Ixazomib In Combination Research Articles

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

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

Ixazomib, Pomalidomide and Dexamethasone (IxPd) in Relapsed or Refractory Multiple Myeloma (RRMM) Characterized with High-Risk Cytogenetics. IFM 2014-01

Background. High risk (HR) cytogenetic remains of poor prognosis, particularly in the RRMM setting. IFM 2010-02 studied pomalidomide and dexamethasone (Pd) and demonstrated limited activity, with a median TTP overall at 5.5 months, and at 7.3 vs 2.8 months in HR RRMM with deletion17p and t(4;14) respectively. We hypothesized that addition of Ixazomib (oral proteasome inhibitor) at increased dose density to Pd (IxPd) in HR RRMM would improve convenience, thus adherence to treatment, and in parallel improve efficacy with no increased toxicity compared to addition of a parental proteasome inhibitor (PI). Methods. Eligible patients had a RRMM, in L2, refractory to lenalidomide, but not to pomalidomide and ixazomib. HR was defined by presence of either del(17p) and/or t(4;14) at diagnosis or study entry. Patients received 17 induction cycles, 21-days long, consisting of ixazomib 3mg/day (d 1, 4, 8 and 11), pomalidomide 4mg/day (d1 to 14) and weekly dexamethasone, followed by a maintenance phase of 28-day cycles with ixazomib 4mg/day (d 1, 8 and 15) and pomalidomide 4mg/day (d 1 to 21), until progression. The primary endpoint was time to progression (TTP). The number of patients to be recruited was initially calculated based on an expected doubling of the median TTP obtained in IFM 2010-02 in either 2 HR RRMM population. No statistical comparison can be done across HR groups given that the study was powered to analyze the 2 groups as a whole. Results. Twenty-six patients were enrolled in the study. Median age at inclusion was 72 years (IQ. 67-78), median age at diagnosis was 70 years (IQ. 63-74). Twelve patients presented with del(17p), 9 with t(4;14), and 5 with del(17p) and t(4;14), all patients refractory to lenalidomide. One patient received the study medication but died with no post baseline efficacy assessment. Analyses were done on the remaining 25 patients and safety analysis were performed on all the 26 patients having received at least one dose of the study medication. Twenty-two patients had progressed on study (of whom 12 had died at end of study), 2 patients died before progression, and one patient had no death and no progression. Study treatment was permanently interrupted in 9 patients before progression or death, including 8 during the induction phase. With a median follow-up time of 27 months, the primary end-point median TTP for the efficacy analysis cohort (n=25) was 10.1 months (CI95%. 4.4;13). The median PFS and OS were 9.9 (CI95%. 4.2;12.7) months and 23.7 (CI95%. 12.7;inf) months, respectively. At end of induction, ORR and VGPR rate was (n=15) 60% and (n=7) 28%, CBR (n=18) 72%; at end of study the response rates were the same as end of induction. The median TTP and OS for del(17p) was 9.9 (CI95%. 3.3;inf) and 23.7 (CI95%.14.3;inf ) months, respectively; and was 10.5 (CI95%. 7.9;inf) months and not reached (CI95%. 27.1;inf), in the t(4;14) cohort respectively. Median TTP and OS for combined del(17p) and t(4;14) was 5.5 (CI95%. 2.7;inf) and 11.1 (CI95%. 9.9;inf) months respectively. The most common adverse events (10% occurrence) were neutropenia (n=15), thrombocytopenia (n=12), asthenia (n=10), anemia (n=8), rash (n=5), back pain (n=5), diarrhea (n=5), peripheral oedema (n=4), dizziness (n=3), general physical health deterioration (n=3), muscle spasms (n=3), pyrexia (n=3) and peripheral sensory neuropathy (n=3). There was no added safety concerns related to the combination of Ixazomib and Pomalidomide in the study protocol. Conclusion. The study IFM 2014-01 /IxPd in HR L2 Len refractory RRMM met its primary end point objective since we observed a doubling of the median TTP with the addition of Ixazomib to pomalidomide and dexamethasone in this very hard to treat population characterized with a very poor outcome. This data confirms the importance of proteasome inhibitors in HR RRMM. This phase 2 study needs confirmation in a larger cohort.

