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.

Lenalidomide, rituximab (R2), and ixazomib for frontline treatment of high risk follicular and indolent non-Hodgkin lymphoma.

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients.

Real-world effectiveness and safety of abrocitinib in 12 Japanese patients with atopic dermatitis and transcriptome analysis with peripheral blood.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, pruritic, and localized eczema. Various types of new drugs have been recently investigated for treating AD. The efficacy and safety of abrocitinib in treating AD has been reported in clinical trials, but the real-world data from Japan has not been reported. Herein, we analyzed 12 Japanese patients with AD treated with 100 mg of abrocitinib using our real-world data. We also performed transcriptome analysis with peripheral blood to investigate the effects of abrocitinib on cytokine expressions and inflammatory pathways in AD from three patients. This study included patients with moderate to severe AD treated with abrocitinib at Gunma University Hospital, Japan. All patients were systemic treatment-naïve. All patients received a 100-mg dose of abrocitinib daily, and used strong or very strong topical steroids and moisturizers. The Eczema Area and Severity Index (EASI) response analysis revealed that after 4 weeks, 25% (three of 12) of the cases reached a 75% reduction in the EASI score (EASI-75) and a 90% reduction in the EASI score (EASI-90). After 12 weeks, 83.3.% (10 of 12), 41.6% (five of 12), and 16.7% (two of 12) of the patients reached EASI-50, a 75% reduction in the EASI score (EASI-75), and EASI-90. Peak Pruritus Numerical Rating Scale was achieved in nine patients (75%) at week 12. The most frequent adverse reaction was acne (six cases [50%]). Gene Ontology pathway analysis using Differentially expressed genes from RNA sequencing analysis revealed attenuation of defense responses to biotic stimulus, virus, and cytokines. Th2 cytokine expression was not suppressed, but several chemokines, especially CXCL1, were suppressed by abrocitinib treatment. Our results indicate abrocitinib as a fast-acting and highly antipruritic agent that is effective for moderate skin eruptions.

Efficacy and safety of crisaborole ointment, 2%, in participants aged ≥45 years with stasis dermatitis: Results from a fully decentralized, randomized, proof-of-concept phase 2a study.

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal topical phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis. OBJECTIVE: To evaluate the efficacy and safety of crisaborole in stasis dermatitis (SD). METHODS: In this randomized, double-blind, vehicle-controlled, decentralized phase 2a study (NCT04091087), 65 participants aged ≥45 years with SD without active ulceration received crisaborole or vehicle (1:1) twice-daily for 6 weeks. The primary end point was percentage change from baseline in total sign score at week 6 based on in-person assessment. RESULTS: Crisaborole-treated participants had significantly reduced total sign score from baseline versus vehicle based on in-person (nondermatologist) assessment (-32.4% vs -18.1%, P = .0299) and central reader (dermatologists) assessment of photographs (-52.5% vs -10.3%, P = .0004). Efficacy according to success and improvement per Investigator's Global Assessment score and lesional percentage body surface area reached statistical significance based on central reader but not in-person assessments. Skin and subcutaneous tissue disorders were common all-causality treatment-emergent adverse events with crisaborole. LIMITATIONS: Small sample size and short treatment duration were key limitations. In-person assessment was not conducted by dermatologists. CONCLUSION: Crisaborole improved signs and symptoms of SD and was well tolerated. Central reader assessment represents a promising approach for siteless clinical research.

Impact of Crisaborole in Treatment-Experienced Patients With Mild-to-Moderate Atopic Dermatitis.

Background: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of patients with mild-to-moderate atopic dermatitis (AD). Objective: To assess the efficacy and safety of crisaborole in patients with AD who had received prior treatment with (a) corticosteroids (systemic or topical) or topical calcineurin inhibitors (TCIs) or (b) topical corticosteroids (TCSs) or TCIs or (c) who were treatment-naive (TN). Methods: This post hoc analysis comprised patients aged ≥2 years with mild-to-moderate AD. Patients were assigned (2:1) to receive crisaborole or vehicle twice daily for 28 days. Patient response was assessed with the Investigator's Static Global Assessment (ISGA), Dermatology Life Quality Index (DLQI), Children's Dermatology Life Quality Index (CDLQI), and Dermatitis Family Impact (DFI) tools. Safety was also assessed. Results: A significantly higher percentage of patients treated with crisaborole versus vehicle achieved ISGA success regardless of treatment history. Patients treated with crisaborole had significant reductions in DLQI, CDLQI, and DFI scores versus those who received vehicle regardless of treatment history, with the exception of DLQI and DFI scores in the TN group. Crisaborole was well tolerated in all subgroups. Conclusion: Crisaborole demonstrated a favorable efficacy and safety profile in both treatment-experienced and TN patients. ClinicalTrials.gov, NCT02118766 and NCT02118792.

