Ixazomib in POEMS syndrome: 'Ixa'ctly what we need?

The role of the proteasome inhibitor ixazomib in the treatment of POEMS syndrome continues to evolve. He and colleagues present the results of a study investigating ixazomib in combination with cyclophosphamide and dexamethasone in newly diagnosed POEMS patients. The triplet showed excellent efficacy and tolerability, and constitutes an effective treatment option for patients with POEMS. Commentary on: He et al. An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly-diagnosed POEMS syndrome. Br J Haematol 2024;205:478-482.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly diagnosed POEMS syndrome.

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

The EASEMENT study: A multicentre, observational, cross-sectional study to evaluate patient preferences, treatment satisfaction, quality of life, and healthcare resource use in patients with multiple myeloma receiving injectable-containing or fully oral therapies.

OBJECTIVE: As multiple myeloma (MM) therapies advance, understanding patients', caregivers', and physicians' perspectives on, and satisfaction with, available treatment options and their impact on quality of life (QoL), is important. METHODS: EASEMENT is a real-world, observational, cross-sectional study conducted in 19 sites within the UK, Canada, and Italy using retrospective chart reviews and surveys. Enrolled patients had clinical history available since diagnosis and had received ≥1 cycle of their current line of therapy. Primary objectives were to describe patient/caregiver QoL (EQ-5D-5L questionnaire), patient preference for oral/injectable therapies (single discrete-choice question), and patient satisfaction (TSQM-9 questionnaire). RESULTS: Between October 2018 and March 2020, 399 patients were enrolled (n = 192 newly diagnosed multiple myeloma [NDMM], n = 206 relapsed/refractory multiple myeloma [RRMM], n = 1 missing). Among NDMM and RRMM patients, 78%/22% and 42%/58% were receiving injectables/orals, respectively. Both NDMM and RRMM patients significantly preferred orals versus injectables (p < .0001). No significant differences were reported in treatment satisfaction or QoL, but treatment convenience favoured orals over injectables with near significance (p = .053). CONCLUSION: MM patients perceived greater convenience and preference for orals versus injectables. Oral treatments are useful for patients who cannot or prefer not to travel to clinics, or cannot perform self-injection within the community.

Efficacy of ixazomib, lenalidomide, dexamethasone regimen in daratumumab-exposed relapsed/refractory multiple myeloma patients: A retrospective analysis.

We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab-exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not-triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), p = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) p = .003). Similar to OS, there was improved PFS in patients, that were not triple-refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), p = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple-refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR).

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.

OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

In-class transition from bortezomib-based therapy to IRd is an effective approach in newly diagnosed multiple myeloma.

Aim: To compare the effectiveness of in-class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

Proteasome Inhibitor Drugs.

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

Ixazomib, Oral Metronomic Cyclophosphamide, and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.

BACKGROUND: Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. METHODS: We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. RESULTS: The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. CONCLUSION: Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.

This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.

Real-world effectiveness of ixazomib combined with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: the REMIX study.

Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients with relapsed and/or refractory multiple myeloma (RRMM). The REMIX study is one of the largest prospective, real-world analysis of the effectiveness of IXA-Rd in the setting of RRMM. Conducted in France between August 2017 and October 2019, the REMIX study, a non-interventional prospective study, included 376 patients receiving IXA-Rd in second line or later and followed for at least 24 months. Primary endpoint was the median progression-free survival (mPFS). Median age was 71 years (Q1-Q3 65.0 - 77.5) with 18.4% of participants older than 80 years. IXA-Rd was initiated in L2, L3 and L4 + for 60.4%, 18.1% and 21.5%, respectively. mPFS was 19.1 months (95% CI [15.9, 21.5]) and overall response rate (ORR) was 73.1%. mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS was similar for patients previously exposed to lenalidomide (19.5 months) than for those lenalidomide naive (not exposed, 22.6 months, p = 0.29). mPFS was 19.1 months in patients younger than 80 years and 17.4 months in those 80 years or older (p = 0.06) with similar ORR (72.4% and 76.8%) in both subgroups. Adverse events (AEs) were reported in 78.2% of patients including 40.7% of treatment-related AE. IXA discontinuation was due to toxicity in 21% of patients. To conclude, the results of the REMIX study are consistent with the results of Tourmaline-MM1 and confirm the benefit of IXA-Rd combination in real life. It shows the interest of IXA-Rd in an older and frailer population, with an acceptable effectiveness and tolerance.

Cardiovascular complications of modern multiple myeloma therapy: A pharmacovigilance study.

AIMS: Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. METHODS: We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events. RESULTS: Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6) and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7) and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8) and 4.6 (3.2-6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS. CONCLUSION: Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.

The Combination of Venetoclax and Ixazomib Selectively and Efficiently Kills HIV-Infected Cell Lines but Has Unacceptable Toxicity in Primary Cell Models.

