Improved Survival of Patients with Multiple Myeloma after the Introduction of Novel Agents and the Applicability of the International Staging System (ISS) An Analysis of the Greek Myeloma Study Group (GMSG)
Authors: Kastritis Efstathios , Zervas Konstantinos , Symeonidis Argiris , Terpos Evangelos , Delimpassi Sossana , Anagnostopoulos Nicolaos , Michali Evridiki , Zomas Athanasios , Katodritou Irini , Gika Dimitra , Pouli Anastasia , Christoulas Dimitrios , Roussou Maria , Economopoulos Theofanis , Dimopoulos Meletios A 
Published: October 2019

Abstract
Since the 1960s the survival of patients with MM had remained rather stable, until the introduction of high-dose melphalan with autologous stem cell transplant (ASCT) in the early 90s which improved the survival of younger patients. In 1999, thalidomide was introduced in the treatment of relapsed/refractory MM, followed by two other novel drugs: bortezomib and lenalidomide. Clinical trials have indicated that novel agent-based treatment are associated with improvement of response and survival in both relapsed/refractory and newly diagnosed patients. A recent report from Mayo Clinic (Kumar et al Blood2008, 111, 1516–20) has indicated that the survival of patients with MM treated at this major referral center, has improved significantly over the last decade. The purpose of our analysis was to confirm this observation in a large number of unselected patients who were treated in several hospitals throughout Greece and to assess the current applicability of ISS, a staging system that has been developed from a large database of patients who were treated with conventional or high-dose therapy before the introduction of novel drugs. Therefore we compared the outcome of two patient cohorts who started treatment before or after the introduction of the first novel drug, thalidomide: since January 1985, 1376 patients were entered in to the database of GMSG: 859 patients started treatment before 31/12/1999 (Group A) and 517 patients after 1/1/2000 (Group B), when thalidomide became available in Greece. Patients in group A were younger (p<0.001), had less often hypercalcemia (p=0.039), less often anemia (p=0.095), lower levels of urine Bence Jones protein (p=0.027) and less bone marrow plasma cell infiltration (p=0.030). One hundred and sixty seven patients (32%) patients in Group B were treated upfront with novel-drug based regimens compared to only 2 (0.2%) in Group A (p<0.0001). At least partial response to first line treatment was significantly higher in Group B compared to Group A (67% vs 56%, p<0.001). Despite more favorable characteristics of patients in Group A, the median overall survival for patients in group A was 36 months and for patients in Group B 48 months (p<0.001). For patients ≤70 years of age, median survival has improved almost two-fold in group B (74 months vs 39 months in group A, p<0.001). For patients >70 years of age, median survival for groups A and B was 26 and 33 months respectively (p=0.27). Early death rates were similar among patients in Group A and B: 8% and 9% (p=0.65) of patients survived less than 3 months in each group respectively. We then validated the applicability of the International Staging System (ISS) in patients of Group B which included patients who could receive either upfront or at a later stage of their disease novel-drug based regimens: 34.5% of patients were rated as ISS stage I, 22.2% as ISS stage II and 43.3% as stage III. The 5-year survival rate was 66% for ISS stage I patients, 45% for ISS stage II patients and 18% for ISS III patients (p<0.001). When only the 169 patients who were actually treated upfront with novel agent-based were analyzed, the 4-year survival rate was 85%, 61% and 26% for ISS stage I, II and III patients respectively (p=0.001). In conclusion, we confirmed that the introduction of novel drugs in the treatment of a large number of unselected patients with MM has significantly improved the outcome of this disease. Our data indicate that the survival benefit was more pronounced in patients ≤70 years of age. The widely available and reproducible ISS is applicable in patients treated with novel agent-based regimens and can be used for the staging of such patients. Despite the improvement of the survival of myeloma patients over the last decade, the outcome of older patients and of those with ISS stage III remains unsatisfactory.