Intensive Therapy in Multiple Myeloma. Long-Term Follow-Up with Focus on Relapse after Transplantation. The Nordic Myeloma Study Group (NMSG).
Authors: Lenhoff Stig , Hjorth Martin , Nielsen Johan Lanng , Turesson Ingemar , Wislöff Finn , Westin Jan 
Published: October 2019

Abstract
1994–97 the NMSG conducted a population-based prospective study evaluating the effect of intensive therapy (IT) including autologous transplantation (ASCT) as up-front therapy in newly diagnosed symptomatic myeloma pts <60 yrs. The primary aim was to compare survival to a historic control group. We have now updated these results with a median follow-up of 62 months (m), focusing on factors influencing survival and the clinical features in pats relapsing after ASCT.
313 pts were included in the treatment protocol, constituting the intensive therapy group (ITG). The control group (CG) was derived from five previous population-based Nordic studies on conventional therapy and comprised 274 pts who retrospectively were found to fulfil the eligibility criteria for IT. Both groups were highly representative, comprising >80% of the known and >60% of the expected new myeloma pts <60 yrs. Response rate in the ITG was 34% CR, 42% PR and 11% MR, EFS at 5 yrs was 23%, and median EFS was 28m. Survival at 5 yrs was 55% in the ITG vs 35% in the CG, and the median survival 63 vs 44m (p<.0001). 247 of the 313 pts (79%) in the ITG actually underwent transplantation at a median of 5m from diagnosis. In this transplanted group (TG) 43% achieved CR, 47% PR and 8% MR. Transplant-related mortality at 100 days was 1.6%. Median EFS and survival for the TG from transplantation was 29 and 66m. A landmark analysis 6m after transplantation showed that achieving CR was significantly associated with prolonged progression-free survival (median 40 vs 27m), but not with survival (71 vs 64m). These observations were maintained in multivariate analyses where the other prognostic factors (beta-2-microglobulin, hemoglobin and LDH at diagnosis) were included.
162 pts in the TG have relapsed and 92 of these have died. The patterns of relapse were heterogeneous but could be divided into four groups; “insidious” (31% of the relapses), “classical” (51%), “plasmocytic” (14%) and “transformed” (4%). The only factor associated with the pattern of relapse was response after transplantation. The “classical” and “plasmocytic” forms were more common in pts relapsing from CR and the “insidious” form was more common in pts relapsing from non-CR. 96% of relapsing pts received therapy, the majority melphalan-based (e.g. MP) or steroid-based (e.g. VAD) regimens. The response rate to relapse therapy was 70%. For the relapsed patients, the median time from diagnosis to relapse was 25m and the median survival after relapse 29m. Time to relapse was strongly associated with survival after relapse. Pts relapsing <6, 6–2 and >12m from transplantation had a median survival after relapse of 3, 16 and 32m, respectively. Pts with “insidious” relapse pattern had the longest survival and pts with “transformed” pattern the shortest. There were no differences between pts relapsing from CR or non-CR regarding response to relapse therapy or survival after relapse.
We conclude that achieving CR after ASCT is significantly associated with prolonged EFS but not with survival. The majority of pts relapsing after ASCT respond to conventional second-line therapy. The clinical features at relapse after transplantation are heterogeneous but do not seem to differ from those seen after conventional therapy.