Improved Survival with Thalidomide Before and after Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma: Long-Term Results from the HOVON-50 Study

Background: The HOVON-50 phase 3 trial compared thalidomide before (thalidomide-adriamycin-dexamethasone; TAD) and after high-dose melphalan (HDM) and autologous stem cell transplantation with classical cytotoxic agents (vincristine-adriamycin-dexamethasone; VAD) prior and interferon-α after HDM in newly diagnosed multiple myeloma (MM) patients. Methods: A total of 556 MM patients were enrolled in this phase 3 randomized clinical trial. Findings: Here, we present the final analysis with an extended median follow-up of 129 months. Event-free survival (EFSc) and progression-free survival (PFSc), both censored at allogeneic stem cell transplantation, remained significantly prolonged in the thalidomide arm, compared to the control arm (EFSc: hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.54 - 0.81, P<0.0001; PFSc: HR =0.64, 95% CI: 0.52 - 0.79, P<0.0001). With long-term follow-up, we now also observed a superior overall survival (censored at allogeneic stem cell transplantation (OSc)) in the thalidomide arm, when adjusted for covariates in multivariate analysis (HR = 0.79, 95% CI: 0.62-0.99, P=0.042). Importantly, at 10 years 21% of patients in the thalidomide arm were still in remission, while this was 9% in the control arm. Survival after progression did not differ between both arms. Also the incidence of second primary malignancies (SPMs) was similar in both arms. Interpretation: Our data indicate, that thalidomide-based treatment is still a valid treatment option for transplant eligible MM patients in countries without access to proteasome inhibitors or other next generation immunomodulatory drugs. Trial Registration Number: This trial was registered on www.trialregister.nl as NTR238 Funding Information: This trial was supported by the Dutch Cancer Foundation. Competing Interests Declaration: NvdD: research support from Celgene, Janssen Pharmaceuticals, Novartis, BMS, and AMGEN; advisory boards for Celgene, Janssen Pharmaceuticals, Novartis, BMS, AMGEN, Takeda, Bayer, and Servier. MCM: advisory boards for Celgene, Jansen Cilag, Amgen, Takeda, Servier; Research funding Celgene. MJK received research funding from Celgene, Roche, and Millennium/Takeda and honoraria from Celgene, Roche, Millennium/Takeda, Novartis, Kite Pharma, Gilead, and BMS. MD: Advisory board and speaker’s honoraria for Celgene. GMB: research support from Celgene SZ: Research funding from Celgene, Janssen, and Takeda; and serves in advisory boards for Celgene, Janssen, Takeda, AMGEN, and Sanofi. PS: Research support and honoraria: Celgene and Janssen HML: Research support and honoraria: Celgene and Janssen Other authors: no conflicts of interest. Ethical Approval Statement: The protocol was approved by the Research Ethics Board of each participating hospital in accordance with the Declaration of Helsinki.