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Abstract Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression‐free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0–4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE‐MM2 receiving ixazomib‐lenalidomide‐dexamethasone (IRd) (n = 351) or placebo‐Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo‐Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo‐Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor‐immunomodulatory drug‐steroid combination is not a negative predictor of outcome.

ABSTRACTObjectives In the absence of head-to-head comparisons across relapsed/refractory multiple myeloma (RRMM) treatments following the approval of the oral proteasome inhibitor ixazomib, in combination with lenalidomide and dexamethasone (IRd), we conducted an indirect comparison of the efficacy of IRd relative to several RRMM therapies using Bayesian fixed-effects network meta-analysis (NMA) models.Methods Data for the NMA were obtained through a systematic literature review (conducted in June 2020), which identified randomized controlled trials (base case) and observational studies (extended network analysis) reporting overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).Results In the base case, IRd was associated with a significantly longer PFS than lenalidomide and dexamethasone (Rd), bortezomib monotherapy (V), dexamethasone (Dex), and pomalidomide and dexamethasone (Pom-dex), a significantly shorter PFS than daratumumab, lenalidomide, and dexamethasone (DRd), and a PFS comparable to elotuzumab, lenalidomide, and dexamethasone (ERd) and carfilzomib, lenalidomide, and dexamethasone (KRd). IRd was associated with a significantly longer OS than V, Dex, and Pom-dex, and an OS comparable to Rd, ERd, KRd, and DRd. The ORR of IRd was significantly higher than Rd, V, and Dex, significantly lower than KRd and DRd, and comparable to Pom-dex and ERd. The extended network analyses and sensitivity analyses were consistent with the base case.Discussion This NMA shows that IRd is relatively efficacious among RRMM treatments. Being an oral regimen, IRd is also convenient to manage.Conclusion IRd could be a preferable treatment option for many patients with RRMM, particularly those seeking an efficacious and convenient therapeutic option.

Abstract Background To compare the response and safety of Ixazomib/Lenalidomide/Dexamethasone (IRd) and Bortezomib/Lenalidomide/Dexamethasone (VRd) treatment in newly diagnosed multiple myeloma (MM). Methods This was a single‐center retrospective analysis in Xiangtan Central Hospital. A total of 52 newly diagnosed MM patients from June 2019 to June 2021 were enrolled and divided into the IRd (n = 21) and VRd (n = 31) groups. After 4 cycles of chemotherapy, the best response and adverse events were recorded. Moreover, the progression‐free survival (PFS) and overall survival (OS) were calculated. Results Patients in IRd group and VRd group showed similar PFS (Log‐rank p = 0.70), OS (Log‐rank p = 0.61) and overall response rate (83.87% vs 90.48%, p = 0.803). In addition, patients in VRd group showed lower Eastern Cooperative Oncology Group scores (p = 0.047), and higher incidence of peripheral sensory neuropathy (0.00% vs 19.35%, p = 0.032) than that of patients in IRd group. Conclusion Compared to VRd regimen, IRd had the similar efficacy, better safety, and may be more convenient for patients with poor basic condition for newly diagnosed MM. This study provides an insight for physicians to use IRd as first‐line treatment in MM.

