Patient demographics and baseline characteristics are described in Table 1. Of the 34 patients in the FAS, the median age was 67 years. Median time from initial diagnosis was 44.4 months, with 71% of MM diagnosed being of the IgG type.
At study entry, 82% of patients were International Staging System stage I, and 74% had an ECOG performance status of 0. Additionally, 29% of patients had a creatinine clearance of 30 to < 60 ml/min, 62% of patients only had one prior line of therapy, 91% of patients had relapsed disease and 9% of patients had refractory disease.
Overall, 68% of patients had undergone ASCT with a median time of 38.8 months since the time of last transplantation to the first dose at study entry. 91% of patients had previous exposure to PIs and 35% to IMiDs. 32% of patients had high-risk cytogenetic abnormalities, whereby cut-offs were 5% positive cells for del(17p), 3% for t(4;14) and 3% for t(14;16), of cells testing positive for these abnormalities.
The study drug exposure is described in Table 2. The median number of treatment cycles for all study drugs was 20, with a median relative dose intensity of 86.0% for ixazomib, 81.6% for lenalidomide and 91.7% for dexamethasone.
The response to treatment is described in Table 3. The primary endpoint of confirmed VGPR + CR rate was 50.0% (95% CI 31.9–68.1), which was above the threshold rate of 39.0% based on the results of the MM1 study. The ORR was 84.4% (95% CI 67.2–94.7) and the CR rate was 28.1% (95% CI 13.7–46.7), with the stringent CR rate being 25.0% (95% CI 11.5–43.4). In the high-risk and standard-risk cytogenetics subgroups, the ORRs were 72.7% and 90.5%, respectively. In the response-evaluable analysis set, stable disease was demonstrated in 15.6% of patients and no patients had PD as their best response.
The median DOR was not estimable for patients with VGPR or better. At the last assessment, no PD was documented in 78% of patients with CR (n = 9), 56% of patients with VGPR or better (n = 16) and 48% of patients with PR or better (n = 27). The median time to response was 2.9 months (95% CI 1.8–5.1) for VGPR or better and 1.0 months (95% CI 1.0–1.8) for PR or better.
PFS is described in Fig. 1. With a median follow-up of 28.1 months, median PFS was 22.0 months (95% CI 17.3–not evaluable); and 18 patients (53%) had PD, including one death.
At the time of data cutoff, the OS data were not mature, and the median OS was not estimable.
The overall summary of treatment-emergent adverse events (TEAEs) is described in Table 4 and the most common TEAEs that were reported in ≥ 10% of patients are described in Table 5. All patients experienced at least one TEAE and drug-related TEAE during the study (n = 34 [100%]). Additionally, 85% of patients had at least 1 TEAE of Grade ≥ 3 and 79% of patients had a drug-related TEAE of Grade ≥ 3. The most common TEAEs of Grade ≥ 3 were neutropenia (21%), decreased platelet count (21%), decreased neutrophil count (18%), diarrhea (15%) and maculopapular rash (12%) (Table 6). Two deaths were observed, with one death due to adverse events (AEs) (subarachnoid hemorrhage and subdural hemorrhage) that were associated with a fall and without study drug causality, and another death due to primary disease or its complications after discontinuation of study treatment for PD.
Serious adverse events (SAEs) were experienced by 35% of patients (n = 12), with 29% experiencing drug-related SAEs. The most common SAEs were pneumonia (9%), diarrhea (6%) and fall (6%), while the most common drug-related SAEs were pneumonia (9%) and diarrhea (6%).
Overall, 32% of patients had at least one TEAE leading to the discontinuation of one or more of the three study drugs; the most common AE was neutropenia, which was reported in two patients. Additionally, 76% of patients had at least one TEAE resulting in dose reduction of any study drug, with the most common AE being maculopapular rash, which was reported in four patients. Two patients were diagnosed with a second malignancy while on study treatment: one patient was reported as having acute myeloid leukemia and the other had malignant lung neoplasm. Both of these AEs were serious, considered to be related to study treatment and resulted in discontinuation of study treatment. Patients were specifically followed up for second malignancies because of the increased risk with lenalidomide [20, 21].
TEAEs occurring in ≥ 20% of patients were constipation (50%), upper respiratory tract infection (47%), diarrhea (41%), rash (35%), nasopharyngitis (32%), nausea (29%), platelet count decreased (26%), influenza (24%), neutropenia (24%), chilblains (21%), dysgeusia (21%), fall (21%) and peripheral sensory neuropathy (21%).
Drug-related TEAEs occurring in ≥ 20% of patients were diarrhea (38%), constipation (38%), rash (29%), platelet count decreased (26%), nausea (24%), peripheral sensory neuropathy (21%), dysgeusia (21%) and neutropenia (21%). Drug-related TEAEs of Grade ≥ 3 occurring in ≥ 10% of patients were platelet count decreased (21%), neutrophil count decreased (18%), neutropenia (18%), diarrhea (15%) and maculopapular rash (12%).
A summary of TEAEs of clinical importance is presented in Table 7. The TEAEs of clinical importance were neutropenia, thrombocytopenia, heart failure, arrhythmia, myocardial infarction, nausea, vomiting, diarrhea, rash, maculopapular rash, urticaria, erythema multiforme, generalized rash, macular rash, peripheral sensory neuropathy and peripheral neuropathy.
AEs of clinical importance reported in this study were similar to those reported in the global MM1 study. No previously unknown safety concerns were identified in this study.