ATRT-12. HYPERACTIVATING THE INTEGRATED STRESS RESPONSE WITH PROTEASOME INHIBITION IN AT/RT

Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric brain tumor with a poor prognosis. AT/RT has increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate various forms of stress. Elevated expression of ATF4 indicates activation of the ISR. Transient or low-level expression of this transcription factor protects cells from stress, while sustained, high-level activation results in cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. Because AT/RT has a high baseline level of ATF4, we hypothesized that this tumor would be susceptible to ISR activators such as ixazomib. After determining the IC50 of ixazomib, AT/RT cell lines were treated with increasing concentrations of the drug. Cleaved caspase-3 immunofluorescence showed a significant increase of apoptosis (CHLA06 p<0.0001 by ANOVA). We are currently testing ixazomib in combination with idarubicin, a brain-penetrant anthracycline, and gemcitabine, a brain-penetrant nucleoside analog. Synergy testing in CHLA06 showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 with inhibitory concentrations of ixazomib and idarubicin in the low nanomolar range (scores of 10 or above indicate synergy). Similarly, ixazomib and gemcitabine synergized to suppress CHLA06 growth and induce apoptosis (67% Annexin V+ cells in combination compared to 14 and 24% Annexin V+ with single agent treatment). In the future, we will determine if ixazomib selectively kills AT/RT while sparing normal cells in iPSC brain organoids. We will also test ixazomib in orthotopic xenografts of AT/RT. These results suggest that ixazomib, especially in combination with idarubicin, gemcitabine or other ISR activators, has the potential to serve as an effective therapy for AT/RT.

Abstract 6720: Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors

Abstract H3K27-altered diffuse midline glioma (DMG) and atypical teratoid/rhabdoid tumor (AT/RT) are aggressive pediatric brain tumors with dismal outcomes. DMG and AT/RT have increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate various forms of stress. This activation is manifested by elevated levels of ATF4 and NRF2 in DMG and AT/RT, respectively. Transient or low-level expression of these transcription factors protect cells from stress, while sustained, high-level activation leads to cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. We hypothesized that the high baseline level of ATF4 in DMG and NRF2 in AT/RT would make these tumors susceptible to ISR activators such as ixazomib. After determining the IC50 of ixazomib, DMG and AT/RT cell lines (JHH-DIPG1, JHH-DIPG16A, and CHLA06) were treated with increasing concentrations of the drug. Cleaved caspase 3 immunofluorescence showed a significant increase of apoptosis in all cell lines (JHH-DIPG16A and CHLA06 p<0.0001, JHH-DIPG1 p=0.0008 by ANOVA). Additionally, western blots for cleaved PARP and phospho-Rb expression detected induction of apoptosis and suppression of cell proliferation in JHH-DIPG1 treated with ixazomib. We are currently testing ixazomib in combination with idarubicin, a brain-penetrant anthracycline, and gemcitabine, a brain-penetrant nucleoside analog. Synergy testing in CHLA06 showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 with inhibitory concentrations of ixazomib and idarubicin in the low nanomolar range (scores of 10 or above indicate synergy). Similarly, ixazomib and gemcitabine synergized to suppress CHLA06 growth and induce apoptosis (67% Annexin V+ cells in combination compared to 14 and 24% Annexin V+ with single agent treatment). In the future, we will determine if ixazomib selectively kills DMG and AT/RT while sparing normal cells in iPSC brain organoids. We will also test ixazomib singly and in combination with traditional chemotherapy in orthotopic xenografts of AT/RT. These results suggest that ixazomib, especially in combination with idarubicin, gemcitabine or other ISR activators, has the potential to serve as an effective therapy for aggressive pediatric brain tumors. Citation Format: Orlandi Valencia Novak, Tyler Findlay, Jeffrey Rubens, Charles Eberhart, Eric H. Raabe. Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6720.

Stem Cell Mobilization with Ixazomib and G-CSF in Patients with Multiple Myeloma.