Summary: Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

Abstract Ixazomib‐lenalidomide‐dexamethasone (ixazomib‐Rd) showed clinical efficacy over placebo‐Rd in patients with relapsed/refractory multiple myeloma (MM) in the TOURMALINE‐MM1 trial. Over a median follow‐up of ∼85 months, as patients showed disease progression, they received subsequent novel therapies that confounded the overall survival (OS) benefit. Here, we conducted a post hoc analysis in 148 patients from seven countries defined as emerging markets, with limited access to novel therapies for MM during the trial period, to describe the impact of these therapies on OS. Patients were randomised to ixazomib‐Rd (n = 71) or placebo‐Rd (n = 77). The median progression‐free survival (PFS) was 18.7 versus 10.2 months, with ixazomib‐Rd versus placebo‐Rd (hazard ratio [HR], 0.504; p = 0.008) demonstrating a statistically significant improvement as observed in the primary trial. The median OS improved by 32.6 months with ixazomib‐Rd over placebo‐Rd (63.5 vs. 30.9 months; HR, 0.794; p = 0.261); however, the statistically significant benefit seen in PFS was not observed for OS. Improvement with ixazomib‐Rd over placebo‐Rd was observed in overall response (81.7% vs. 64.9%; odds ratio [OR], 2.38; p = 0.019) and complete response (22.5% vs. 3.9%; OR, 7.57; p < 0.001). Patient‐reported quality of life and use of subsequent therapies were similar across treatment groups. No new safety concerns were identified. Compared with the main cohort, median OS was 10 months longer with ixazomib‐Rd and 21 months shorter with placebo‐Rd in this subgroup, indicating a clinically meaningful survival benefit of ixazomib‐Rd treatment in this patient population with limited access to subsequent novel therapies.

Abstract In this work, the preparation of a PEG@ multi-walled carbon nanotubes (MWCNTs) composite has shown a great potential effect in tumor therapy using graphite powder at room temperature. PEGylated MWCNTs were created and used as a carrier for targeting the antineoplastic drug Ixazomib to myeloma cancer cells (abnormal plasma cells). Ixazomib (MLN2238) was covalently encapsulated into functionalized carbon nanotubes modified with polyethylene glycol (PEG 600) to obtain MWCNTs-PEG-MLN2238. The Ixazomib@ MWCNTs-PEG composite shows promising results as an effective nanocarrier and using a small amount of MWCNTs-PEG-Ixazomib that has a low toxicity compared with that of Ixazomib alone. A multifunctional MWCNTs-PEG-Ixazomib composite is used to test biological effects on multiple myeloma cell lines RPMI 8226 using the MTT assay to enhance treatment efficiency. The cytotoxicity of free Ixazomib citrate (69% cell viability of RPMI8226 cells) was higher than that of MWCNTs-PEG-Ixazomib (91% cell viability) at the same maximum concentration of Ixazomib citrate (50 µg/ml). In this work, we performed a study of preparation of MWCNTs with an acceptable Ixazomib loading efficiency and determination of the drug systemic toxicity for the first time. In this study, the preparation of MWCNTs with acceptable Ixazomib loading efficiency and determination of the drug systemic toxicity was performed for the first time. The MTT assay results show decreasing the toxicity of Ixazomib after loading with the MWCNTs-PEG composite. The MWCNTs-PEG @ Ixazomib show promising results as an effective carrier of Ixazomib and lead to a decrease in the cost of using Ixazomib. Graphical Abstract

Abstract Background Maintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long‐term use. An efficacious, tolerable, and convenient PI option is needed. Methods In this single‐center, real‐world study, we retrospectively analyzed the outcome and safety profile of ixazomib‐based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib‐based induction therapy in MM patients not undergoing transplantation. Results Of all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6–14) of bortezomib‐based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2–25) of ixazomib‐based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow‐up, median progression‐free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p

IntroductionMedullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.Aim of the studyThis review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC.Materials and methodsWe performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.ResultsOur search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.ConclusionWe found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials’ implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients’ outcome and survival.

Proteasome inhibitors and immunomodulators (IMiDs), primarily bortezomib and lenalidomide, are essential components of treatment for both newly diagnosed and relapsed/refractory multiple myeloma (MM), producing high response rates and resulting in improved overall survival. However, bortezomib often induces a dose-limiting toxicity in the form of peripheral neuropathy (PN). Neurotoxicity often affects patient’s quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, vitamin B12 deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Usually, bortezomib-induced PN is a sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution while motor neuropathy is less frequently observed. Dose adjustment of bortezomib could be necessary during treatment. Anticonvulsants (pregabalin, gabapentin, carbamazepine, etc.) and tricyclic antidepressants (amitriptyline) are most often used to relieve neurological pain. In this review we focus on the clinical manifestations of bortezomibinduced PN, current understanding of the pathophysiological mechanisms as well as clinical and pharmacological aspects of prevention and management this complication. New proteasome inhibitors such as ixazomib and carfilzomib do not have the neurotoxicity of bortezomib. An early switch within the class of proteasome inhibitors from bortezomib to oral ixazomib appears to be an important approach to prevent severe PN. Our own clinical case of an early switch from bortezomib-based induction to IRd triplet (ixazomib, lenalidomide, dexamethasone) is cited as an illustration of the success of this approach.

