"Real World" Data on the Efficacy and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: A Combined Study from the Greek, Czech and UK Databases

Introduction

Ixazomib (Ixa) represents the first orally available proteasome inhibitor (PI) approved by FDA and EMA for the treatment of RRMM, based on results of the Tourmaline-MM1 trial, which compared the combination of Ixa-Lenalidomide-dexamethasone (IRd) with placebo-Rd, in patients who had received one to three prior lines of therapy. We sought to investigate the efficacy and safety of IRd in a "Real World" environment in Europe where data remain limited. We thus performed an observational study, which analysed retrospectively IRd treatment data from RRMM patients participating in a Named-Patient Program of compassionate Ixa use in Greece (GR), UK and the Czech Republic (CZ). Overall Response Rate (ORR) according to IMWG criteria was chosen as the primary endpoint while secondary endpoints included the treatment & response duration, percentage of patients experiencing adverse events (AEs), dose modification, treatment discontinuation and estimation of PFS and TTP.

Patients

Out of 152 patients screened in the three databases, 138 patients (GR:35, UK:46, CZ:57), who had received at least one cycle of therapy, were included in the present study. Median age was 68 years (range: 40-92 years), M/F ratio was 85/53, with ECOG 0-1: 71.8% and ECOG 2-3: 27.2% of patients. The median number of previous therapies was 1.5 (range:1-7); more specifically 50.0% (69/138) of patients had received one line of prior treatment, 30.4% (42/138) two lines, 14.5% (20/138) three lines and 5.1% (7/138) had received 4-7 prior lines of anti-myeloma therapies. Overall, 94.2% of patients had been exposed to PIs [bortezomib 89.1%] prior to IRd, 59.4% to IMiDs [thalidomide 46.4% lenalidomide 26.1% and pomalidomide 1.4%], while 26.1% had undergone high dose melphalan and autologous transplantation (ASCT).

Results

The median follow-up of patients was 9.1 months. Median treatment duration for IRd was 7.2 months (range: 1.0-27.5). Among 94.1% (130/138) response-evaluable cases, a response of sCR/CR was recorded in 10.8% (14/130), VGPR in 18.5% (24/130), PR in 39.2% (51/130), MR in 4.6% (6/130), stable disease in 10.0% (13/130), and progressive disease in 16.9% (22/130) of them. The ORR (≥PR) was estimated at 68.5% (95% CI: 60.5-76.4) in the overall population; 76.6% in patients receiving IRd as second line, 64.3% in those as third line and 55% in those beyond third line (patients administered IRd beyond second line therapy had an ORR of 60.6%; 95% CI: 48.8-72.4). Median time to best response was 1.3 months. Increased exposure time to IRd was found to significantly influence ORR, as patients receiving IRd for at least 6, 7 and 8 months displayed ORR rates of 84.4%, 87.0% and 94.2%, respectively. Furthermore, patients treated with IRd for ≥6 months were 9.5 times more likely to achieve a best response of ≥PR compared to those treated for <6 months (adj.OR: 9.50; 95% CI: 2.51-36.02; p=0.001). Similarly, patients who received previous ASCT were 3.48 times more likely to achieve PR or better (OR: 3.48; 95% CI: 1.24-9.80; p=0.018). The median PFS for all patients was 27.6 (95% CI: 11.3-27.6) months. The median Kaplan-Meier estimated TTP was also 27.6 months (95% CI: 15.2-27.6).

Treatment interruptions were observed in 8.7% (12/138) of patients and were mainly due to AEs (75%). Treatment discontinuation rate was 13.7% with AEs, second ASCT and administrative reasons being responsible for 53%, 26%, and 21% of cases, respectively. The median time to IRd discontinuation was 4.0 (IQR: 2.4-7.4) months. A total of 28.3% (39/138) of patients experienced peripheral neuropathy (PN); PN resolved in 38.5% (15/39) of the cases, while in the 24 remaining patients PN was graded as 1 or 2. Additional AEs included pneumonia in 8%, hypertension in 5.9%, DVT in 3.6%, and herpes zoster in 2.9% of patients. No cardiac events or bone fractures were recorded during the study. A total of eleven (8%) deaths were observed during the study, from which 4 (36%) were due to progressive disease.

Conclusion

Our results corroborate clinical trial data of IRd in a "Real World" setting and suggest IRd is an attractive oral therapeutic option in RRMM, achieving an ORR of 68.5% and an estimated median PFS of 27.6 months. Patients with limited previous treatment exposure and prior ASCT appear to benefit more from the IRd regimen. Regimen is tolerable in this "Real World" cohort comprising large proportion (73%) of transplant ineligible patients.