Oral Proteasome Inhibitor Ixazomib Research Articles

Alliance A061202: ixazomib, pomalidomide and dexamethasone for patients with lenalidomide-refractory multiple myeloma in first relapse

Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma (MM) in first relapse remains poorly defined. We therefore undertook a randomized phase II study evaluating the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) for this patient population. The overall response rate (ORR) for POM-DEX was 43.6% and 63.2% for IXA-POM-DEX. Depth of response, as measured by attainment of a very good partial response or better favored the triplet over the doublet, 28.9% vs 5.1%, respectively (p = 0.0063). A pre-planned interim analysis after 75% of the progression events had occurred demonstrated a progression-free survival (PFS) advantage favoring IXA-POM-DEX that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI] 4.8 - 13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI 7.7 - 26.0 months, hazard ratio 0.437 [upper 90% bound = 0.657]). ORR and median PFS for the 26 of 30 eligible patients who crossed over from the doublet to the triplet at progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the two groups. More hematologic toxicities were seen with the triplet, but non-hematologic adverse events were similar between the two arms. Our data support further testing of this all-oral triplet vs current standard triplet therapy in the context of phase III studies for patients with LEN-refractory disease in first relapse. This trial is registered at www.clinicaltrials.gov as NCT02004275.

Ixazomib plus daratumumab and dexamethasone: Final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma.

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.

Efficacy, safety, and molecular response predictors of oral ixazomib and short-course rituximab in untreated iNHL.

Patients with indolent B-cell non-Hodgkin lymphoma (iNHL) generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve patients with iNHL needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary end point was overall response rate (ORR) during the ixazomib monotherapy window. Correlations included gene expression profiling and response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Thirty-three patients with follicular lymphoma (FL) (n= 20), marginal zone lymphoma (n= 7), and other iNHL were treated with a median follow-up of 30.3 months. During the 6-month ixazomib window, the ORR was 24%, including 35% in FL. The best ORR over the entire study period was 52% overall and 65% in FL; complete response was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0-49.7), and the 24-month progression-free and overall survival rates were 51% (95% confidence interval [CI], 32-67) and 91% (95% CI, 74-97), respectively. Ixazomib was well tolerated. Baseline downregulation of proteasome genes, PSMB9 (P= .03) and PSMB8 (P= .007), were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, with a median of 254.9 binding arbitrary unit per mL. Ixazomib demonstrated efficacy alone and with short-course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of the B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

Network meta-analysis of efficacy of ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma

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

Initial Results of a Phase 1 Study of Daratumumab, Ixazomib, and Dexamethasone in Newly Diagnosed and Previously Treated AL Amyloidosis