Introduction and objective Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM. Material and methods Nine patients aged 52–82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months. Results One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses. Conclusions Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

Abstract 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.

Kai Ding ,* Hong Yu ,* Yuan-Yuan Shao, Li-Yan Li, Chao-Meng Wang, Jia Song, Li-Juan Li, Rong Fu Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong Fu Tel +86-18622008752Email florai@sina.comObjective: To assess the short-term efficacy and safety of ixazomib in Chinese multiple myeloma (MM) patients in the real world.Methods: Fifty-nine MM patients who received at least one cycle of ixazomib-based therapy between 1 June 2018 and 30 September 2019 were retrospectively analyzed in Tianjin Medical University General Hospital. Thirteen newly diagnosed MM (NDMM), 13 refractory/relapsed MM (RRMM) and 33 continuous therapy (27 bortezomib peripheral neuritis (PN) intolerant and six maintenance therapy) MM patients were included. The indicated overall response rate (ORR), time to overall response (TOR), and adverse events (AEs) were investigated.Results: The ORR in NDMM was 76.9%, with one complete response (CR), five very good partial response (VGPR), four partial response (PR), median PFS, and TOR were 122 (66– 272) days and 49 (22– 108) days. The ORR in RRMM was 46.2%, with one CR, two VGPR, three PR, median PFS, and TOR were 79 (28– 169) days and 59 (23– 88) days. The ORR in continuous therapy MM patients was 100%, with nine stringent CR, 15 CR, six VGPR and three PR, median TOR was 75 (25– 141) days. There were no significant differences regarding ORR between patients with cytogenetic high risk and standard risk in three subgroups (all P> 0.05). The most frequent hematological AEs were anemia (13.6%) and thrombocytopenia (10.2%). The most common nonhematological AEs were PN (25.0%) and diarrhea (13.6%).Conclusion: The real-world data demonstrated that ixazomib-based therapy was generally effective and safe in the short term for MM patients.Keywords: multiple myeloma, ixazomib, real world, overall response rate, adverse events

The prognosis for patients with multiple myeloma has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens, and improved management of toxicities. Treatment of relapsed or refractory multiple myeloma represents a vital aspect of the overall care for patients with multiple myeloma and a critical area of ongoing biologic and clinical research. The choice of regimen at relapse is usually based on the prior response, toxicities, assessment of prognostic factors, age and comorbidities of individual patients, their somatic condition and expected effectiveness and tolerability. The new drugs, such as ixazomib, carfilzomib, pomalidomide, daratumumab and elotuzumab in combinations in doublet or triplet regimens, have greatly increased the treatment armory against myeloma. Long-term continuous therapies as a new strategy for relapsed or refractory multiple myeloma have been shown to provide an eradicating of minimal residual disease and deep prolong responses, with the goal of improving progression-free survival and overall survival. The integration of novel agents into the treatment paradigm has shifted the perception of multiple myeloma from an incurable fatal disease to a manageable chronic one. This review discusses the most recent and effective regimens for the relapsed or refractory multiple myeloma treatment, based on the results of recently published phase II and III clinical trials. Analyses the current clinical trial data discussed with a focus on lenalidomide or bortezomib as a basis of new treatment regimens.