The antiapoptotic protein BCL2 inhibits death of HIV-infected cells. Previously, we showed that the BCL2 inhibitor venetoclax selectively kills acutely HIV-infected cells and reduces HIV DNA in latently infected CD4 T cells ex vivo after reactivation with anti-CD3/anti-CD28. However, there is a need to identify a combination therapy with venetoclax and a clinically relevant latency reversal agent. Ixazomib is an oral proteasome inhibitor which we have shown reactivates latent HIV and predisposes reactivated cells to cell death. Here, we determined that the combination of venetoclax and ixazomib kills more latently HIV-infected cells and leads to greater reduction in HIV replication than either treatment alone in vitro in a T cell model. However, combination treatment of ex vivo CD4 T cells from antiretroviral therapy (ART)-suppressed, HIV-positive participants resulted in unanticipated and unacceptable nonspecific toxicity in primary cells. Therefore, while we show proof of concept that multiple agents can enhance selective killing of HIV-infected cells, the combination of venetoclax and ixazomib has unacceptable toxicity in primary cells, and so further investigation is needed to identify a clinically relevant latency reversal agent to combine with venetoclax as a novel strategy to reduce the size of the HIV reservoir.IMPORTANCE A cure for HIV would require eliminating cells that contain the virus in a latent form from the body. Current antiretroviral medications are unable to rid the body of latently infected cells. Here, we show that a combination of investigational agents-ixazomib plus venetoclax-which reactivate latent virus and predispose infected cells to apoptosis may reduce latent virus in a T cell model, but at the expense of nonspecific toxicity in primary cells.

Comprehensive Analysis of Ixazomib-Induced Adverse Events Using the Japanese Pharmacovigilance Database.

BACKGROUND: Ixazomib is an orally available proteasome inhibitor for multiple myeloma with adverse effects such as gastrointestinal symptoms, skin rashes, and thrombocytopenia reported in clinical trials and post-marketing surveillance, resulting in treatment discontinuation. However, comprehensive adverse event (AE) assessments for ixazomib are lacking. OBJECTIVES: Herein, we aimed to determine the frequency and risk of AEs associated with ixazomib in Japanese patients using the Japanese Adverse Event Reporting Database (JADER). Additionally, the time to onset and post hoc outcomes of unique AEs were clarified. METHODS: To investigate the association between ixazomib and AEs, we analyzed the JADER database, comprising voluntary AE reports submitted to the Pharmaceuticals and Medical Devices Agency, between April 2004 and June 2021. AEs with ≥10 reports were included in the analysis, and criteria for the presence of AE signals were defined as meeting the requirements of proportional report ratio ≥2 and χ2 ≥ 4. Characteristic AEs were analyzed considering time to onset and onset outcomes. RESULTS: Of 34 extracted AEs, 18 presented AE signals. The 12 post hoc outcomes with fatality rates ≥10% included septic shock (50.0%), infection (41.2%), heart failure (16.7%), pneumonia (14.2%), and tumor necrosis syndrome (13.3%). A median of the time to onset showed that 11 of the 18 AEs occurred from ixazomib initiation to approximately 1 month later. CONCLUSION: Our results suggest that ixazomib may increase the incidence of 18 AEs, 11 of which occurred within the first month of treatment. Furthermore, 8 AEs were found to have potentially fatal outcomes at a rate of ≥10%. Therefore, monitoring AEs during the first month of treatment appears necessary.

Ixazomib, lenalidomide, and dexamethasone combination in "real-world" clinical practice in patients with relapsed/refractory multiple myeloma.

Ixazomib is approved for use in combination with lenalidomide and dexamethasone (IRd) for patients with multiple myeloma (MM) who received at least one previous therapy. Registration study "TOURMALINE MM-1" was published in 2016. Nevertheless, clinical trials are significantly different from real-world use. From June 2016 to December 2018, IRd was available for Slovak patients with relapsed/refractory MM through a Named Patient Program. The aim of this study was to evaluate the efficacy and safety of ixazomib. We analyzed in this cohort study outcomes of 106 MM patients treated with IRd at 2 academic centers. The median age at diagnosis was 63 years (44-78). The median number of prior lines was 2 (1-7). The majority had high international staging system (ISS) score: 18, 29, and 59 were in the ISS I, ISS II, and ISS III groups, respectively. Treatment continued until progression, unacceptable toxicity, or death. The median follow-up for the entire cohort was 29 (0-49) months. The overall response rate was 74.5% (complete remission, 7.5%; partial remission, 67%). The median overall survival was not reached. Median progression-free survival (PFS) was 43 months (95% CI 35.6-50.4). The Kaplan-Meier method was used to generate survival curves, and we compared the influence of different factors on PFS. The most common hematological adverse events of any grade were neutropenia (90.4%), anemia (55.6%), and thrombocytopenia (43.4%). Our real-world data support the use of IRd as a highly effective and well-tolerated oral treatment protocol for relapsed myeloma.