(1) Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM) and for a subset of patients with relapsed/refractory disease. For stem cell mobilization, G-CSF alone or in combination with chemotherapy mobilizing agents and/or plerixafor are commonly used. Ixazomib is an oral proteasome inhibitor with less neurotoxic potential, which previously showed the ability to mobilize stem cells in preclinical studies. (2) Methods: Prospective single-center phase 1 study assessing the efficacy and safety of stem cell mobilization with ixazomib and G-CSF in patients with newly diagnosed or relapsed/refractory MM undergoing HDCT and ASCT. Primary endpoint was percentage of patients achieving a yield of at least 6.0 × 106/kg CD34+ cells within the first apheresis. G-CSF (filgrastim) 10 μg/kg/day was administered subcutaneously (s.c.) from day 1 to day 5 (planned apheresis) and ixazomib 4 mg orally at day 4. Plerixafor 24 mg s.c. was administered if the stem cell mobilization with ixazomib and G-CSF was not sufficient. (3) Results: 19 patients were treated within the study between 06/2020 and 02/2021. The primary endpoint was reached in 17 (89%) patients, with a median of 7.1 × 106/kg CD34+ cells collected within the first apheresis, comparable to previously published results, and only 2 (11%) patients required a second apheresis. Median number of circulating CD34+ cells was 14.0 × 106/L (2.0-95.2) before the administration of ixazomib, and 33.0 × 106/L (4.2-177.0) pre-apheresis. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. (4) Conclusions: The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity in patients with MM prior to HDCT and ASCT. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM.

Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma in a Real-Life Population in France: The Remix Study