Background: Achieving a functional or sterilizing cure for HIV will require identification of therapeutic interventions that reduce HIV reservoir size in infected individuals. Proteasome inhibitors, such as ixazomib, impact multiple aspects of HIV biology including latency, transcription initiation, viral replication, and infected cell killing through the HIV protease – Casp8p41 pathway, resulting in latency reversal and reduced measures of HIV reservoir size ex vivo. Methods: We conducted a phase 1b/2a dose escalating, open label trial of weekly oral ixazomib for 24 weeks in antiretroviral (ART)-suppressed, HIV positive adults (NCT02946047). The study was conducted from March 2017 to August 2019 at two tertiary referral centers in the United States. The primary outcomes were safety and tolerability of oral ixazomib. Secondary outcomes included changes in immunologic markers and estimates of HIV reservoir size after ixazomib treatment. Findings: Sixteen participants completed the study. Ixazomib up to 4mg weekly was safe and well-tolerated, yielding no treatment-emergent events above grade 1. In exploratory analyses, ixazomib treatment was associated with detectable viremia that was below the lower limit of quantification (LLQ) in 9 participants, and viremia that was above LLQ in 4 of 16 participants. While treatment was associated with reduced CD4 counts [baseline 783 cells/ mm3 vs. week-24 724 cells/ mm3 p=0.003], there were no changes in markers of cellular activation, exhaustion or inflammation. Total HIV DNA and proviral sequencing were not altered by ixazomib treatment. Intact proviral DNA assay (IPDA) identified intact proviruses in 14 patients pre-treatment, and in 10/14 of those subjects post treatment values were reduced (P=0.068), allowing a calculated intact proviral half life of 0.6 years (95% CI 0.3, 2.5), compared to 7.1 years (95% CI 3.9, 18, p=0.004) in historical controls. Differentiation Quantitative Viral Outgrowth Assays (dQVOA) identified measurable proviruses in 15 subjects pre-treatment; post-treatment values were numerically reduced in 9, but overall differences were not significantly different. Interpretation: Our study successfully met its primary endpoint of demonstrating the safety of ixazomib for 24 weeks in HIV infected persons. Exploratory analyses suggest that the effects observed ex vivo of latency reversal and reductions in HIV reservoir size, also occur in vivo. Future controlled studies of ixazomib are warranted. Funding: This study was funded by Millennium Pharmaceuticals Inc..; the Mayo Clinic Foundation; the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, Division of AIDS, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse. Mayo Clinic also acknowledges generous funding support from Mr. Joseph T. and Mrs. Michele P. Betten.

Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy. The prognosis of ALL is excellent in paediatric population, however the outcome of relapse/refractory disease is dismal. Adult ALL has less favourable prognosis and relapse/refractory disease is not uncommonly encountered. Bortezomib is the first generation proteasome inhibitor licensed to treat plasma cell myeloma and mantle cell lymphoma with favourable side effect profile. Efficacy of bortezomib had been proven in other solid tumors. Clinical studies showed promising response for proteasome inhibitors in treating relapse/refractory ALL. Thus, proteasome inhibitors are attractive alternative agents for research in treating ALL. In the review article, we will introduce different proteasome inhibitors and their difference in pharmacological properties. Moreover, the mechanism of action of proteasome inhibitors on ALL will be highlighted. Finally, results of various clinical studies on proteasome inhibitors in both paediatric and adult ALL will be discussed. This review article provides the insights on the use of proteasome inhibitors in treating ALL with a summary of mechanism of action in ALL which facilitates future research on its use to improve the outcome of ALL.

Abstract Elevated NF‐kB levels have been identified in primitive bone marrow cells from patients with MDS/AML, suggesting NF‐kB as a therapeutic target in MDS/AML. We herein describe an MDS patient ineligible for SCT who, following treatment with azacitidine and bortezomib, transformed to leukemia, but maintained complete remission after monotherapy with ixazomib.