Background: Systemic light chain (AL) amyloidosis is a rare disease that is characterized by the tissue deposition of misfolded protein aggregates, leading to progressive organ dysfunction and significant morbidity and mortality. Novel therapeutic combinations with improved safety, tolerability, and efficacy profiles remain a paramount need. We herein report initial results of a phase 1 investigator-initiated study evaluating the safety and preliminary efficacy of the novel combination of the anti-CD38 monoclonal antibody (mAb) daratumumab, the oral proteasome inhibitor ixazomib, and dexamethasone (DId) in AL amyloidosis (NCT03283917). Methods: This phase 1, single center, open-label study enrolled AL amyloidosis patients (pts) who were either treatment naïve or previously treated with evidence of clonal relapse or with refractory disease defined as less than a hematologic very good partial response (VGPR) to prior therapy. Key exclusion criteria included NT-proBNP ≥8500 ng/L, clinically overt myeloma (hypercalcemia and/or bone lesions), and previous ixazomib or anti-CD38 mAb therapy. Treatment was administered on a 28-day cycle for up to 12 cycles with daratumumab weekly x 8 weeks, then every other week x 16 weeks, and then every 4 weeks thereafter. Daratumumab was initially administered intravenously (16 mg/kg) but later changed to subcutaneous injection (1800 mg) with a protocol amendment. Ixazomib was administered orally 4 mg on days 1, 8, and 15, and dexamethasone administered 20 mg weekly for cycle 1 and increased to 40 mg weekly for cycle 2 and beyond depending on patient tolerance. The primary study endpoint is to confirm the safety and tolerability of DId in AL amyloidosis. Key secondary endpoints include hematologic response rate and organ (cardiac and renal) response rates. Planned enrollment is 20 pts with toxicity monitoring in cohorts of 5 pts. Results: A total of 18 pts have been dosed to-date including 13 treatment-naïve pts and 5 previously treated pts with a median of 1 prior line of therapy. Baseline characteristics are summarized in the Table. Median age was 66 (range 39-75), 8 (44%) pts were female, and 3 (17%) pts were Black. Median baseline difference between the involved and uninvolved free light chain (dFLC) was 194 mg/L (range 71-2787), and 6 of 17 (35%) pts with available FISH testing had t(11;14). Median number of organs involved was 2 (range 1-4), including 9 (50%) pts with cardiac involvement and 11 (61%) pts with renal involvement. Overall hematologic response rate (≥PR) on treatment was 100%, ≥VGPR rate 72%, and complete response (CR) rate 11%. Cardiac response rate was 43% among 7 response evaluable pts (baseline NT-proBNP ≥650 ng/L), and renal response rate was 36% among 11 pts. Among 5 previously treated pts, there were 4 hematologic VGPRs and 1 hematologic CR. The median number of DId treatment cycles was 8.5, with 7 (39%) pts completing all 12 treatment cycles, and treatment is ongoing in 3 (17%) pts. Intent to proceed with high dose chemotherapy and autologous stem cell transplantation was the most common reason for early treatment discontinuation (4 pts, 22%). The most common treatment emergent adverse events (TEAEs) of any grade regardless of attribution were anemia (56%), thrombocytopenia (56%), dyspnea (56%), fatigue (56%), hypoalbuminemia (56%), and nausea (56%). The most common grade 3 or 4 TEAEs (≥20%) were lymphopenia (33%), lung infection (22%), and thrombocytopenia (22%). Treatment emergent peripheral neuropathy (PN) was 28% (all grade 1 and 2), among whom 4 of 5 pts had baseline amyloid PN, other PN, and/or prior bortezomib exposure. There were 3 deaths on study, all unrelated to treatment (1 related to post-operative complications from small bowel obstruction due to congenital Meckel's diverticulum, 1 related to progressive hepatic amyloidosis, and 1 related to pulmonary embolus in setting of COVID-19 infection). Conclusion: Treatment with DId in both newly diagnosed and previously treated AL amyloidosis pts is safe at standard doses of daratumumab and ixazomib with a predictable and manageable AE profile compatible with the expected toxicities of the individual study drugs. Preliminary efficacy is seen with deep (≥VGPR) hematologic responses attained in the majority of pts. These results support the use of DId as a therapeutic option in AL amyloidosis with longer follow-up needed to assess the depth and durability of hematologic and organ responses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Late vs Early Response and Depth of Response Are Associated with Improved Outcomes in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with Ixazomib-Lenalidomide-Dexamethasone (IRd) or Placebo-Lenalidomide-Dexamethasone (pbo-Rd) in the Phase 3 TOURMALINE-MM2 Trial

Late vs Early Response and Depth of Response Are Associated with Improved Outcomes in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with Ixazomib-Lenalidomide-Dexamethasone (IRd) or Placebo-Lenalidomide-Dexamethasone (pbo-Rd) in the Phase 3 TOURMALINE-MM2 Trial

Interim Analyses of Overall Survival (OS) from the TOURMALINE MM3 & MM4 Studies of Ixazomib Maintenance Following Primary Therapy in Multiple Myeloma (MM)

Interim Analyses of Overall Survival (OS) from the TOURMALINE MM3 & MM4 Studies of Ixazomib Maintenance Following Primary Therapy in Multiple Myeloma (MM)

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

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

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.

The Oral Proteasome Inhibitor Ixazomib, Alone and in Combination with Ibrutinib, Induces Lethality in Waldenstrom Macroglobulinemia Cells That Are Resistant to Ibrutinib