Proteasome inhibitor immunotherapy for the epithelial to mesenchymal transition: assessing the A549 lung cancer cell microenvironment and the role of M1, M2a and M2c 'hydrocortisone-polarised' macrophages.

BACKGROUND: Lung cancer is a leading cause of cancer-related deaths, primarily as a result of metastases. In this metastasis, the epithelial-to-mesenchymal transition (EMT) is essential. Interaction with the cancer cell microenvironment is primarily dependent on M1- and M2-polarized macrophage. METHODS AND RESULTS: In this study, we revealed the EMT-associated activity of M1, M2a and M2c macrophages in A549 lung cancer cells. We established a co-culture model of A549 lung cancer cells utilizing THP-1-derived M1/M2 polarised macrophages to explore the involvement of macrophages in the immune response, apoptosis, and EMT in lung cancer. Although multiple polarising agents are routinely used for M1 and M2 conversion, we assessed a new possible polarising agent, hydrocortisone. CONCLUSIONS: M1 increased A549 cell sensitivity to proteasome inhibitors and decreased A549 cell viability by inducing apoptosis. EMT was induced in the presence of M2c macrophages in A549 cells by the levels of vimentin, fibronectin, E-cadherin, NF-kB, CCL-17. We also revealed the antiproliferative effects of bortezomib and ixazomib on A549 cells in both 2D and 3D cultures. Our findings could help develop an immunotherapeutic strategy by shedding light on a previously undiscovered part of the EMT pathway. Furthermore, additional investigation may reveal that polarising tumour-associated macrophages to M1 and eliminating the M2a or particularly the M2c subtype are effective anti-cancer strategies.

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma.

BACKGROUND: TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. METHODS: This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. RESULTS: In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9-68.1) and the overall response rate was 84.4% (95% confidence interval 67.2-94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3-not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. CONCLUSIONS: The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. CLINICALTRIALS. GOV IDENTIFIER: NCT02917941; date of registration September 28, 2016.

Ixazomib-associated cardiovascular adverse events in multiple myeloma: a systematic review and meta-analysis.

Prolonged survival and expanded treatment options in myeloma patients have led to adverse events associated with treatment getting increased attention. This systematic review and meta-analysis aimed to determine the incidence of ixazomib-associated cardiovascular adverse events (CVAEs) and to compare the rates of ixazomib-associated CVAEs and related therapies. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and high-grade CVAEs and study characteristics were recorded. A total of 266 potentially relevant articles were identified, and 246 were excluded after review. Twenty studies of 1715 patients with multiple myeloma were thus considered in this study. The estimated rates of all-grade and high-grade ixazomib associated CVAEs were 11.2 and 3.7%, respectively. Subgroup analysis showed that median age ≥65 years, none phase 1 trial and combination regimen were associated with higher rates of high-grade ixazomib associated CVAEs. Ixazomib was association with increased high-grade CVAEs risk (RR = 1.679, 95% CI: 1.078-2.615, P = 0.022). Ixazomib was associated with a significant rate of high-grade CVAEs. Future studies are needed to identify patients at high risk for high-grade CVAEs.

A phase II trial of continuous ixazomib, thalidomide and dexamethasone for relapsed and/or refractory multiple myeloma: the Australasian Myeloma Research Consortium (AMaRC) 16-02 trial.

We evaluated the efficacy and tolerability of continuous ixazomib-thalidomide-dexamethasone (ITd: 4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly). A total of 39 patients with relapsed/refractory multiple myeloma (RRMM) aged ≥18 years with one to three prior lines of therapy were enrolled from two tertiary centres in Victoria and South Australia, Australia. The overall response rate (ORR) was 56·4% with a clinical benefit rate of 71·8%. The median progression-free survival was 13·8 months [95% confidence interval (CI) 8·2-22·2] and median overall survival was not reached. The median time to best response and duration of response was 3·7 months (95% CI 2·8-10·5) and 18·4 months (95% CI 10·2-31·0) respectively. Prior immunomodulatory drug (IMID) exposure was associated with a lower ORR (40% vs. 73·7%, P = 0·03). Survival outcomes in patients with prior proteasome inhibitor (PI) and/or IMID exposure were similar. Patients received a median (range) of 11 (1-31) cycles of therapy and six patients (15%) remained on therapy at the time of final analysis. Grade 3/4 haematological and non-haematological adverse events were reported in 7·7% and 20·6% of patients respectively. ITd dose reductions were required in 15·4%, 48·7% and 35·9% of patients respectively. The present study demonstrates promising effectiveness and tolerability of ITd as an affordable all-oral PI-IMID approach for RRMM.