Background Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Efficacy and safety have been demonstrated in the phase 3 Tourmaline-MM1 clinical trial (1), which has recently reported the longest median overall survival (mOS) in phase III studies of Rd-based triplets (53.6 months, mo) (2). The REMIX study has been conducted since IXA became available in France in 2017. It is the largest cohort of RRMM pts receiving IXA-Rd combination in real life. The final analysis was performed with a median follow-up of 28.7 mo. Methods REMIX is a non-interventional, prospective study conducted in 59 sites (public and private) in pts with RRMM in France. To be eligible pts had to receive IXA-Rd in second line or later and IXA had to be initiated concomitantly to Rd (pts who started lenalidomide (lena) more than 6 weeks before IXA were excluded). After inclusion, pts were assessed every 3 mo during 24 mo and then every 6 mo as per standard practice. Analysis comprised OS, progression-free survival (PFS), overall response rate (ORR), very good partial response (VGPR) and tolerance. The analysis was conducted for the overall population and in subgroups of interest: age and lines of treatment (L2, L3 or L4+). Results A total of 376 eligible pts were included. Median age was 71 years (y) with 18.4% of patients aged ≥80y. At IXA-Rd initiation, 48.8% of pts were frail and 21.8% had renal clearance ≤50 ml/min. Comorbidities were reported in 62.8% of pts, including diabetes (8.8%), renal disease (8.8%) or solid tumour (6.4%). At inclusion, the cytogenetic risk was standard, high or unknown in 44.4%, 12% and 43.6% of pts, respectively. MM was diagnosed at a median of 4y before IXA-Rd initiation. 44.5% of pts had previous autologous stem cell transplantation (ASCT). IXA-Rd was initiated in L2, L3 or advanced lines (L4+) in 60.4%, 18.1% and 21.5% of pts, respectively. Regarding previous treatment received, 66.0% of pts had received IMID (including 39.2% lena and 11.7% pomalidomide), 93.1% had received PI (including 91.7% bortezomib and 7.5% carfilzomib) and 13.9% had received daratumumab. Most pts were previously exposed to lena in L3 (73.5% of L3, n=50/68, for a median duration of 16 mo) and L4+ (91.3% of L4+, n=73/81, for 17 mo) compared to L2 (10.6% of L2, n=24/227, for 18 mo). Out of all pts, 26, (7.9%) were considered lena-refractory during previous therapy. The median washout (WO) period between lena discontinuation and IXA-Rd start was 22.8 mo (SD: ±23.9). IXA was used for a median of 12.4 mo (13 cycles) at a 4-mg dose for 90.4% of pts. The median PFS (mPFS) was 19.1 mo (95% CI: 14.9-21.5) for the overall cohort, with a mPFS of 21.5 mo (95% CI: 19.2-24.8) for L2 (n=213), 21.9 mo (95% CI: 16.2-28.7) for L3 (n=65) and 5.8 mo (95% CI: 4.8-9.4) for L4+ (n=80). In the subgroups of pts aged <80y (n=293) and ≥80y (n=65), mPFS were 19.1 mo (95% CI: 15.9-21.9), and 17.4 mo (95% CI: 10.8-23.0), respectively. The mOS was not reached for the overall cohort; 36mo and 48mo OS rates were respectively 58.3% (95% CI: 52.6%-63.9%) and 52.4% (95% CI: 44.2%-60.5%). The 36mo OS rates were 63.4% (95% CI: 56.1-70.8%), 68.9% (95% CI: 57.1-80.7%) and 35.3% (95% CI: 23.9-46.7%) in L2, L3 and L4+ pts respectively. Among the 331 pts with available response according to investigators, the ORR was 73.1% (79.8% in L2, 70% in L3 and 54.4% in L4+ patients) and the VGPR rate was 45% (52.7% in L2, 41.7% in L3 and 25% in L4+ pts). IXA discontinuation was reported in 74.1% of pts (n=278). Discontinuation was related to AE in 21% of cases (n=79). Serious adverse events (SAE) were reported in 54.3% (n=204), including 57 (15.2%) pts with SAE considered related to IXA. Most frequent (>10%) AEs were diarrhoea (52%), thrombocytopenia (45.9%), asthenia (29.7%), neutropenia (23.6%) and anaemia (22.3%). Conclusion The REMIX study reported a mPFS in real-world conditions of 19.1 mo consistent with MM1 (20.6 mo), while half of patients were considered frail and 39.2% had previously received lenalidomide. The effectiveness in third line of treatment is similar to that in second line but was lower in L4+ as expected (5.7 mo). mOS is not reached at 48mo which aligns with MM1 final analysis. Reported AEs are consistent with the known safety profile of Ixazomib. Funding Takeda Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Introduction: Outcome in acute myeloid leukemia (AML) for patients aged >60 years is poor with a median survival of approximately 11 months. Targeting the proteasome in AML is attractive, since leukemia stem cells demonstrate sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB or MCL-1 through stabilizing effects on NOXA. AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the recommended phase II dose (RP2D) of ixazomib in combination with intensive induction and consolidation chemotherapy for AML. A secondary objective was to determine if the level of CD74 in blasts correlated with response, since prior studies showed that CD74 may be a poor prognostic indicator, but its effect might be diminished with proteasome inhibition. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent (HMA) therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidation or transplant in this phase was at the discretion of the treating physician. In the second phase (B), induction was administered with the established RP2D of ixazomib in phase A. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A classical 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). Secondary objectives included rate of complete remission (CR), disease-free survival (DFS), overall survival (OS), and outcome relationship with CD74. Results: Thirty-nine patients were enrolled, including 15 (38%) patients with secondary AML, either with antecedent myeloid malignancy or therapy-related AML. Twenty-six patients (67%) were male, and the median age was 68 years (range 61-80 years). There were no grade 5 toxicities attributed to study drug. Four patients died before day 30 with persistent leukemia, 3 of whom were replaced for assessment of the MTD. Three other patients were not evaluable and were replaced. Nearly all grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There were no grade 3 or 4 neurotoxicity events attributable to ixazomib. Among the 38 patients evaluable for response, 26 achieved CR, and 2 achieved CR with incomplete count recovery (CRi), for a composite remission rate (CCR) of 74%. Among the 15 patients with secondary AML, 9 achieved CR and 2 achieved CRi, for a CCR of 73%. The median OS for the 39 patients is 40.8 months [95% CI, 17.6, Inf]. The 18-month OS estimate was 63% [95% CI, 49-80%]. Of note, 30 patients underwent stem cell transplantation. There was no significant association between level of CD74 expression on blasts at baseline and response. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction and consolidation in this trial has been reached safely and is the recommended phase 2 dose for both. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate for this regimen in this older adult population appears favorable. With ixazomib added in treatment, we saw no association of response rate with level of CD74 in blasts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimization of treatment of patients with plasma cell myeloma with high cytogenetic risk in Poland

Plasma cell myeloma (PCM) is a hematologic malignancy that derives from mature B cells. The prognosis of patients with PCM is highly dependent on the presence of cytogenetic aberrations. Determination of cytogenetic risk enables informing patients about their prognosis and allows for individual choice of therapy. In Poland, cytogenetic risk assessment is a fully reimbursed procedure, and it is recommended to perform such an examination in every diagnosed patient. Therapy of patients with high cytogenetic risk should be planned with consideration of tandem autotransplantation of hematopoietic cells in eligible patients. In patients with refractory or relapsed PCM, treatment with ixazomib in combination with lenalidomide and dexamethasone appears to remove cytogenetic risk.