The landscape of multiple myeloma treatment transformed at the last 15 years by the introduction of novel agents (bortezomib, lenalidomide) and wide application of autologous hematopoietic stem cell transplantation, which have prolonged the survival of multiple myeloma patients. Despite the fact that multiple myeloma remains an incurable disease due to the new options, the median overall survival of patients with multiple myeloma in Russia in 2006–2016 was about 55–68 months. Drug resistance and clonal evolution remain a problem. The novel proteasome inhibitors (carfilzomib, ixazomib) differ in chemical structure and pharmacological characteristics. Thereby the next-generation proteasome inhibitor (IPs)-based regimens (KRd (carfilzomib, lenalidomide, dexamethasone), IRd (ixazomib, lenalidomide, dexamethasone), and Kd (carfilzomib, dexamethasone)) are emerging as new standards for the treatment of patients with relapsed and/or refractory multiple myeloma. In a randomized trial phase 3 ENDEAVOR, carfilzomib demonstrated improved survival in direct comparison to bortezomib. The dose-dependent activity of carfilzomib demonstrated in the study of A.R.R.O.W. Аctivity of ixazomib is comparable to that of bortezomib, the oral method of administration and the absence of neurological toxicity, allow for long-term control of the disease. The new PIs are an important advance in relapsed and/or refractory multiple myeloma treatment, increasing survival, response rate and quality of life, even in subgroups of patients with poor prognosis. This review summarizes the main pharmacological properties, mechanisms of action and clinical outcomes of major clinical studies with these agents. A separate issue discusses the problem of overcoming new proteasome inhibitors of drug resistance to bortezomib.

The emergence of significant arboviruses and their spillover transmission to humans represent a major threat to global public health. No approved drugs are available for the treatment of significant arboviruses in circulation today. The repurposing of clinically approved drugs is one of the most rapid and promising strategies in the identification of effective treatments for diseases caused by arboviruses. Here, we screened small-molecule compounds with anti-tick-borne encephalitis virus, West Nile virus, yellow fever virus and chikungunya virus activity from 2580 FDA-approved drugs. In total, 60 compounds showed antiviral efficacy against all four of the arboviruses in Huh7 cells. Among these compounds, ixazomib and ixazomib citrate (inhibitors of 20S proteasome β5) exerted antiviral effects at a low-micromolar concentration. The time-of-drug-addition assay suggested that ixazomib and ixazomib citrate disturbed multiple processes in viruses’ life cycles. Furthermore, ixazomib and ixazomib citrate potently inhibited chikungunya virus replication and relieved virus-induced footpad swelling in a mouse model. These results offer critical information which supports the role of ixazomib as a broad-spectrum agent against arboviruses.

Abstract Background Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. Methods Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. Discussion Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. Trial registration EudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.

Multiple myeloma (MM) is a plasma cell disease characterized by a clonal proliferation of malignant plasma cells. Pomalidomide, a novel immunomodulating imide drug (IMiD), prolongs survival in relapsed or refractory cases. Cutaneous toxicity is one of the most common side effects of anti-cancer therapy that may even lead to discontinuation of treatment. We report a case of pomalidomide induced cutaneous lupus-like hypersensitivity reaction in a 75-year-old male diagnosed with MM. The patient relapsed on lenalidomide after 7 years. Pomalidomide and ixazomib were considered the next best treatment options. Treatment was complicated by a generalized rash (grade 3) after 2 cycles (3 weeks on and 1 week off cycle). Multiple pink, dusky plaques on the lower back and abdomen, some light pink and edematous areas on the chest, abdomen, neck, and hairline, and a few on arms were seen. The patient did not report pruritis. There was no involvement of the mucosa. Palms and soles were spared. No prior history of a rash with lenalidomide. A punch biopsy showed a moderate number of eosinophils within the inflammatory infiltrate, a finding which favored a lupus-type hypersensitivity reaction rather than true lupus erythematosus or leukemia cutis. Both medications were discontinued, and topical betamethasone was administered. The patient's symptoms resolved in 2 weeks. Ixazomib single-agent therapy was subsequently resumed without any adverse effects. It is essential to differentiate between disease progression itself vs. drug-induced lupus hypersensitivity reaction vs. systemic lupus erythematosus (SLE) vs. drug-induced hypersensitivity reaction. Therefore, all such lesions should always be biopsied. Our case study is unique because of the incongruent timeline and because it is unusual to expect such a reaction in a patient who has previously tolerated one such treatment. In our case, punch biopsy showed that the patient had a lupus-like hypersensitivity reaction. Pomalidomide was determined to be the most likely trigger preceding his presentation. Timely identification of the culprit drug is critical. The mainstay of management is to discontinue the drug. In severe cases, systemic steroids can be considered.

