Gastrointestinal toxicities of proteasome inhibitor therapy.

PURPOSE: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib. METHODS: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events. RESULTS: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048). CONCLUSION: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.

Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

BACKGROUND: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. METHODS: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. RESULTS: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. CONCLUSION: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.

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.

Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy. For relapsed and refractory MM, a proteasome inhibitor, carfilzomib (CFZ), has become one of the few clinical options. CFZ suffers, nevertheless, metabolic instability and poor bioavailability and may induce severe cardiovascular and renal adverse events. Here, we report that daratumumab (Dar)-decorated polypeptide micelles (Dar-PMs) mediate the targeted delivery of CFZ to CD38-positive MM, effectively boosting its anti-MM efficacy. CFZ-loaded Dar-PMs (Dar-PMs-CFZ) exhibited an average diameter of ca. 80 nm and Dar density-dependent cell endocytosis and anti-MM activity, in which over 6-fold greater inhibitory effect to LP-1 and MM.1S MM cells than nontargeted PMs-CFZ control was achieved at a Dar density of 3.2 (Dar3.2-PMs-CFZ). Interestingly, Dar3.2-PMs-CFZ markedly enhanced the growth inhibition of orthotopic LP-1 MM in mice and significantly extended the median survival time compared with PMs-CFZ and free CFZ (95 days vs 60 and 54 days, respectively). In line with its high MM targetability and anti-MM efficacy, Dar3.2-PMs-CFZ revealed little toxic effects and effectively prevented osteolytic lesions. The antibody-targeted nanodelivery of a proteasome inhibitor appears to be an appealing strategy to treat multiple myeloma.

Proteasome inhibitors as anticancer agents.

INTRODUCTION: The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors. AREAS COVERED: This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The development of selective and potent proteasome inhibitors with improved pharmacological properties is described from the synthesis to their basic biological, and clinical validation. EXPERT OPINION: Proteasome inhibitors have transformed the treatment landscape for hematological malignancies and hold great promise for cancer therapy. Combination therapies targeting multiple pathways, the development of novel inhibitors or 'hybrid-inhibitors,' and the optimization of treatment protocols are key areas for future exploration. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future.

In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management.

Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs.

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

Microangiopathy in multiple myeloma: a case of carfilzomib-induced secondary thrombotic microangiopathy successfully treated with plasma exchange and complement inhibition.

BACKGROUND: Thrombotic microangiopathy (TMA) is a potentially organ and life-threatening condition affecting patients with multiple myeloma (MM). Cases of proteasome inhibitor-induced TMA and specifically carfilzomib-induced TMA have been rarely reported and standards for diagnostic workup and treatment are not available. CASE PRESENTATION: We describe a case of a male MM patient under salvage therapy including proteasome inhibitor carfilzomib following chemotherapy and autologous stem cell transplantation. The patient then developed acute kidney injury with clinical and laboratory signs of TMA. Hemodialysis became necessary and treatment with plasma exchange was initiated followed by therapy with C5 complement inhibitor eculizumab which led to amelioration of kidney function and hemolysis parameters. CONCLUSION: We report a patient with suspected proteasome inhibitor-induced secondary thrombotic microangiopathy that has been successfully treated with plasma exchange and eculizumab, a monoclonal antibody targeting complement factor C5.

Cardiac toxicities in multiple myeloma: an updated and a deeper look into the effect of different medications and novel therapies.

With the continuous improvement in survival of cancer patients, including those with multiple myeloma, related to the novel treatment agents and therapeutic approaches, the probability for patients to develop cardiovascular disease has significantly increased, especially in elderly patients and those with additional risk factors. Multiple myeloma is indeed a disease of the elderly population and so these patients are, solely by age, at an increased risk of cardiovascular disease. Risk factors for these events can be patient-, disease- and/or therapy-related, and they have been shown to adversely impact survival. Cardiovascular events affect around 7.5% of patients with multiple myeloma and the risk for different toxicities has considerably varied across trials depending on patients' characteristics and treatment utilized. High grade cardiac toxicity has been reported with immunomodulatory drugs (odds ratio [OR] around 2), proteasome inhibitors (OR 1.67-2.68 depending on the specific agent, and generally higher with carfilzomib), as well as other agents. Cardiac arrhythmias have also been reported with various therapies and drug interaction plays a significant role in that setting. Comprehensive cardiac evaluation before, during and after various anti-myeloma therapy is recommended and the incorporation of surveillance strategies allows early detection and management resulting in improved outcomes of these patients. Multidisciplinary interaction including hematologists and cardio-oncologists is critical for optimal patient care.

