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.

• Keywords
• Clinical trial, Dexamethasone, Ixazomib, Lenalidomide, Multiple myeloma, Patient registry,
• MeSH
• Administration, Oral MeSH
• Drug Resistance, Neoplasm MeSH
• Dexamethasone pharmacology   therapeutic use   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Glycine analogs & derivatives   pharmacology   therapeutic use   MeSH
• Kaplan-Meier Estimate MeSH
• Lenalidomide pharmacology   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   mortality   pathology   MeSH
• Multiple Myeloma drug therapy   mortality   pathology   MeSH
• Follow-Up Studies MeSH
• Prospective Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   therapeutic use   MeSH
• Registries statistics & numerical data   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Boron Compounds pharmacology   therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Dexamethasone MeSH
• Glycine MeSH
• ixazomib MeSH Browser
• Lenalidomide MeSH
• Boron Compounds MeSH

Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and -6, and aza-Asn derivatives that inhibited S. mansoni and I. ricinus legumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initial in vitro selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

• Keywords
• Proteasome inhibitor, anticancer, antiparasitic, aza-peptide carbonyls, caspase and legumain inhibitors,
• MeSH
• Aldehydes chemistry   pharmacology   MeSH
• Aza Compounds chemistry   pharmacology   MeSH
• Cysteine Endopeptidases metabolism   MeSH
• Protease Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Ketones chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Peptides chemistry   pharmacology   MeSH
• Proteasome Endopeptidase Complex metabolism   MeSH
• Drug Design * MeSH
• Cattle MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aldehydes MeSH
• Aza Compounds MeSH
• Cysteine Endopeptidases MeSH
• Protease Inhibitors MeSH
• Ketones MeSH
• Peptides MeSH
• Proteasome Endopeptidase Complex MeSH

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1-4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413.

• Keywords
• Adverse events, Ixazomib, Maintenance therapy, Multiple myeloma, Safety,
• MeSH
• Autografts MeSH
• Glycine administration & dosage   adverse effects   analogs & derivatives   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma * mortality   therapy   MeSH
• Follow-Up Studies MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   MeSH
• Aged MeSH
• Silicates administration & dosage   adverse effects   MeSH
• Boron Compounds administration & dosage   adverse effects   MeSH
• Stem Cell Transplantation * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Glycine MeSH
• ixazomib MeSH Browser
• Silicates MeSH
• Boron Compounds MeSH
• tourmaline MeSH Browser

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

• Keywords
• Ixazomib, Lenalidomide, Myeloma, Real world, Relapsed,
• MeSH
• Dexamethasone administration & dosage   adverse effects   MeSH
• Adult MeSH
• Glycine administration & dosage   adverse effects   analogs & derivatives   MeSH
• Lenalidomide administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma drug therapy   mortality   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   MeSH
• Recurrence MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Boron Compounds administration & dosage   adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Names of Substances
• Dexamethasone MeSH
• Glycine MeSH
• ixazomib MeSH Browser
• Lenalidomide MeSH
• Boron Compounds MeSH

This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

• MeSH
• Administration, Oral MeSH
• Glycine administration & dosage   analogs & derivatives   therapeutic use   MeSH
• Induction Chemotherapy MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Melphalan administration & dosage   MeSH
• Neoplasm Metastasis MeSH
• Multiple Myeloma diagnosis   drug therapy   mortality   MeSH
• Prednisone administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Boron Compounds administration & dosage   therapeutic use   MeSH
• Neoplasm Staging MeSH
• Maintenance Chemotherapy MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glycine MeSH
• ixazomib MeSH Browser
• Melphalan MeSH
• Prednisone MeSH
• Boron Compounds MeSH

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.

• MeSH
• Glycine administration & dosage   analogs & derivatives   MeSH
• Proteasome Inhibitors administration & dosage   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma drug therapy   mortality   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Boron Compounds administration & dosage   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glycine MeSH
• Proteasome Inhibitors MeSH
• ixazomib MeSH Browser
• Antineoplastic Agents MeSH
• Boron Compounds MeSH