Patients and Previous Therapy
The baseline characteristics of both the IRD and RD cohorts are summarized in Table 1. The cohorts were overall well balanced, with some statistically significant differences. The median age of the IRD cohort was slightly younger than the RD cohort (66.0 vs 68.0 years, p = 0.002). On the other hand, more extramedullary myeloma (EM) was recorded in the IRD cohort (14.2% vs 6.7%, p = 0.034). Finally, a higher proportion of patients in the IRD cohort had been pretreated with autologous stem cell transplant (ASCT) (62.0% vs 43.3%, p ˂ 0.001) and proteasome inhibitor (96.9% vs 91.2%, p = 0.047). All other variables were evenly distributed with no significant differences between the cohorts. We tested the impact of selected variables on response rates and survival measures in a univariable analysis in order to define whether any of them had an efect on the treatment outcomes. Significant results were found in the case of „disease status“ (relapsed/refractory/primary refractory/relapsed and refractory) for all, PFS, OS and ORR. In the case of age and extramedullary disease, there was a significant result for OS only. We therefore performed a multivariable and paired analysis in order to adjust for the significantly different baseline characteristics. The multivariable analysis showed no impact of uneven baseline variables on ORR, PFS and OS.
Altogether, 15 patients (5 in the IRD arm and 10 in RD arm) proceeded to ASCT and discontinued induction therapy after 3–6 cycles of lenalidomide-based induction. In order to eliminate possible bias from transplant, results were calculated for both the total cohort as well as the cohort of patients without subsequent ASCT.
The median number of previous lines of therapy was 1, with similar percentages of patients being treated after ≥4 prior lines in both cohorts (10.2% vs 7.8%). Most patients had received prior bortezomib (94.5% vs 89.9%), followed by thalidomide (43.3% vs 48.4%) and lenalidomide (17.3% vs 15.2%). Despite this being an exclusion criterion for the TOURMALINE-MM1 clinical trial, some patients in the IRD cohort had disease that was refractory to either PI- or IMiD-based therapy, including bortezomib (18.9%), thalidomide (7.1%), lenalidomide (5.5%), and carfilzomib (2.4%).
Treatment
The proportion of the various starting doses of lenalidomide were similar in both cohorts: 25 mg (72.8% vs 63.3%), 15 mg (20.8% vs 17.2%), 10 mg (6.4% vs 16.7%), and 5 mg (0% vs 2.2%) the starting dose was significantly higher in the IRD cohort but the multivariable analysis showed no impact on the final results; 44.8% of patients underwent dose reduction in the IRD cohort compared to 37.8% in the RD cohort. The starting dose of ixazomib in IRD cohort was 4 mg in 93.6% of patients and 3 mg in 6.5% of patients; a total of 17.7% of patients underwent dose reduction for ixazomib. At the time of analysis, treatment was still ongoing in 40.2% of patients in the IRD cohort and in 34.1% of patients in the RD cohort. The most common reason for treatment withdrawal was disease progression (29.9% vs 21.2%), followed by death (5.5% vs 11.1%) and insufficient response (3.9% vs 6.0%).
Response Assessment
The registry data cut-off for this analysis was June 2019. Median follow-up was slightly longer in the IRD cohort (20.8 vs 15.5 months). The overall response rate (ORR) was 73.0% in the IRD cohort vs 66.2% in the RD cohort. Maximal treatment response rates in both cohorts are reported in Table 2: complete response (CR) (11.1% vs 8.8%), very good partial response (VGPR) (22.2% vs 13.9%), partial response (PR) (39.7% vs 43.5%) and minimal response (MR) in (8.7 vs 15.7%). Although ORR was not statistically different between cohorts, patients in the IRD cohort reached significantly more ≥VGPR responses than in the RD cohort (33.3% vs 22.7%, p = 0.042).
Median progression free survival (PFS) was significantly improved in the IRD cohort (17.5 vs 11.5 months, p = 0.005); in patients with 1–3 prior relapses median PFS was improved further (23.1 vs 11.6 months p = 0.001), as shown in Fig 1. The hazard ratio for disease progression or death for patients in the IRD cohort compared to RD was 0.67 (95% CI 0.51 – 0.89, p = 0.006). A higher percentage of patients in the IRD cohort were progression-free at 6 months (80.1% vs 68.3%), 12 months (59.6% vs 49.1%) and 24 months (44.3% vs 28.3%).
Median OS was significantly improved in the IRD cohort (36.6 months vs 26.0 months, p = 0.008); in patients with 1–3 prior relapses median OS was not yet reached for the IRD cohort (NR vs 27.1 months, p = 0.002). A higher percentage of patients in the IRD cohort were still alive at 6 months (88.9% vs 83.4%), 12 months (76.8% vs 71.5%), and 24 months (66.4% vs 52.7%), as shown in Fig 2.
In the analysis conducted for all patients who did not undergo subsequent ASCT (n=329), response rates in both the IRD cohort (n=122) and RD cohort (n=207) were not different, nor did they significantly affect PFS or OS. Adjusted response rates were as follows: CR (10.8% vs 7.8%), VGPR (23.1% vs 13.6%), PR (38.8% vs 43.7%) and MR (9.1% vs 16.0%). The significant difference between cohorts for patients who reached ≥VGPR was maintained (33.9% vs 21.4%, p = 0.018). Among the 5 patients who were treated with IRD induction followed by ASCT, one reached CR, three reached PR and one progressed on treatment. Among the 10 patients who were treated with RD induction followed by ASCT, three reached CR, two reached VGPR, four reached PR and one reached MR.
Patients in the the majority of pre-specified subgroups (e.g., age, ISS stage, maximal treatment response, and pretreatment) also experienced longer PFS if they were in the IRD cohort, as shown in Fig 3. Analysis of the number of prior relapses also showed that the IRD cohort experienced longer median PFS up to the third relapse: 1st relapse (32.7 vs 14.8 months, HR 0.63 [0.42-0.94]), 2nd relapse (23.1 vs 9.3 months, HR 0.51 [0.28-0.91]), 3rd relapse (9.7 vs 9.0 months, HR 0.89 [0.40-2.01]), and ≥4th relapse (5.0 vs 9.9 months, HR 1.38 [0.60-3.17]). In addition, patients in the IRD cohort who had prior ASCT experienced longer median PFS than patients without previous transplant (23.0 vs 15.1 months), as shown in Figs 3 and 4.
Notably, patients in the IRD cohort with EM disease did not benefit from treatment and their median PFS was similar to patients in the RD cohort (6.5 vs 10.9 months, HR 1.24 [0.54-2.86]), as shown in Figs 3 and 5. Two additional patient subgroups in the IRD cohort experienced at interim analysis shorter median PFS, including those with previous IMiD treatment (11.3 months) and with refractory disease in the previous line of treatment (9.7 months); however, the IRD cohort reported better hazard ratios for median PFS in both subgroups, (HR 0.76 [0.52-1.09] and 0.69 [0.34-1.41] respectively), as shown in Fig 3.
In both cohorts, median PFS decreased with advanced ISS stage: stage 1 (32.7 vs 17.1 months, HR 0.54 [0.32-0.92]), stage 2 (25.8 vs 9.7 months, HR 0.54 [0.30-0.98]), and stage 3 (9.9 vs 6.4 months, HR 0.80 [0.48-1.33]). Although clinical outcomes were generally more favorable in younger patients, the IRD cohort reported longer median PFS regardless of age: ≤65 years (23.0 vs 10.8 months, HR 0.66 [0.42-1.03]), 66–75 years (17.8 vs 11.5 months, HR 0.73 [0.48-1.11]), and ˃75 years (11.1 vs 11.7 months, HR 0.68 [0.30-1.55]).
Cytogenetics
Results from at least one cytogenetic assessment was available for 69% (87/127) of patients in the IRD cohort and 49% (106/217) of patients in the RD cohort. Cytogenetic data recorded in the registry were acquired at the time of MM diagnosis (± 6 months), as shown in Table 3. In the IRD cohort, 12.1% (8/66) of assessed patients were positive for del(17p13), 10.2% (6/59) of asssessed patients were positive for t(4;14), and 5.8% (3/52) of assessed patients were positive for t(14;16). In the RD cohort, 13.2% (12/91) of assessed patients were positive for del(17p13), 7.0% (6/86) of assessed patients were positive for t(4;14), and 4.3% (3/69) of assessed patients were positive for t(14;16). There were no significant differences in the presence of high-risk cytogenetic features between the cohorts. High-risk features as defined by the presence at least one cytogenetic abnormality including t(4;14), t(14;16), or del(17p13) were present in 11.8% (15/127) patients in the IRD cohort and 8.8% (19/217) patients in the RD cohort. Among those patients in the IRD cohort whose disease was considered high-risk, one patient reached VGPR, six reached PR, four reached MR, two had stable disease (SD) and two progressed (PD). Among those patients in the RD cohort whose disease was considere high-risk, one patient reached VGPR, seven reached PR, five reached MR, three maintained SD and three had PD.
Adverse events
Adverse events were graded according to the National Cancer Institute´s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The frequency of adverse events (AEs) associated with IRD and RD was consistent with published clinical trial experience.1 The majority of grade ≥3 AEs included hematological toxicity, and there was no statistically significant difference between the occurence of cytopenia between the cohorts, as seen in Table 4. Grade ≥3 anemia was reported in 12.0% vs 25.6%, neutropenia in 28.4% vs 23.1% and thrombocytopenia in 21.3% vs 22.6% of patients in the cohorts, respectively. The IRD cohort reported significantly more episodes of grade 1 and 2 infection (50.0% vs 29.1%, p=0.005) but the rates of grade ≥3 infection was similar in both cohorts (21.4% vs 22.5%). Similarly, the IRD cohort reported slightly more cases of peripheral neuropathy (PN), but grade ≥3 neuropathy was recorded for only three patients and most PN cases were associated with previous pretreatment with bortezomib or thalidomide. Grade 1 PN in both cohorts was present in 36.0% vs 32.8%, grade 2 in 16.0% vs 7.8%, grade 3 in 4.0% vs 0%, the difference between the cohorts was small but significant (p = 0.011). We looked thoroughly at “regimen specific toxicities” (i.e., non-hematological toxicities that were most often reported by other trials in association with ixazomib treatment): fatigue, nausea and vomiting, diarrhea and rash. Among these, only diarrhea was significantly more frequent in the IRD cohort but only 1 patient had grade ≥3 diarrhea. The reason for treatment discontinuation due to toxicity was in 3.1% in the IRD cohort (4/127) and 4.1% in the RD cohort (9/217).