Introduction: Dysregulated B-cell receptor (BCR) signaling drives proliferation of Waldenstrom macroglobulinemia (WM) cells, which characteristically secrete excessive IgM. To maintain IgM production and preserve cellular homeostasis, WM cells rely on optimally functioning proteasomes to degrade and recycle proteins. This biological dependence has been clinically exploited using the proteasome inhibitor (PI), bortezomib (Btz), which is capable of inducing remission in 85% of WM patients (Treon et al Clin Canc Res, 2007) as a single agent. Despite, its activity, Btz use is associated with a high incidence of sensory and autonomic neuropathies as well as its cumbersome dosing schedule and non-oral route of administration. Thus, new agents that 1.) build on the activity of Btz, 2.) have a more favorable toxicity profile and 3.) can be combined with standard of care agents such as, ibrutinib (Ibr), are highly attractive and should be prioritized for investigation. Here we describe the preclinical activity of ixazomib (Ixa), a PI that is administered orally and is associated with significantly less peripheral neuropathy; in combination with Ibr, in WM cells.Methods: WM cell lines (BCWM.1 and RPCI.WM1) and their drug-resistant subclones were used. Genomic data including whole exome sequencing (WES) and copy number variations (CNV) was used in creation of digital simulation avatars of RPCI-WM1 and RPCI-WM1/IR (Ibr-resistant, Ibr-R variant), where the salient and prominently dysregulated cellular pathways were identified. Ixa +/- Ibr was tested in digital avatars and dose-dependent impact on simulated disease growth was assessed (Fig 1A). The predictive results were experimentally validated. Cell viability was measured using trypan blue or CellTiter Glo. Apoptosis was examined by annexin-V/PI staining of drug-treated cells followed by flow cytometry analysis. Mitochondrial membrane permeability (MOMP) was determined by TMRM staining of drug-treated cells followed by flow cytometry.Results: We first profiled the growth inhibitory action of Ixa in WM cell lines (n=9); all of which were sensitive to Ixa irrespective of acquired resistance to Btz, Ibr or carfilzomib with a median IC50 of 95.59nM. We then tested whether Ixa could cooperate with Ibr to enhance WM cell kill. Indeed, the Cellworks modeling tool, predicted a significant loss of viability and induction of apoptosis in both wildtype and Ibr-R cells treated with Ibr + Ixa, as compared to either single agent (Fig 1B-D). We confirmed this in vitro, where viability of wildtype WM cells treated with Ixa (20nM), Ibr (5uM) or Ibr + Ixa for 6h significantly decreased; most notable with Ixa + Ibr (25.5% viable cells). And this effect was similar in Ibr-R cell lines (30.3% viable cells) after combination treatment. Further confirming in silico predictive modeling results, we noted a significant increase in annexin-V/PI positivity in Ixa treated wildtype (24.5%) and Ibr-R WM cell lines (33.1%). Whereas Ibr alone exhibited minimal apoptosis in WM cell lines (~11 - 15%), the combination of with Ixa + Ibr enhanced programmed cell death in wildtype (40.2%) and Ibr-R cells (50.5%). As intrinsic apoptosis is triggered through mitochondrial disruption, we also examined mitochondrial transmembrane permeability (MOMP) in cells treated with Ibr, Ixa or Ixa + Ibr. In wildtype cells, mean MOMP induced by single agent Ixa was 23.5% and in Ibr-R cells 33%; increasing to 39% and 50.4%, respectively, after treatment with Ibr + Ixa. Mechanistic studies revealed changes in proteins regulated by the ubiquitin proteasome system and those associated with BTK signaling. While Ixa alone downregulated Bcl-2 and Mcl-1 levels, this effect was more marked in cells (both wildtype and Ibr-resistant) treated with Ixa + Ibr combination. Similar effects were noted in pPLCg2, albeit with some variability between the cell lines.Conclusion: Using a combination of in silico modeling and experimental approaches, we provide first preclinical evidence on the antitumor effects of Ibr combined with the oral PI, Ixa, in WM cells, including those resistant to Ibr. Whereas further investigation on the precise molecular mechanisms of how Ibr + Ixa cooperate to induce apoptosis in WM cell is ongoing, our studies provide the basis for clinical testing of the Ibr + Ixa regimen; with a phase II clinical study in development. [Display omitted] DisclosuresSingh:Cellworks Research India Pvt. Ltd: Employment. Kumar:Cellworks: Employment. Basu:Cellworks: Employment. Trivedi:Cellworks: Employment. Majumdar:Cellworks: Employment. Abbasi:Cellworks Group Inc.: Employment. Vali:Cellworks Group Inc.: Employment. Martin:Janssen: Consultancy, Honoraria, Other: travel expenses; Genentech: Consultancy; Celgene: Consultancy; Teva: Research Funding; Novartis: Consultancy; Gilead: Consultancy, Other: travel expenses. Ansell:Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Celldex: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding. Ailawadhi:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria.