A phase II study of ibrutinib in combination with ixazomib in patients with Waldenström macroglobulinaemia.

This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

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).

Dose Titration of Ixazomib Maintenance Therapy in Transplant-Ineligible Multiple Myeloma: Exposure-Response Analysis of the TOURMALINE-MM4 Study.

Ixazomib has been approved in several countries as single-agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant-ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1-4. Here, we report the results of exposure-response analyses of TOURMALINE-MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression-free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3 mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg. Collectively, these results highlight the value of safety-driven personalized dosing to maximize patient benefit/risk.

Increased Bone Volume by Ixazomib in Multiple Myeloma: 3-Month Results from an Open Label Phase 2 Study.

Multiple myeloma (MM) is an incurable bone marrow cancer characterized by the development of osteolytic lesions due to the myeloma-induced increase in osteoclastogenesis and decrease in osteoblastic activity. The standard treatment of MM often involves proteasome inhibitors (PIs), which can also have a beneficial off-target bone anabolic effect. However, long-term treatment with PIs is unadvised due to their high side-effect burden and inconvenient route of administration. Ixazomib is a new-generation, oral PI that is generally well tolerated; however, its bone effect remains unknown. Here, we describe the 3-month results of a single-center phase II clinical trial investigating the effect of ixazomib treatment on bone formation and bone microstructure. Thirty patients with MM in stable disease not receiving antimyeloma treatment for ≥3 months and presenting ≥2 osteolytic lesions received monthly ixazomib treatment cycles. Serum and plasma samples were collected at baseline and monthly thereafter. Sodium 18 F-Fluoride positron emission tomography (NaF-PET) whole-body scans and trephine iliac crest bone biopsies were collected before and after three treatment cycles. The serum levels of bone remodeling biomarkers suggested an early ixazomib-induced decrease in bone resorption. NaF-PET scans indicated unchanged bone formation ratios; however, histological analyses of bone biopsies revealed a significant increase in bone volume per total volume after treatment. Further analyses of bone biopsies showed unchanged osteoclast number and COLL1A1High -expressing osteoblasts on bone surfaces. Next, we analyzed the superficial bone structural units (BSUs), which represent each recent microscopic bone remodeling event. Osteopontin staining revealed that following treatment, significantly more BSUs were enlarged (>200,000 µm2 ), and the distribution frequency of their shape was significantly different from baseline. Overall, our data suggest that ixazomib induces overflow remodeling-based bone formation by decreasing the level of bone resorption and promoting longer bone formation events, making it a potentially valuable candidate for future maintenance treatment. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma.

Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval [CI]: 0.59-0.93; median PFS [mPFS] 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62-0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64-0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59-0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48-0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63-0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.

Real-world toxicity and effectiveness of ixazomib, lenalidomide, and dexamethasone in Korean patients with relapsed and/or refractory multiple myeloma.

BACKGROUND/AIM: Ixazomib, lenalidomide, and dexamethasone (IRd) have proven efficacy and an excellent safety profile in relapsed and/or refractory multiple myeloma (RRMM). However, there are limited reports on the real-world safety and effectiveness of IRd regimens in Asian patients with RRMM. PATIENTS AND METHODS: This was a retrospective study of 60 patients with RRMM who were treated with IRd. RESULTS: The median patient age was 68 years. Forty percent of patients did not meet the eligibility criteria for the TOURMALINE-MM1 trial. Patients received a median of one prior line of therapy. Non-hematologic adverse events (AEs) were more common than hematologic AEs. The most common AE was skin rash, followed by gastrointestinal toxicities. Most grade 3 or higher AEs were observed in less than 5% of the patients, except for skin rashes and infections. IRd therapy did not aggravate peripheral neuropathy (PN) in 20 of the 24 patients with pre-existing peripheral neuropathy. The overall response rate was 85%. After a median follow-up of 26.3 months, the median progression-free survival was 25.9 months and overall survival was not reached. CONCLUSION: Ixazomib and Rd combination therapy had a comparable toxicity profile and effectiveness in real-world RRMM patients.

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.

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.

Population pharmacokinetic/pharmacodynamic joint modeling of ixazomib efficacy and safety using data from the pivotal phase III TOURMALINE-MM1 study in multiple myeloma patients.

