Ultra Long-Term Myeloma Survivors (>15 years): Characteristics of a Unique Group of Myeloma Patients

Background: Multiple myeloma (MM) remains an incurable disease for most patients, associated with substantial reduction of survival compared to age-matched individuals. Recent advances, especially over the last decade, are expected to improve the survival of MM patients but also lead to cure a significant proportion among them. It is important, however, to identify patient subgroups which may have extremely favorable outcomes and which could help to further refinement of MM treatments and potential alternative treatment strategies. Yet, the demonstration of long-term benefit requires prolonged follow up and historical controls may be useful for the evaluation of new therapies and regimens, allowing earlier interpretation of the results of the ongoing trials and of those with relatively short follow up. Aim: we analyzed a cohort of patients with very long follow up (minimum of at least 15 years) to identify patients with very long survival (i.e >15 years) and within them those with very long disease remissions. Methods: We analyzed the clinical data off 323 patients with newly diagnosed symptomatic MM and a minimum follow up of at least 15 years; these patients were treated between 1994 and 2009 in a single center (Department of Clinical Therapeutics , Athens, Greece). Results: Among the 323 patients, 40 (12.4%) have survived at least 15 years, and the calculated 15-year cumulative survival rate (adjusting for censoring) was19% and 20-year survival rate was 13%. Among them, 12 patients (3.7% of the total cohort) have not had disease progression during their disease course and remain alive up to the date of last follow up. The first line treatments that were used, in the whole cohort, were based on chemotherapy in 42%, included an IMiD (Thalidomide mostly) +/- chemo in 44%, a PI(bortezomib) +/- chemo in 6%, a bortezomib + thalidomide in 5% while 3% received only high dose dexamethasone. Consolidation with high dose Melphalan (HDM) and ASCT was performed in 27% of the patients. Long term survivors were younger (median 52 vs 73 years, p<0.001), had mostly ISS-1 disease (in 53% vs 23% for the others) and less often ISS-3 (11% vs 40%) (p<0.001), anemia with hemoglobin <10 gr/dl (15% vs 46%, p<0.001), or severe renal dysfunction (defined as eGFR<30 ml/min/1.73 m2)(3.5% vs 20.5%) (P=0.049), when compared to the rest of the patients. There were no statistically significant differences in the frequency of elevated serum LDH, hypercalcemia although were numerically lower among long survivors. Among those with available cytogenetics (N=83), although numerically lower, there was no statistical difference in the prevalence of high-risk cytogenetics (20% vs 30%). There was no significant difference in the induction regimens but 75% of long-term survivors had received ASCT as part of their primary therapy (vs 20% of the other group)(p<0.001). The median survival of the whole cohort is 51 months (IQR 22-130) and the median survival of the “long term” survivors is 19.4 years. The best response achieved to primary therapy among long term survivors was CR in 87.5%, VGPR in 5% and PR in 7.5%. The median PFS among long term survivors was 11 years; there were 4 patients that had disease relapse after at least 15 years of complete remission, and received second line therapy. We further focused on the small group of patients that had not evidence of disease relapse/progression after at least 15 years (N=12). All were younger than 65 years (median 52 years, range 26-64) and although all had at least one CRAB criterion, none had hypercalcemia, anemia with hemoglobin <10 gr/dl was present in only 10%; 8% had severe renal dysfunction, 8% low platelet counts, 70% had lytic bone disease; 75% had received ASCT at first remission and all had achieved CR after first line therapy. At the last follow, the median age of these patients is 71 years (range 46-89) and have achieved a median PFS of 16 years. Conclusions: Among patients diagnosed and treated in the era before the availability of the new agents in the frontline setting , about 15% of patients were long term survivors for >15 years. These were young at the time of initial diagnosis, had mostly low risk disease and received ASCT as part of their primary therapy. This data supports the role of ASCT as a very effective therapy, especially for low-risk disease, and raises research questions about the potential benefits that could be associated with earlier intervention, when MM may have more “favorable” characteristics.