Abstract Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types.

Ixazomib (NINLARO, Takeda Pharmaceutical Company Limited) is the first oral proteasome inhibitor which approved in combination with lenalidomide and dexamethasone (IRd) for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is a boron-containing selective and reversible proteasome inhibitor that have high antitumor activity with excellent safety. This combination was approved based on the results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival (PFS) for IRd versus placebo-Rd: median: 20.6 vs 14.7 months; hazard ratio (HR): 0.74, P = 0.012. PFS was improved in both high-and standard-risk cytogenetics subgroups with median PFS in high-risk patients 21.4 vs 9.7 months (HR 0.54; P = 0.021) and in standard-risk patients 20.6 vs15.6 months (HR 0.64; P = 0.007). The addition of ixazomib to Rd regimen was associated with minimal additional toxicity. Common grade ≥3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. No significant inhibition of neuronal cell survival protease HtrA2/Omi was noted in response on ixazomib treatment in vitro that explains its minimal clinical peripheral neuropathy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patient and the prospects for further expansion of therapeutic indications.

Paul G Richardson,1 Shaji Kumar,2 Jacob P Laubach,1 Claudia Paba-Prada,1 Neeraj Gupta,3 Deborah Berg,3 Helgi van de Velde,3 Philippe Moreau4 1Division of Hematologic Malignancy, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA; 2Division of Hematology, Mayo Clinic, Rochester, MN, USA; 3Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA; 4Hematology Department, University Hospital Hotel-Dieu, Nantes, France Abstract: Ixazomib is the first oral proteasome inhibitor to be approved, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was on the basis of results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival with the all-oral combination of ixazomib plus lenalidomide–dexamethasone versus lenalidomide–dexamethasone alone (median: 20.6 vs 14.7 months; hazard ratio: 0.74, p=0.012; median follow-up 14.7 months). The addition of ixazomib to the lenalidomide–dexamethasone regimen was associated with limited additional toxicity and had no adverse impact on patient-reported quality of life. Common grade ≥3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. Here, we review the efficacy, safety, pharmacokinetics, and patient-reported quality of life data seen with ixazomib, and discuss the role of this oral agent in the treatment of patients with relapsed/refractory multiple myeloma, including in patients with high-risk cytogenetic abnormalities and those with multiple prior therapies. Keywords: ixazomib, multiple myeloma, proteasome inhibitor, clinical, efficacy, tolerability, pharmacokinetics

Abstract Background The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide–dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. Methods Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd). Results At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%). Conclusions This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. Trial registration ClinicalTrials.gov, NCT01564537

Introduction: The appraisal of medicines is often a complex and iterative process. We compared the health technology assessment (HTA) process in England and France taking as a case study the example of ixazomib for multiple myeloma. Methods: We undertook an analysis of eight relevant published documents identifed from the websites of the French and English HTA bodies (HAS and NICE, respectively). We analyse patients’ availability of ixazomib resulting in the different stages of the appraisal process. Results: We identified differences in the assessment, one of these being the use of an appraisal scope in England allowing the differentiation of populations and comparators according to previously approved treatments. Ixazomib became available earlier in France as part of an early access programme, but the availability was soon discontinued for newly eligible patients following an HAS determination that Ixazomib yielded no additional benefit. This opinion resulted in long pricing discussions. In England, despite the absence of an early access programme and following a process that included cost-effectiveness evaluation combined with pricing discussions, the medicine was fairly rapidly recommended for use. Conclusions: Differences in the HTA process may result in appreciable differences in time from marketing authorisation to health service adoption of newly licensed drugs.