Oral Proteasome Inhibitor Ixazomib for Switch-Maintenance Prophylaxis of Recurrent or Late Acute and Chronic Graft-versus-Host Disease after Day 100 in Allogeneic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is a frequent complication in the first year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced-intensity (RI) or nonmyeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor with a wide safety profile that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, and anti-tumor activity. We hypothesized that switch-maintenance GVHD prophylaxis using ixazomib would facilitate CNI taper without increased GVHD frequency and severity while maintaining graft-versus-tumor (GVT) effect and an acceptable safety profile. We conducted an open-label, prospective, single-center pilot study in patients with hematologic malignancies who received an RI or NMA conditioning and CNI-based GVHD prophylaxis that were within day 100 to 150 after HCT (n=18). Patients were treated with ixazomib once weekly on a 28-day cycle (3 weeks on, 1 week off). Treatment was safe; most adverse events were grade 1 or 2, with cytopenia and elevation in transaminases the most common. Five patients were removed from the study because of toxicity or side effects. Only 5 of 18 patients developed GVHD during the study, and its severity was driven by acute manifestations while chronic involvement was mild. The cumulative incidence of grade II-IV acute and chronic GVHD at 1-year after HCT was 33% (95% confidence interval [CI], 13-55). No patients died during the study, and only 1 had malignant relapse. An additional patient relapsed after completion of the study but within 1 year after HCT. The probability of progression-free survival and GVHD-free/relapse-free survival (composite endpoint) at 1 year were 89% (95% CI, 75-100) and 78% (95% CI, 61-100), respectively. Immune reconstitution analysis showed a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution, and vaccine response in a subset of patients demonstrated continuing or de novo positive protective antibody titers. This study demonstrated low incidence of recurrent and late acute and chronic GVHD within 1 year after HCT possible associated with switch-maintenance GVHD prophylaxis using ixazomib. This approach allowed for CNI taper while preserving GVT effect, without aggravating GVHD. Our findings support further development of this approach and provide a proof-of-concept for switch-maintenance GVHD prophylaxis.

Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma

AbstractContinuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.

84 - Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

84 - Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients with Multiple Myeloma with Extramedullary Disease or Plasma Cell Leukemia

Background: Multiple myeloma is typically characterized by clonal expansion of malignant plasma cells within the bone marrow compartment. Presence of extramedullary disease (EMD) either in the form of soft tissue plasmacytoma or circulating plasma cells can be seen at diagnosis but is more common in the relapsed and refractory patients. Presence of EMD is typically associated with a poor prognosis, both in the newly diagnosed and relapsed setting, but trials designed specifically for patients with EMD are sparse. Treatment of EMD can be challenging and the responses even when seen are often short lasting, highlighting the need for developing specific treatment approaches aimed at these patients. Based on initial trials suggesting activity of pomalidomide in the setting of EMD and the increased tissue distribution with the oral proteasome inhibitor ixazomib, we designed this trial to examine if the all oral combination of ixazomib, pomalidomide and dexamethasone can be effective in the setting of EMD. Patients and Methods: Patients with previously treated multiple myeloma, with adequate hematologic and organ function were enrolled if there was evidence, at study entry, of EMD defined as one or more plasmacytomas, outside the bone marrow that were non-contiguous with a bone lesion and had a single diameter of ≥2 cm OR as plasma cell leukemia, with circulating plasma cells &amp;gt; 5% of peripheral blood leukocytes or at least 0.5 X 109/L or 200 cells/150000 events by flowcytometry. Patients were treated on 28-day cycles, with ixazomib 4 mg on days 1, 8, and 15 along with pomalidomide 4 mg PO daily on days 1-21 and dexamethasone 40 milligrams weekly until disease progression or unacceptable toxicity. The goals of the study were to determine confirmed response rate (≥ PR), toxicities of this combination, differential response rates and progression-free survival (PFS). Confirmed response rate, differential response rates and PFS were estimated using Duffy and Santner approach, exact binomial distributions and Kaplan Meier curves, respectively. The study was designed to accrue 30 patients. Results: This study was designed to enroll up to 30 patients but was closed after enrolling 17 patients due to slow accrual. The baseline characteristics are as indicated in Table 1. Eleven patients were enrolled with an extramedullary plasmacytoma while the remaining six patients had plasma cell leukemia. Median number of lines of prior therapy was 3 (range: 1, 7). Overall, 10 (58.8%) patients had progressive disease and 11 (64.7%) patients have died, median (range) follow-up for the live patients is 22.2 (2.1, 37.9) months. Patients were treated for a median of 2 (range 1-34) cycles. A grade 3+ AE, at least possibly attributed, was seen in 53%. Grade 3+, at least possibly related, hematologic toxicity was noted in 41%, with 29% experiencing grade 3+ neutropenia. Notable grade 3+ non-hematologic toxicities (regardless of attribution), with &amp;gt;10% incidence rate were anemia, hypoxia, infections and lung infection. The confirmed response rate in evaluable patients was 35% (1 CRs and 5 PRs), with a 90% CI of 6% - 37%. While 33% (4/12; 95% CI: 1-8%) of patients reported a biochemical response, 40% (2/5; 95% CI: 0-4%) of patients reported an extramedullary response. The median PFS was 4.5 (95% CI: 2-11.8) months. Conclusions: The combination of ixazomib, pomalidomide and dexamethasone resulted in disease response in a third of this group of high-risk patients with EMD; however, the responses were not very durable, with a median PFS of only 4.5 months. The trial highlights the feasibility of doing clinical trials specifically targeted towards this high-risk patient population. Future trials should explore combinations of novel agents, including monoclonal antibodies through multicenter collaborative efforts. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding.

