Ixazomib with lenalidomide and dexamethasone for patients with relapsed multiple myeloma: impact of 17p deletion and sensitivity to proteasome inhibitors from a real world data-set

A number of new treatments have been approved for patients with multiple myeloma (MM) and the survival of patients continues to improve. However, discrepancies in outcomes of clinical trials and the real world are observed predominantly due to a combination of patient, treatment and cost factors. Data reported from the Connect MM registry suggested that 40% of patients would have been ineligible for inclusion in most randomized controlled trials [1]. Therefore, the evaluation of real word outcomes in unselected heterogeneous patient populations are an important consideration for novel therapies, particularly following registration of a new drug or combination. Ixazomib, an oral proteasome inhibitor (PI) is approved for the treatment of patients with relapsed and refractory MM in combination with lenalidomide-dexamethasone (IRd). This was based on the phase III TOURMALINE-MM1 trial [2] that demonstrated a median progression-free survival (PFS) of 20.6 vs. 14.7months versus Rd for patients with 1–3 prior lines of therapy. To investigate how this regimen performed following market authorization in the real world, we performed a single-centre, retrospective, observational study of MM patients treated with IRd. The primary aims of this analysis was to assess the median PFS in a real world population, with secondary aims of overall response rate (ORR), time-to-next-treatment (TNT), overall survival (OS) within prespecified subgroups: adverse risk cytogenetics, 17p deletion, age >75 years, previously refractory to a PI and according to prior lines of treatment. TNT was used because it is often a more comparable parameter in real world data as outside of clinical trials MM response assessments are not always made every 4weeks. Patients received ixazomib 4mg on D1, 8, 15 in combination with lenalidomide (dose per label) days 1–21 and dexamethasone 40mg weekly or as tolerated every 28 days until disease progression or intolerance. Supportive medications including thromboprophylaxis followed institutional guidance. Overall response rate (ORR) and PFS were assessed by modified IMWG criteria [3] and toxicities graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Descriptive statistics were performed using the survival package in R version 3.6. 2. For inclusion in the analysis, patients had to have completed at least 1 cycle of treatment. 85 patients were included in this study. The median age was 65 years (32–84) and patients had received a median of 2 (1–4) prior lines of therapy. All patients had prior exposure to at least one PI (bortezomib, 81 (95.3%), carfilzomib 13 (15.3%)) of which 13 (15.3%) were refractory to a PI. 11 (12.9%) had prior lenalidomide (none were refractory), 52 (61.2%), prior thalidomide and 65 (76.5%) had prior autologous stem cell transplant (baseline characteristics are shown in Table 1). 50 (58.8%) patients discontinued IRD, of which 35 were due to disease progression on treatment (Supplementary Table 1). Of those that had progressed, 5 were previously refractory to a PI. After a median follow-up of 20.8m, the median PFS was 16.6m (95% CI 10.2–not reached (NR)) (Figure 1(A)). The median time to next treatment (TNT) was 19.0m (95% CI 13.1–NR). The overall response rate (ORR) for the cohort was 77.6% ( VGPR 22 (25.9%), PR 44 (51.8%)).