Thalidomide Combined With High Dose Melphalan Improves Event Free and Overall Survival In Patients With Newly Diagnosed Multiple Myeloma: Extended Follow-Up Of The HOVON-50 Trial
Authors: Lokhorst Henk , Holt Bronno van der , Zweegman Sonja , Vellenga Edo , Croockewit Sandra , Van Oers Marinus H.J. , dem Borne Peter von , Wijermans Pierre W. , Schaafsma M. R , de Weerdt Okke , Wittebol Shulamiet , Delforge Michel , Bos Gerard M.J. , Sinnige Harm , MarwijkKooy Marinus , Joosten Peter , Minnema Monique C. , Ammerlaan Rianne , Sonneveld Pieter 
Published: October 2019

Abstract

Background
The randomised, open-label, phase III trial HOVON-50 was designed to evaluate the effect of thalidomide during induction and maintenance in newly diagnosed multiple myeloma patients. The previous analysis showed that thalidomide improved the primary endpoint EFS, but had no impact on OS (Lokhorst et al; Blood 2010 115: 1113-1120).

Method
Patients with Salmon & Durie stage II or III, age 18-65 years inclusive, were randomly assigned to arm A: 3 cycles of VAD (Vincristine, Adriamycin, Dexamethasone) or to arm B, 3 cycles of TAD (Thalidomide 200 orally, days 1-28 instead of Vincristine) Thalidomide was given from day 1 until 2 weeks before the stem cell mobilization with CAD (Cyclophosphamide 1000 mg/m2 iv day 1)and G-CSF. After induction therapy patients received 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with alpha-Interferon (Arm A) or Thalidomide 50 mg daily (arm B) until relapse or progression. Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 536 patients were eligible for evaluation. As of July 2013 the median follow up of the 201 patients still alive is 99 months, range 65 – 130 months.

Results
The best responses achieved on protocol after extended follow-up were improved and significantly higher in the patients randomized to thalidomide: ≥ PR 88% vs 80 % (p<0.01), at least VGPR 66 % vs 55% (p<0.01), CR 31% vs 24 % (p=0.04), respectively. Similar to the previous analysis thalidomide improved EFS (censored at allo-SCT) from median 22 months to 33 months,; HR = 0.63, 95% CI [0.51 - 0.78], p<0.001) and PFS from median 25 to 33 months (HR =0.70, 95% CI [0.58 - 0.84], p<0.001). After 5 years of randomization the overall OS curves
diverged and thalidomide improved median OS from 65 to 75 months. 10 years from randomization 27 % of patients randomized to alpha-Interferon are still alive and 35% of patients randomized to Thalidomide. For OS multivariate analysis showed prognostic significance for the whole group of patients for LDH (HR=1.52, 95% CI [1.15-2.00], P= 0.004) and ISS (HR=1.31, 95% CI [1.11-1.53, P=0.001]. For the secondary endpoint OS the thalidomide arm was superior when adjusted for covariates in multivariate analysis (HR = 0.80, 95% CI [0.64 – 0.99], P=0.045).
The incidence of second primary malignancies (SPM) was similar between the two arms, as well as the actuarial probability to get an SPM within 5 years from start of the therapy (5-6%) or 10 years (9-10%)

Conclusion
After long term follow-up thalidomide in induction and maintenance treatment and in combination with HDM improves the quality of response and achieves superior EFS and OS. No increased incidence of SPM was observed as compared to patients not receiving thalidomide. This trial was registered on www. Trialregister.nl as NTR238 and was supported by the Dutch Cancer Foundation.

Disclosures:
Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.