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). The mechanism of action (proteasome subunit inhibition, apoptosis induction) and growth inhibitory potential of IXA vs. BTZ were tested in vitro in human (BTZ-resistant) leukemia cell lines. Ex vivo activity of IXA vs. BTZ was analyzed in 15 acute lymphoblastic leukemia (ALL) and 9 acute myeloid leukemia (AML) primary pediatric patient samples. BTZ demonstrated more potent inhibitory effects on constitutive β5 and immunoproteasome β5i proteasome subunit activity; however, IXA more potently inhibited β1i subunit than BTZ (70% vs. 29% at 2.5 nM). In ALL/AML cell lines, IXA conveyed 50% growth inhibition at low nanomolar concentrations, but was ~10-fold less potent than BTZ. BTZ-resistant cells (150–160 fold) displayed similar (100-fold) cross-resistance to IXA. Finally, IXA and BTZ exhibited anti-leukemic effects for primary ex vivo ALL and AML cells; mean LC50 (nM) for IXA: 24 ± 11 and 30 ± 8, respectively, and mean LC50 for BTZ: 4.5 ± 1 and 11 ± 4, respectively. IXA has overlapping mechanisms of action with BTZ and showed anti-leukemic activity in primary leukemic cells, encouraging further pre-clinical in vivo evaluation.

Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin–proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs significantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug–drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.

Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.

Multiple myeloma is a clonal B-cell malignancy characterized by proliferation of plasma cells that accumulate mainly in bone marrow and usually secrete monoclonal Ig and/or Ig light chains. The history of therapy development in this disease has more than 50 years. After ubiquitin-proteasome system of apoptosis become apparent bortezomib has been included in the mains therapy regimes. Simultaneously, the group of proteasome-inhibitor drugs is continually developing and opening more therapeutic options in refractory or relapse forms.

Barbara Muz,1 Rachel Nicole Ghazarian,1,2 Monica Ou,1,3 Micah John Luderer,1 Hubert Daniel Kusdono,1,2 Abdel Kareem Azab1 1Department of Radiation Oncology, Cancer Biology Division, Washington University in St Louis School of Medicine, 2Department of Pharmaceutical and Administrative Sciences, St Louis College of Pharmacy, 3Department of Biology, St Louis University, St Louis, MO, USA Abstract: Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib. Keywords: proteasome inhibitor, oral administration, biological mechanism, clinical trials

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

Background: The design and development of prodrugs is the most common and effective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected number of prodrugs have been reached the drugs market throughout history and the recent years have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs for an efficient treatment of various ailment. Methods: A Scan conducted to find recent approved prodrugs and prodrugs in development. Results: Selected prodrugs were reported and categorized in accordance to their target systems. Conclusions: the prodrug approach has shown many successes and still remains a viable and effective approach to deliver new active agents. This conclusion is supported by the recent approved prodrugs and the scan of clinical trials conducted between 2013−2018.

It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy. PIs, either the first generation (bortezomib), second generation (carfilzomib) or oral agent (ixazomib), all take advantage of the heavy reliance of myeloma cells on the 26S proteasome for their degradation of excessive or misfolded proteins. Inhibiting the proteasome can create a crisis specifically for myeloma cells due to their rapid production of immunoglobulins. PIs have relatively few side effects and can be very effective, especially in combination therapy. If PI resistance can be overcome, these drugs may prove even more useful to a greater range of patients. Both soluble and insoluble (contact mediated) signals drive PI-resistance via activation of various intracellular signaling pathways. This review discusses the currently known mechanisms of non-autonomous (microenvironment dependent) mechanisms of PI resistance in myeloma cells. We also introduce briefly cell-autonomous and stress-mediated mechanisms of PI resistance. Our goal is to help researchers design better ways to study and overcome PI resistance, to ultimately design better combination therapies.