Impact of Age on Survival after Intensive Therapy in Newly Diagnosed Multiple Myeloma. The Nordic Myeloma Study Group (NMSG).
Authors: Lenhoff Stig , Hjorth Martin , Gimsing Peter , Tangen Jon Magnus , Westin Jan 
Published: October 2019

Abstract
Introduction: Intensive therapy (IT) including autologous stem cell transplantation (ASCT) is considered superior to conventional therapy in newly diagnosed myeloma pts <60 yrs. For older pts the benefit of IT is less clear. In 1998 the NMSG started a population-based, prospective trial (#7/98) aiming to study the impact of age on event-free survival (EFS) and survival after IT, and to compare survival to a conventionally treated historic control group.
Patients: Newly diagnosed symptomatic pts <65 yrs were included into a protocol with four phases; I) VAD x 3–4; II) cyclophosphamide 2g/sqm, G-CSF (filgrastim) and stem cell harvest; III) melphalan 200 mg/sqm, stem cell infusion and G-CSF; IV) interferon maintenance. Double ASCT was optional. From Jan 1998 to June 2000, 452 pts were registered and 414 (92%) of these were included into the IT protocol (=Intensive Therapy Group (ITG)). 294 were <60 yrs (=ITG-60) and 120 were 60–64 yrs (=ITG-65). The historic control group was derived from a previous population-based, randomized NMSG study (#4/90) where melphalan and prednisone +/− interferon was given as initial therapy. Of the 281 pts <65 yrs registered in this trial, 243 (86%) fulfilled the eligibility criteria for IT stated in the #7/98 protocol and constituted the Control Group (CG). 146 were <60 yrs (=CG-60) and 97 were 60–64 years (=CG-65).
Results: In the ITG-60, 261 pts (89%) were actually transplanted (80% single ASCT, 18% double ASCT and 2% allogeneic SCT). In the ITG-65, 98 pts (82%) were transplanted (84% single and 16% double ASCT). Median follow-up is 50 months. Major response rate (CR+PR) was 88% in the ITG-60 and 81% in the ITG-65. EFS at 4 yrs for the ITG-60 was 37% and median EFS 36 months, while the corresponding figures for the ITG-65 were 19% and 24 months (P=.005). Survival at 4 yrs for the ITG-60 was 67% and median survival 67 months, while the corresponding figures for the ITG-65 was 50% and 48 months (P=.004). In a multivariate analysis of the entire ITG, two variables were significantly associated with EFS and survival; beta-2-microglobulin at diagnosis and age < or ≥ 60 yrs.
The survival in the ITG-60 was prolonged compared to the CG-60 with a risk ratio (RR) of 0.50 (95%CI 0.38–0.67; p<.0001). Survival at 4 yrs was 67% in the ITG-60 and 44% in the CG-60, with a median survival of 67 and 43 months, respectively. The survival advantage persisted (RR 0.57, 95%CI 0.42–0.78; p=.0004) after statistical analysis of prognostic factors and correction for differences between the groups.
Also for patients 60–64 yrs old survival was prolonged in the ITG compared to the CG with a RR of 0.65 (95%CI 0.42–0.92; p=.02). Survival at 4 yrs was 50% in the ITG-65 and 40% in the CG-65 with a median survival of 48 and 28 months, respectively. However, after correction for the difference in prognostic factors between the groups there was no significant difference in survival (RR 0.80, 95%CI 0.55–1.16; p=.23).
Conclusions: In this population-based study older age was found to have a negative influence on outcome after IT. Our results indicate that there is an upper age limit that remains to be defined for superiority of IT over conventional chemotherapy.