Cardiac Adverse Events Associated with Multiple Myeloma Patients Treated with Proteasome Inhibitors.

BACKGROUND: Proteasome inhibitors (PIs) are standard treatments for multiple myeloma (MM). The risk of cardiac adverse events (CAEs) with PIs has been documented with bortezomib and carfilzomib; however, only a few studies have been reported on ixazomib. Furthermore, the effects of concomitant medications including dexamethasone and lenalidomide remain unclear. OBJECTIVES: This study aimed to determine the safety signals of adverse events related to CAEs, the effect of concomitant medications, the time to the occurrence of CAEs, and the incidence of fatal clinical outcomes after the occurrence of CAEs for three PIs using the US Pharmacovigilance database. METHODS: We examined 1,567,240 cases of 231 drugs registered as anticancer drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1997 to March 2021. We compared the odds of developing CAEs between patients who received PIs and those who received non-PI anticancer drugs. RESULTS: Bortezomib treatment resulted in significantly higher reporting odds ratios (RORs) for cardiac failure, cardiac failure congestive, and atrial fibrillation. Carfilzomib treatment resulted in significantly higher RORs for cardiac failure, congestive cardiac failure, atrial fibrillation, and QT prolonged. However, no adverse event CAE signals were observed with ixazomib treatment. A signal was detected for the safety of cardiac failure with bortezomib or carfilzomib, regardless of the presence or absence of concomitant medications. Safety signals for cardiac failure congestive with bortezomib and for cardiac failure congestive, atrial fibrillation, and QT prolonged with carfilzomib were observed only with dexamethasone combination therapy. Co-administration of lenalidomide and its derivatives did not affect the safety of bortezomib and carfilzomib. CONCLUSION: We identified CAE safety signals for bortezomib and carfilzomib exposure when compared with 231 other anticancer agents. The safety signal for developing cardiac failure for both the drugs did not differ between patients with and without concomitantly administered medications.

Chemotherapy-Associated Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.

Carfilzomib-induced Thrombotic Microangiopathy: A Case Based Review.

Carfilzomib is an irreversible proteasome inhibitor currently approved for the treatment of relapsed multiple myeloma. It has been implicated as a cause of thrombotic microangiopathy (TMA) in several case reports. The incidence, risk factors, and treatment of carfilzomib-related TMA remain unclear. Here we describe the clinical presentation and outcome of a 58-year-old man with biopsy-proven TMA that occurred following treatment with carfilzomib-based therapy. We also reviewed the published literature with regard to the incidence, risk factors, treatment options, and outcome of carfilzomib-related TMA.

Cardiovascular Toxicity of Proteasome Inhibitors in Multiple Myeloma Therapy.

The treatment for multiple myeloma has advanced significantly over the past few decades. Proteasome inhibitors have become the cornerstone of the treatment of multiple myeloma. However, proteasome inhibitors have shown cardiovascular complications such as hypertension, pulmonary hypertension, heart failure, arrhythmias, ischaemic heart disease and thromboembolism. Detection, monitoring and management of proteasome inhibitor-related cardiovascular toxicity are essential to improve clinical outcomes for patients. Proposed mechanisms of proteasome inhibitor-related cardiovascular toxicity are apoptosis, prolonged inhibition of the ubiquitin-proteasome system, accumulation of improperly folded proteins within cardiomyocytes and higher protein phosphatase 2A activity. To better understand the mechanisms underlying cardiotoxicity, further in vitro and in vivo experiments are required to investigate these hypotheses. Combined use of metformin or angiotensin II receptor blockers with the proteasome inhibitor, carfilzomib, showed an emerging role as a prophylactic therapy because they can preserve heart function in multiple myeloma patients. Metformin is expected to be an effective therapeutic intervention for the management of carfilzomib-induced cardiotoxicity. There has been evidence that three compounds, apremilast, rutin, and dexrazoxane, can reverse carfilzomib-induced cardiotoxicity in rats. The future transition from animal experiments to clinical trials is worth waiting for.

An update on the safety of ixazomib for the treatment of multiple myeloma.

INTRODUCTION: Treatment options for multiple myeloma (MM) have rapidly expanded over the past few years with several newly approved drugs. While there is need to explore treatments that lead to longer responses and survival, special consideration should be given on reducing treatment burden, reducing toxicities, and improving quality of life. Ixazomib is the first oral proteasome inhibitor for the treatment of MM, combining clinical efficacy with a favorable safety profile. AREAS COVERED: Here, we discuss the clinical efficacy and safety of ixazomib. Pharmacokinetic considerations, management of common toxicities, and the impact of the drug on the current and future treatment strategies are also discussed. EXPERT OPINION: Ixazomib is an effective and welltolerated MM drug. It is also being studied in combination with other newer agents. It does not have long-term cumulative toxicities, and the most adverse events are mild and manageable. These findings, along with the ease of oral administration, make it a possible option for long-term treatment approaches for MM patients, as well as in the frail/elderly patient population.

