Significant Improvement of the Survival of Patients with Multiple Myeloma Presenting with Severe Renal Impairment After the Introduction of Novel Agents

Abstract ⁹⁴⁸

Renal impairment (RI) is a common presenting complication of multiple myeloma (MM) and is associated with increased risk of treatment related toxicity and early death. The management of RI in patients with MM requires vigorous supportive measures and the immediate institution of antimyeloma therapy. After the introduction of novel agents a significant improvement of the survival of patients with MM has been observed; however, the impact of these therapies on the survival of MM patients who present with RI has not been extensively studied. In order to analyze the impact of RI in newly diagnosed patients with MM over the past 20 years, we analyzed 1773 patients with symptomatic myeloma who were treated within the Greek Myeloma Study Group (GMSG). Patients were divided in groups according to the date of initial treatment (1/1/1990-31/12/1994, 1/1/1995-31/12/1999, 1/1/2000-31/12/2004, after 1/1/2005). Thalidomide became available in Greece after 1/1/2000 and bortezomib after 1/1/2005. eGFR was calculated by the modified MDRD formula and the degree of RI was rated as severe when eGFR was <30 ml/min, moderate when eGFR was 30–59 ml/min and mild (or no RI) when eGFR >60 ml/min. The frequency of RI over time was similar as well as the proportion of patients who presented with severe RI (17% vs. 21% vs. 17% vs. 19%) for the respective time periods (p=0.496). More patients >65 years started therapy after 2000 (44% vs. 50% vs. 59% vs. 59%, respectively, p<0.001), especially patients >75 years (13% vs. 18% vs. 24% vs. 32%, respectively, p<0.001). Anemia (Hb <10 g/dl; p=0.007) and ISS-3 disease (p=0.001) were more common after 1/1/1995; there were no other significant differences in the characteristics of the patients during the respective time periods. No patients received upfront novel agents before 31/12/1999, while 20% received upfront novel agent in the period 2000–2004 (almost exclusively thalidomide) and 73% after 1/1/2005 (mostly thalidomide and bortezomib). Myeloma response (≥PR) to frontline therapy was achieved in 56.5% & 54% of patients in the period 1990–1994 & 1995–1999 vs. 67% and 72% of patients in the periods 2000–2004 and after 2005 (p<0.001). The median survival of patients has improved significantly during the past 20 years: 39 months (1990-1994), 31 months (1995-1999), 40.5 months (2000-2004), 54 months after 2005 (p<0.001). The median OS for patients with severe RI has improved significantly from 18 months & 19.5 months in the 1990–1994 & 1995–1999 to 29 months and 32 months for the periods 2000–2004 and after 2005 (p=0.005). For patients with moderate RI the OS improved from 33 & 26 months between 1990–1994 & 1995–1999 to 40 & 44 months in the periods 2000–2004 and after 2005 (p=0.003). For patients with an eGFR ≥60 ml/min the OS improvement was less pronounced (48.5 months vs. 45 months vs. 51 months for the periods 1990–1994 & 1995–1999 & 2000–2004 respectively (p=0.076) and only after 2005 a significant improvement in OS is observed (median OS has not been reached; 3-year OS rate is 73%, p<0.001). For patients with severe RI early death rates (<2 months from initiation of therapy) were 12% vs. 7% for patients with moderate RI vs. 3% for patients with mild or no RI (p<0.001) and remained unchanged over time. We then adjusted for differences between groups in a multivariate model: treatment after 1/1/2000 was independently associated with improved survival compared to patients treated before 31/12/1999 (p<0.001). After adjusting for the degree of RI in the model, the hazards ratios (HR) for death for patients with severe RI for the 2000–2004 and after 2005 periods were 0.485 & 0.387 respectively compared to patients treated before 2000 (p<0.001 for both comparisons). For patients with moderate RI the respective HRs were 0.65 (p=0.003) & 0.57 (p=0.001), while for patients with mild or no RI the HRs were 0.85 (p=0.1) & 0.66 (p=0.003) for the 2000–2004 and after 2005 periods, respectively. In conclusion, the incidence of RI at diagnosis of MM has remained unchanged during the past 20 years, despite the increasing numbers of older patients who are diagnosed and treated for MM. The risk of early death is almost 2 to 4-fold higher in patients with severe RI vs. patients with moderate or no RI and has not improved over time. However, after the introduction of novel therapies there has been a significant improvement of the survival of patients with RI, which is more pronounced in patients with severe RI.