Prognostic Importance of Measurable Residual Disease (MRD) Kinetics and Progression-Free Survival (PFS) Benefit in MRD+ Patients (Pts) with Ixazomib Vs Placebo As Post-Induction Maintenance Therapy: Results from the Multicenter, Double-Blind, Phase 3 TOURMALINE-MM4 Trial in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Pts

Prognostic Importance of Measurable Residual Disease (MRD) Kinetics and Progression-Free Survival (PFS) Benefit in MRD+ Patients (Pts) with Ixazomib Vs Placebo As Post-Induction Maintenance Therapy: Results from the Multicenter, Double-Blind, Phase 3 TOURMALINE-MM4 Trial in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Pts

Progression-Free Survival (PFS) Benefit Demonstrated and Quality of Life (QoL) Maintained across Age and Frailty Subgroups with the Oral Proteasome Inhibitor (PI) Ixazomib Vs Placebo As Post-Induction Maintenance Therapy in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Analysis of the TOURMALINE-MM4 Phase 3 Trial

Progression-Free Survival (PFS) Benefit Demonstrated and Quality of Life (QoL) Maintained across Age and Frailty Subgroups with the Oral Proteasome Inhibitor (PI) Ixazomib Vs Placebo As Post-Induction Maintenance Therapy in Non-Transplant Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Analysis of the TOURMALINE-MM4 Phase 3 Trial

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Ixazomib vs placebo maintenance for newly diagnosed multiple myeloma (NDMM) patients not undergoing autologous stem cell transplant (ASCT): The phase III TOURMALINE-MM4 trial.

8527 Background: Maintenance therapy delays disease progression in non-ASCT NDMM patients. However, in practice, currently used maintenance therapies may be limited to fixed duration due to toxicity and route of administration; additional options are needed. Methods: 706 non-ASCT NDMM patients who received 6–12 months of standard-of-care induction therapy and achieved at least a partial response (≥PR) were randomized 3:2, double-blind, to the oral proteasome inhibitor (PI) ixazomib (n = 425; 3 mg, cycles 1–4, then, if tolerated, 4 mg, cycle 5 onwards) vs placebo (n = 281) on days 1, 8, and 15 of 28-day cycles for ≤2 yrs. Patients were stratified by prior PI exposure (yes vs no), pre-induction International Staging System (ISS) disease stage (I/II vs III), age ( &lt; 75 vs ≥75 yrs), and post-induction best response (complete or very good partial response [CR/VGPR] vs PR). Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics were well balanced. Overall median age was 73 yrs, 38% of patients were aged ≥75 yrs, 35% were ISS stage III, and 22%/40%/38% had CR/VGPR/PR post induction. Overall, 82% of patients received a PI and 33% an immunomodulatory drug as part of their induction regimen. At a median follow-up of 21.1 months, median PFS was 17.4 months with ixazomib vs 9.4 months with placebo (hazard ratio [HR] 0.659, 95% confidence interval [CI] 0.542–0.801, p &lt; 0.001). Significant (p &lt; 0.001) PFS benefit was seen in patients who achieved CR/VGPR post induction (Table). Overall survival data are not yet mature (19% of events); follow-up is ongoing. Treatment-emergent adverse events (TEAEs) were mostly grade 1–2 (37% vs 23% of patients had grade ≥3 TEAEs with ixazomib vs placebo). Common TEAEs for ixazomib vs placebo included nausea (27% vs 8%), vomiting (24% vs 4%), and diarrhea (23% vs 12%); 5% vs 6% of patients had new primary malignancies. No cumulative toxicities were observed. Conclusions: Ixazomib maintenance therapy in non-ASCT NDMM patients showed a clinically meaningful 34% reduction in the risk of progression or death, with a well-tolerated safety profile. Ixazomib is the first oral PI maintenance option for non-ASCT NDMM patients. Clinical trial information: NCT02312258 . [Table: see text]