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Revised International Staging System (R-ISS), combining the ISS score with cytogenetics and serum LDH, represents the most recent prognostic model for stratifying newly diagnosed multiple myeloma (MM) patients into three different survival groups. Although data for R-ISS development have been obtained from patients enrolled in clinical trials, this prognostic score has been validated also in real-life scenario (Tandon et al, 2017). In both non-clinical trial setting and IMWG experience, the majority of patients (about 65%) belonged to the intermediate risk group (R-ISS II) that, probably, needs better prognostication.

The aim of this study was to search for a closer stratification of MM patients with R-ISS II, taking into consideration dynamic aspects, such as therapeutic strategy and response to therapy.

We investigated the impact of variables, such as initial therapy, response to therapy and maintenance therapy, on PFS and OS in 108 newly diagnosed MM patients classified as R-ISS stage II, diagnosed between 2005 and 2015, who received novel agents such as immunomodulatory drugs and proteasome inhibitors. Score weights of the prognostic factors, found to be significant according to Cox regression model, were determined based on the regression coefficients.

Median age of the 108 patients was 69 years (range 44-93) and 35% of them were older than 75 years. Thalidomide- and lenalidomide-based regimens were administered to 12% and 28% of patients, respectively, whereas 60% of the patients received bortezomib (54%) or carfilzomib-based (6%) regimens as induction therapy. Thirty-eight percent of the study population underwent ASCT and 40% received maintenance therapy. Regarding the response to the therapy, at least CR, VGPR and PR were documented in 35%, 66% and 87% of the patients, respectively. Five-year PFS and OS were 31% and 65%, respectively, similar to those reported by IMWG. Patients who did not achieve a CR, showed a significantly shorter 5yr-PFS (27% vs 50%; HR=2.9, 95%CI=1.6-45.0; p<0.0001) and 5yr-OS (53% vs 80%; HR=2.8, 95%CI=1.3-5.9; p=0.006) compared to those who did. Moreover, a significant better 5yr-PFS was documented in patients receiving maintenance therapy, compared to those who did not receive maintenance therapy (48% vs 20%; HR=1.9, CI95%=1.2-3.3; p=0.010) whereas initial therapy did not affect the outcome. Assigning a value to the variables found to be significantly related to survival measures, according to the above methods, patients were stratified into the following two groups: low-risk (LR), including 38 patients with score 0-1, i.e. patients achieving CR and receiving maintenance therapy (score 0) or achieving CR but not receiving maintenance (score 1); high-risk (HR) group, including 70 patients with score 2-3, i.e. not achieving CR, who underwent maintenance therapy (score 2) or not achieving CR and not receiving maintenance (score 3). Five year PFS of HR patients was significantly shorter compared to the LR group (20% vs 58%; HR=2.5, CI95%=1.6-3.8; p<0.0001), whereas 5-year OS was 57% vs 80% (HR=1.9, CI95%=1.1-3.3; p=0.021).

Our results suggest that in the R-ISS II MM patients, the outcome of those achieving a CR and undergoing long-term therapy, is comparable with the outcome of the R-ISS I group. On the other hand, patients not achieving CR have a poor outcome, similar to those in the R-ISS III group. Therefore, these patients should require personalized therapy, aimed to achieve CR and to maintain therapy continuously.