on OS (p<0.000002), EFS (p< 0.0002), PFS (p <0.00006) and TTP (p<0.0000002). Quality of Life analysis showed significant improvement of disease-related variables in double intensive treatment.
In conclusion, in this trial second intensification by myeloablative treatment with cyclophosphamide/TBI when added to intensified chemotherapy alone resulted in a superior EFS, PFS and TTP, but not OS. The results of this trial indicate that double intensive treatment results in superior outcome, but not cure in multiple myeloma.
Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma.