Ixazomib With or Without Rituximab Following Maintenance Autologous Stem Cell Transplant in Mantle Cell Lymphoma: A Single-Center Phase I Trial.

BACKGROUND: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard first-line treatment for fit patients with mantle cell lymphoma (MCL). We conducted a single-center phase I trial investigating post-transplant maintenance with ixazomib, an oral proteasome inhibitor. METHODS: Patients enrolled between days +70 and +180 post ASCT. Patients received ixazomib per dose cohort on days 1, 8, and 15 of each 28-day cycle for up to 10 cycles. During recruitment, published phase III data reported a survival benefit with rituximab maintenance, so all subsequent patients received ixazomib 4 mg at the same schedule along with rituximab 375 mg/m2 on day 1 of cycles 1, 3, 5, 7, and 9. All patients were in complete remission at enrollment. RESULTS: Seven patients received ixazomib monotherapy; 1 dose limiting toxicity (grade 3 neutropenia) occurred at dose level 2 (4 mg). Five patients received combination Ixazomib plus rituximab, with 2 experiencing DLTs (both Grade 4 neutropenia). Grade 3-4 neutropenia, lymphopenia, and thrombocytopenia occurred in 57%, 8%, and 8% of patients, respectively. Non-hematologic adverse events (AE) included nausea (42%), peripheral neuropathy (42%), and abdominal discomfort (33%), all of which were grade 1 or 2 in severity. There were no infectious AEs. With a median follow up of 46 months, all patients are alive and in complete remission. CONCLUSION: The trial was closed to further accrual due to high rates of treatment-related myelosuppression. The current dose and schedule of ixazomib, especially when combined with rituximab, results in unacceptable hematologic toxicity when administered as post-transplant maintenance in MCL. Ixazomib maintenance micro abstract: The authors conducted a phase I study investigating the use of ixazomib, an oral proteasome inhibitor, with or without rituximab in patients with mantle cell lymphoma in first remission following chemoimmunotherapy and autologous stem cell transplantation. All patients treated on study remain in complete remission with a median follow-up of 46 months, but the study was closed early due to a high rate of hematologic adverse events.

Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: a patent review from 1998 to 2021.

INTRODUCTION: Leishmaniasis is a neglected tropical infectious disease. The available limited therapeutic options for leishmaniasis are inadequate due to their poor pharmacokinetic profile, resistance, toxicity, high cost, and compliance problems. This warrants identification of new targets for the development of safer and effective anti-Leishmania therapy. The kinetoplastid specific proteasome (KSP) is a novel validated target to develop drugs against leishmaniasis. AREA COVERED: This review focuses on all the published patent applications and granted patents related to the studied small molecules as KSP inhibitors (KSPIs) against Leishmania from 1998 to 31 December 2021. EXPERT OPINION: A little amount of work has been done on KSPIs, but the study results are quite encouraging. LXE408 and GSK3494245 are two KSPIs in different phases of clinical trials. Some other small molecules have also shown KSP inhibitory potential, but they are not in clinical trials. The KSPIs are promising next-generation orally active patient compliant drugs against kinetoplastid diseases, including leishmaniasis. However, the main challenge to discover the KSPIs will be the resistance development and their selectivity against the proteasome of eukaryotic cells.

Oral ixazomib-dexamethasone vs oral pomalidomide-dexamethasone for lenalidomide-refractory, proteasome inhibitor-exposed multiple myeloma: a randomized Phase 2 trial.

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535-1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547-2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368-1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.

Influenza-induced thrombotic microangiopathy in a patient with cancer on proteasome inhibitor: a diagnostic dilemma.

Thrombotic microangiopathy (TMA) in a cancer patient is a common complication of either cancer itself or anticancer therapy. Incidence of TMA from anticancer therapy was found to be > 15%, since the introduction of anti-angiogenic drugs like anti-vascular endothelial growth factor agents. It is, however, important to not ignore other causes of TMA such as bacteria, viruses, antiplatelet drugs, hereditary complement mutations, and autoimmune disorders. We present such a diagnostic dilemma in our patient who was admitted with influenza and was found to have TMA on renal biopsy, while on proteasome inhibitor (PI) therapy. With this case, we would like to highlight the importance of understanding the true cause of TMA to avoid unwarranted long-term discontinuation of life saving anti-cancer drugs after TMA resolution.