Combined Therapy with Ixazomib, Lenalidomide, and Dexamethasone for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome.

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.

Phase 2 trial of ixazomib, cyclophosphamide, and dexamethasone for previously untreated light chain amyloidosis

AbstractBortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib's favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01864018.

P1105: FINAL RESULTS OF THE PHASE I/II HOVON124/ECWM-R2 STUDY INCLUDING 2-YEAR RITUXIMAB MAINTENANCE AFTER INDUCTION WITH IXAZOMIB, RITUXIMAB AND DEXAMETHASONE IN RELAPSED WALDENSTRÖM’S MACROGLOBULINEMIA

Background: In the phase I/II HOVON124/ECWM-R2 trial, induction treatment with the combination of ixazomib, subcutaneous (s.c.) rituximab and dexamethasone (IRd) showed promising efficacy with manageable toxicity in patients with relapsed Waldenström’s Macroglobulinemia (WM). Aims: Here we report the final analysis of the trial after two years of rituximab maintenance and with a median follow-up (FU) on study of 45.6 months (range, 12.4-72.2). Methods: In total, 59 patients were enrolled (median age, 69 years; range, 46-91 years) of which 48 patients completed at least six cycles of induction with IRd; 41 patients (median age 66 years, 66% male) with at least a minimal response (MR) continued to 2 years of rituximab maintenance (1400 mg s.c., q 3 months) starting 3 months after the last induction cycle. The primary endpoint of the study was overall response rate (ORR, ≥ MR)) after 8 induction cycles and was 71% (Kersten/Amaador et al, JCO, 2022). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and ORR after 2 years of rituximab maintenance and improvement of response after maintenance. Results: In total, 22 (54%) out of 41 patients completed 2 years of rituximab maintenance. The median number of cycles was 8 (range, 1-8). Nineteen patients did not complete maintenance treatment due to progression (n=16), excessive toxicity (n=1), non-compliance (n=1), and other unknown reason (n=1). The best ORR after maintenance was 85% (2% complete response [CR], 24% very good partial response [VGPR], 39% partial response [PR], and 20% MR). Improvement of response after maintenance occurred in 9 (22%) patients; VGPR to CR in one (2%), PR to VGPR in 6 (15%), and MR to PR in 2 (5%). A further decrease in IgM levels was seen after 2 years of maintenance (IgM 3.62 g/dl at baseline; 1.3 g/dl after induction and 0.42 g/dl after end of maintenance, p-value<0.001; Figure 1A), accompanied by a further increase in Hb levels (Hb 10.5 to 14.3 g/dl, p-value<0.001; Figure 1B). The median progression-free survival (PFS) was 23.6 months (95% CI, 13.4 to 43.2; Figure 1C), and median overall survival (OS) was not reached; at 45 months, 85% of patients were alive (95% CI, 0.72 to 0.92; Figure 1D). The median time to best response was 7 months, the median duration of response (DOR) was 34.8 months, and the median time to next treatment (TTNT) was 36 months[MM(1]. After a median FU of 45.6 months, 29 patients had received subsequent therapy and the median time to progression after subsequent therapy was 53.7 months[MM(2]. During maintenance, rituximab was administered i.v. instead of s.c. in 7 (17%) patients. None of the patients treated with s.c. rituximab developed systemic hypersensitivity reactions but 2 patients had an injection site reaction (1 grade 1, 1 grade 2). Grade 3/4 toxicity was seen in 10% and 5% of patients, respectively (grade 3/4 neutropenia (n=1 and n=2), grade 3 chronic kidney disease (n=1), and grade 3 elevations of transaminases (n=2)). In the 41 patients who started maintenance, 8 SAEs were reported in 6 patients, of which 4 occurred during maintenance (mostly infections) and 4 (mostly secondary malignancies, considered unrelated to study drug) during FU. Three patients died during maintenance therapy due to progressive disease, intracranial bleeding, and acute myeloid leukemia, respectively. Image:Summary/Conclusion: Rituximab maintenance after IRd induction is feasible and well tolerated. The ORR improved in 22% of patients, confirming the efficacy of this chemo-free regimen in combination with rituximab maintenance in relapsed/refractory WM.

Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results

The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9–1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.

Ixazomib in addition to chemotherapy for the treatment of acute lymphoblastic leukemia in older adults

We sought to assess the safety of adding ixazomib, an oral proteasome inhibitor, to a multi-agent treatment regimen for older adults with acute lymphoblastic leukemia (ALL). Patients 51 to 75 years of age with newly diagnosed ALL were screened. Induction consisted of prednisone (P), vincristine (V), and doxorubicin (D). For BCR-ABL1+ patients, dasatinib was added. On Days 1, 8, 15 of induction, ixazomib was given orally. After induction patients received 1 cycle of consolidation in which ixazomib was given on Days 1, 8, 15. After consolidation, patients in remission (CR) were offered stem cell transplantation. Among the 19 patients treated, 15 (79%) [90% CI, 58–92%] achieved CR or CRi. At 2 years, the overall survival was 47% [95%CI, 29–72%]. In this study the dose of 2.3 mg of ixazomib in combination was the MTD for older patients with ALL and is the recommended dose for future phase 2 studies.

Blocking autophagy overcomes resistance to dual histone deacetylase and proteasome inhibition in gynecologic cancer

Histone deacetylase (HDAC) inhibitors and proteasome inhibitors have been approved by the FDA for the treatment of multiple myeloma and lymphoma, respectively, but have not achieved similar activity as single agents in solid tumors. Preclinical studies have demonstrated the activity of the combination of an HDAC inhibitor and a proteasome inhibitor in a variety of tumor models. However, the mechanisms underlying sensitivity and resistance to this combination are not well-understood. This study explores the role of autophagy in adaptive resistance to dual HDAC and proteasome inhibition. Studies focus on ovarian and endometrial gynecologic cancers, two diseases with high mortality and a need for novel treatment approaches. We found that nanomolar concentrations of the proteasome inhibitor ixazomib and HDAC inhibitor romidepsin synergistically induce cell death in the majority of gynecologic cancer cells and patient-derived organoid (PDO) models created using endometrial and ovarian patient tumor tissue. However, some models were not sensitive to this combination, and mechanistic studies implicated autophagy as the main mediator of cell survival in the context of dual HDAC and proteasome inhibition. Whereas the combination of ixazomib and romidepsin reduces autophagy in sensitive gynecologic cancer models, autophagy is induced following drug treatment of resistant cells. Pharmacologic or genetic inhibition of autophagy in resistant cells reverses drug resistance as evidenced by an enhanced anti-tumor response both in vitro and in vivo. Taken together, our findings demonstrate a role for autophagic-mediated cell survival in proteasome inhibitor and HDAC inhibitor-resistant gynecologic cancer cells. These data reveal a new approach to overcome drug resistance by inhibiting the autophagy pathway.

POSC5 Adjusting for Subsequent Therapies in the Tourmaline-MM1 Study Shows Clinically Meaningful Improvement in Overall Survival with Ixazomib in Combination with Lenalidomide and Dexamethasone (IXA+LEN+DEX) Compared to LEN+DEX

The TOURMALINE-MM1 clinical trial assessed the efficacy of IXA+LEN+DEX vs. LEN+DEX in patients with relapsed and/or refractory multiple myeloma (RRMM; 1+ prior lines). The final data cut reflects a median follow-up of 85-months, with patients treated with IXA+LEN+DEX or LEN+DEX for a median of 18 and 16 cycles, respectively. 70.64% of patients received between 1- 12 lines of subsequent therapies. It is important to explore the potential for confounding from the subsequent therapies on overall survival (OS) outcomes given the importance of this outcome to patients, the clinical community and payers.