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE-MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time-to-event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M-protein] and progression-free survival [PFS]) outcomes observed in TOURMALINE-MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M-protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M-protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens.

Subgroup Analysis of Crisaborole for Mild-to-Moderate Atopic Dermatitis in Children Aged 2 to < 18 Years.

OBJECTIVES: This post hoc analysis of pooled data from two phase III studies (AD-301: NCT02118766; AD-302: NCT02118792) explored the efficacy and safety of crisaborole ointment, 2%, a nonsteroidal phosphodiesterase 4 inhibitor, for the treatment of mild-to-moderate atopic dermatitis (AD) in pediatric patients (aged 2 to < 18 years) only, stratified by baseline characteristics. METHODS: Pediatric patients with mild or moderate AD per Investigator's Static Global Assessment (ISGA) and percentage of treatable body surface area (%BSA) ≥ 5 at baseline were assessed. Crisaborole or vehicle (2:1 randomization ratio) was applied twice daily for 28 days. Of the 1313 pediatric patients included in this study, 874 received crisaborole and 439 received vehicle. ISGA success was defined as clear (0) or almost clear (1) with ≥ 2-grade improvement from baseline. Efficacy and safety were stratified by age group, sex, baseline ISGA, baseline %BSA per published severity strata, and prior AD therapy. RESULTS: Overall, the proportions of crisaborole-treated and vehicle-treated pediatric patients with ISGA success at week 4 were 32.5 and 21.5%, respectively. ISGA success rates at day 29 (week 4) were generally higher in crisaborole-treated (21.9-38.1%) than vehicle-treated (15.7-26.9%) patients across subgroups. Rates of treatment-related application site pain were 2.4-10.1% for crisaborole-treated patients and 0.6-2.2% for vehicle-treated patients across subgroups. No new safety concerns were noted in any patient subgroup. CONCLUSION: Crisaborole improved global disease severity and was reasonably well tolerated across all pediatric baseline characteristic subgroups. Application site discomfort was greater with crisaborole than with vehicle, but few patients discontinued treatment. GOV REGISTRATION NUMBERS: NCT02118766; NCT02118792 (registration date: April 21, 2014).

Crisaborole is an ointment approved for the treatment of mild-to-moderate eczema. In two phase III clinical trials, eczema improved after 28 days of crisaborole use in patients aged ≥ 2 years. Patients with eczema rashes used crisaborole or plain ointment twice a day for 28 days. The clinical trials excluded patients with serious infections. Eczema treatment within 2 weeks of the trials was not allowed. We looked at whether traits of children aged 2­17 years affected how well crisaborole improved eczema. We studied boys and girls by age and how bad their eczema was at the start of the study. We combined data from both clinical trials to calculate the percentages of children with clear or almost clear skin at day 29. We also studied the frequency of side effects at day 29. After 4 weeks, 33% of children receiving crisaborole compared with 22% of children receiving plain ointment had clear or almost clear skin, a meaningful difference in favor of crisaborole. This was also true across groups. Most patients did not have side effects related to crisaborole. The most common side effect related to crisaborole was application site pain. This side effect occurred in up to one in ten children receiving crisaborole. Up to 1 in 50 patients receiving plain ointment had application site pain. Few children stopped crisaborole treatment, and there were no new safety concerns. In conclusion, compared with plain ointment, crisaborole improved eczema in more children, and side effects were minor.

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.

Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma.

PURPOSE: In this study, the addition of ixazomib to lenalidomide maintenance post-autologous stem cell transplant (ASCT) in 64 patients with newly diagnosed multiple myeloma was evaluated on the basis of the observed benefit of lenalidomide-only maintenance in prior studies. PATIENTS AND METHODS: Patients were started on maintenance therapy with lenalidomide and ixazomib within 60-180 days of stem cell infusion. RESULTS: Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 43% and median overall survival was not reached with a median follow-up of 62 months (range, 25-82 months). Median PFS (mPFS) for all patients was 73 months and has not been reached for those with International Staging System (ISS) stage 1 disease. mPFS in 9 patients who had ISS stage 3 disease and 14 patients who had high-risk cytogenetics was 34 and 25 months, respectively. Twenty-two patients had progressive disease, while 19 patients continue to receive dual maintenance. The most common grade 3/4 adverse events included neutropenia, leukopenia, thrombocytopenia, lung infections, diarrhea, and maculopapular rash. Second primary malignancies occurred in 9 patients. Toxicity led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to toxicity occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. CONCLUSIONS: The addition of ixazomib to lenalidomide maintenance demonstrated a better than expected PFS compared with historical data using lenalidomide alone and was safe and tolerable.