Intensive Versus Double Intensive Therapy in Untreated Multiple Myeloma: Final Analysis of the HOVON 24 Trial.
Authors: Sonneveld Pieter , van der Holt Bronno , Vellenga Edo , Croockewit Sandra , Verhoef Gregor , Segeren Christine , Lokhorst Henk 
Published: April 2020

Abstract
The benefit of high-dose therapy for multiple myeloma has been demonstrated in phase lI/lII studies. HOVON started a randomized multicenter trial to compare the efficacy of intensified treatment followed by myelo-ablative therapy with intensified treatment alone in newly diagnosed patients. We now report the results of the final analysis in 441 eligible patients with stage II (22%) and stage III (78%) disease. The median age was 55 years (range 31–65 ). Remission induction consisted of 3–4 cycles of VAD. 63 patients who had an HLA identical sibling were candidates for an allogeneic transplantation. After VAD, patients were randomized to receive melphalan 140 mg/m2 divided in 2 doses of 70 mg/m2 (IDM) without stem cell rescue (arm A) or the same regimen followed by myelo-ablative treatment with cyclophosphamide (120 mg/kg) and TBI with stem cell transplantation (ASCT, arm B). Peripheral stem cells were mobilized by cyclophosphamide (4 g/m2) and G-CSF after VAD. Interferon-a -2a was given as maintenance therapy in both arms.
Of 441 registered patients, 303 were eligible for randomization. Patient characteristics with regard to sex, age, stage of disease, Ig isotype, and b2-M were not 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 actually received myeloablative therapy followed by ASCT in arm B. Median duration of Interferon-a-2a maintenance treatment was 12 months (arm A) vs 7 months (arm B). CR rate was significantly better in Arm B (28% vs 13%, p=0.002), while the overall response rate (PR + CR) was not different (90% vs 86%, p=0.23). Median event-free survival (EFS) from randomization was 22 months (arm B) vs 20 months (arm A) (logrank p=0.014). Median progression-free survival (PFS) was significantly better in patients treated with double intensification (24 vs 23 months, logrank p=0.032). 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 between the 2 treatment arms became only evident after 4 years of follow-up. Overall survival (OS) was not different between both treatments (median 55 months vs 50 months, logrank p=0.39). Multivariate analysis showed that treatment arm A, higher age, hemoglobin &gt; 6.21 mmol/l, stage 3 and high serum LDH were significant adverse prognostic factors for EFS. Cytogenetic analysis in 151 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&lt;0.001), calculated from start VAD. Del 13/13q- was highly correlated with 1p/q abnormalities. By combining B2M &gt; 3 mg/L with del13/13q- and 1p/q, prognostic groups were defined with a significant impact on OS (p&lt;0.000002), EFS (p&lt; 0.0002), PFS (p&lt;.00006) and TTP (p&lt;0.0000002).
In conclusion, second intensification when added to intensified chemotherapy alone resulted in a superior EFS, PFS and TTP, but not OS. The latter difference is probably due to the high proportion of patients from the control arm who were treated with ASCT at first relapse. It is concluded that double intensive therapy leads to a higher CR rate and a longer PFS.