A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

A Phase I/II Study of Twice Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

A Phase I/II Study of Twice Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Long-time progression-free survival in relapsed, refractory multiple myeloma with the oral ixazomib-lenalidomide-dexamethasone regime

Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID-19 pandemic. Orv Hetil. 2021; 162(36): 1451-1458.

Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed By Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Initial Results from the Randomized Phase II HOVON-126/Nmsg 21.13 Trial

IntroductionA triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in the setting of newly diagnosed multiple myeloma (NDMM). In addition, a role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. However, in elderly patients especially non-hematological toxicity is a concern and an oral drug is preferred as maintenance therapy. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with the PI ixazomib in combination with thalidomide, followed by a randomization between maintenance therapy with either ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the efficacy and toxicity of the induction therapy of the first 120 patients, with subgroup analyses based on frailty and cytogenetic risk. The study is currently ongoing and results with longer follow up and the maintenance part will be reported at future meetings. This trial was registered at www.trialregister.nl as NTR4910.MethodsIn this prospective multicenter phase II trial nte-NDMM patients were treated with nine 28 day-cycles consisting of ixazomib 4mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomisation between either ixazomib or placebo (both day 1, 8, 15 every 28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo and to determine the overall response rate of induction therapy.Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points).High risk cytogenetics was defined as del17p, t(4;14) or t(14;16).ResultsPatient characteristics are presented in table 1. The median follow up is 17.0 months (range 0.9-28.1 months). Following induction treatment overall response rate (ORR, i.e. ≥PR) was 81% (95% confidence interval (CI) 73-87%), 44% (95% CI 35-54%) of patients reached ≥ VGPR and 10% (95% CI 5-17%) ≥ CR. ORR was 85% in patients ≤75 years versus 73% in ≥76 years (p=0.15), while for ≥VGPR these were 45% vs 42% (p=0.85) and for ≥CR 13% vs 4% (p=0.21). In responding patients, the median time to response was 1.1 month.Using the revised IMWG Frailty Index 47% of patients were frail, 28% unfit and 21% fit (4% unknown). Frailty status did not affect the efficacy of induction therapy with ITd with ORR 75%, ≥ VGPR 43% and ≥ CR 9% in frail versus 85%, 53% and 9% in unfit and 88%, 36% and 16% in fit patients (p=0.34, p=0.43 and p=0.62, respectively).At the time of this analysis cytogenetic risk could be determined in 77/120 (64%) patients, with 23% of high risk patients. Response rates were comparable in high versus standard risk patients: ORR 14/18 (78%) versus 50/59 (85%), ≥ VGPR 7/18 (39%) versus 25/59 (42%) and ≥ CR 1/18 (6%) and 4/59 (7%) (p=0.49, p=1.0 and p=1.0).Toxicity is presented in table 2. The incidence of severe neuropathy was low; 3% grade 3 and no grade 4. During induction 18/120 (15%) patients discontinued therapy due to toxicity; 6 neurotoxicity, 3 infection, 2 dermatological toxicity, 2 gastro-intestinal toxicity and 5 other toxicity. Discontinuation was comparable in patients ≥76 versus age ≤75, however none of the 10 patients > 80 years reached maintenance therapy, of whom 6/10 due to toxicity. Early mortality was higher in patients ≥76; 4/45 (9%) versus 1/75 (1%) in patients ≤75, mainly due to infections (4/5). The discontinuation rate due to toxicity was 1/25 (4%), 5/34 (15%) and 9/56 (16%)(p=0.34) in fit, unfit and frail patients respectively.ConclusionInduction treatment with ITd in NDMM results in high overall response rate of 81%, with 44% ≥ VGPR. Median time to response was 1.1 month. In frail and high risk cytogenetic patients induction therapy with ITd was equally effective with respect to response. Therapy was found to be feasible with limited toxicity and a low resulting discontinuation rate of 15%, although in patients >80 years toxicity was higher. [Display omitted] DisclosuresZweegman:Janssen: Other: advisory board participation, Research Funding; Celgene: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation; Takeda: Other: advisory board participation, Research Funding. Waage:Celgene, Takeda: Honoraria. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria. Abildgaard:Takeda: Research Funding.