Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice.

BACKGROUND: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. METHODS: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. RESULTS: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. CONCLUSIONS: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma.

The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Adoption of triplet therapy and clinical outcomes in routine practice among newly diagnosed multiple myeloma patients not receiving frontline stem cell transplant in the USA.

BACKGROUND: Immunomodulator (IMID) and proteasome inhibitor (PI) triplet frontline therapy (FT) in newly diagnosed multiple myeloma (NDMM) trials improve overall survival (OS); reported outcomes in routine practice are lacking. Authors compared outcomes in NDMM patients in the USA by use of triplet vs doublet FTs. METHODS: In this retrospective study of NDMM patients without FT transplant between 1/1/2008 and 6/30/2017, FT was categorized as: PI+IMID-triplet (≥ 3 drugs including PI+IMID), non-PI+IMID-triplet (≥ 3 drugs, not PI+IMID), doublet (≤ 2 drugs). Univariate and multivariate analyses identified FT triplet predictors and compared time-to-next-treatment (TTNT)/OS. RESULTS: Among 4,982 NDMM patients, 68% and 32% initiated doublet and triplet FTs (PI+IMID: 36% in 2017). Triplet FT predictors included: age, cytogenetics, ISS stage, certain CRAB symptoms. Median TTNTPI+IMID-triplet = 18.9 months vs 13.7 (non-PI+IMID-triplet) and 16.5 months (doublet) FTs (P< 0.01); adjusted HRPI+IMID-triplet = 0.86; P= 0.009; HRnon-PI+IMID-triplet = 1.10; P = 0.083 vs doublet FT. Median OSPI+IMID-triplet = 58.7 months vs 43.6 (non-PI+IMID-triplet) and 45.7 months (doublet) FTs (P< 0.01); adjusted HRPI+IMID-triplet = 0.83; P= 0.016; HRnon-PI+IMID-triplet = 1.02; P = 0.727 vs doublet FT. CONCLUSION: PI+IMID-triplet FT is not utilized for most non-frontline-transplant NDMM patients in routine care but is associated with prolonged TTNT/OS.

Ixazomib for the treatment of multiple myeloma.

INTRODUCTION: Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy. Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications. Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including 'poor prognosis' patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens.

Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting.

Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches.

Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma.

Ixazomib is the first oral proteasome inhibitor to enter the clinic. Given the efficacy of bortezomib in combination with cyclophosphamide and dexamethasone, we studied the combination of ixazomib, cyclophosphamide and dexamethasone (ICd) in newly diagnosed multiple myeloma (NDMM) and patients with measurable disease, irrespective of transplant eligibility, were enrolled. The phase 1 was to determine the maximum tolerated dose (MTD) of cyclophosphamide in the combination. Patients received ixazomib 4 mg (days 1, 8, 15), dexamethasone 40 mg (days 1, 8, 15, 22), and cyclophosphamide 300 or 400 mg/m2 days 1, 8, 15, 22; cycles were 28 days. We enrolled 51 patients, 10 in phase 1 and 41 patients in phase 2. The median age was 64.5 years (range: 41-88); 29% had high or intermediate risk FISH. The MTD was 400 mg/m2 of cyclophosphamide weekly. The best confirmed response in all 48 patients included ≥ partial response in 77%, including ≥ VGPR in 35%; 3 patients had a sCR. The response rate for all 48 evaluable patients at 4-cycles was 71%; the median time to response was 1.9 months. Common adverse events included cytopenias, fatigue and GI intolerance. ICd is a convenient, all oral combination that is well tolerated and effective in NDMM.

Patient-reported health-related quality of life from the phase III TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone versus placebo-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma.

TOURMALINE-MM1 is a phase III, randomized, double-blind, placebo-controlled study of ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma following 1-3 prior lines of therapy. The study met its primary endpoint, demonstrating significantly longer progression-free survival (PFS) in the IRd arm versus placebo-Rd arm (median 20.6 vs 14.7 months, hazard ratio 0.74, P = .01), with limited additional toxicity. Patient-reported health-related quality of life (HRQoL) was a secondary endpoint of TOURMALINE-MM1. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and Multiple Myeloma Module 20 (QLQ-MY20) were completed at screening, the start of cycles 1 and 2, every other cycle, the end of treatment, and every 4 weeks until progression. Over median follow-up of 23.3 and 22.9 months in the IRd and placebo-Rd arms, mean QLQ-C30 global health status (GHS)/QoL scores were maintained from baseline over the course of treatment in both groups, with no statistically significant differences between groups. EORTC QLQ-C30 function domain scores were also generally maintained from baseline; similarly, physical, emotional, and social function domains were maintained with IRd versus placebo-Rd, with slightly higher mean change from baseline scores at earlier time points with IRd. Findings from this double-blind study demonstrate that addition of ixazomib to Rd significantly improved efficacy while HRQoL was maintained, reflecting the limited additional toxicity seen with IRd versus placebo-Rd, and support the feasibility of long-term IRd administration.

Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses.

BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. METHODS: We report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. RESULTS: Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. CONCLUSIONS: These analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537.

Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial.

PURPOSE: Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL. MATERIALS AND METHODS: Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer. RESULTS: Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient. CONCLUSIONS: In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates.