In the TOURMALINE-MM3 study, post-autologous stem cell transplantation maintenance therapy with the oral proteasome inhibitor ixazomib versus placebo significantly improved progression-free survival ...(PFS), with a favorable safety profile. With ixazomib versus placebo maintenance, deepening responses occurred in 139/302 (46%) versus 60/187 (32%) patients with very good partial response or partial response (VGPR/PR) at study entry (relative risk 1.41, P = 0.004), and median time to best confirmed deepened response was 19.9 versus 30.8 months (24-month rate: 54.2 versus 41.4%; hazard ratio (HR): 1.384; P = 0.0342). Median PFS in patients with VGPR/PR at study entry was 26.2 versus 18.5 months (HR: 0.636, P < 0.001) with ixazomib versus placebo; in a pooled analysis across arms, in patients with versus without deepening responses, the median PFS was not reached versus 15.9 months (HR: 0.245, P < 0.001). In patients with deepening responses, 24-month PFS rate was 77.4 versus 68.3% with ixazomib versus placebo (HR: 0.831; P = 0.466); in patients without deepening responses, median PFS was 17.9 versus 14.1 months (HR: 0.741; P = 0.028). These analyses demonstrate the significantly higher rate of deepening responses with ixazomib versus placebo maintenance and the association between deepening response and prolonged PFS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell ...transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (
n =
395) or placebo (
n =
261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1–4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
BackgroundTAK-573, a humanized, anti-CD38, IgG4, monoclonal antibody genetically fused to two attenuated IFNα2b molecules, was designed for targeted delivery of attenuated IFNα2b to CD38 expressing ...(CD38+) cells, utilizing a unique epitope of CD38 that does not compete with current anti-CD38 therapies. Preclinical evaluation of TAK-573 confirmed activation of type I IFN signaling in CD38+ cells inducing direct anti-proliferative effects on multiple myeloma (MM) cells and direct and indirect immune cell activation. Here we provide the preliminary analyses of the pharmacodynamic data currently available from the ongoing Ph I/II TAK-573-1501 clinical study in patients with relapsed/refractory MM (NCT03215030).MethodsPeripheral blood (PB) and bone marrow (BM) aspirates were collected from patients at pre- and post-dose time points for exploratory biomarker analyses. CD38 receptor occupancy (RO) and receptor density (RD) were determined using a 9-color flow cytometry assay. Whole transcriptome sequencing of bulk RNA was performed and analyzed to assess the type I IFN gene signature. Serum samples were analyzed using Olink’s Proximity Extension Assay Immuno-Oncology panel to measure changes in cytokine levels. Mass cytometry-based immunophenotyping was utilized to characterize changes in immune cell prevalence and activation status of cryopreserved cells.ResultsAdministration of TAK-573 resulted in a dose dependent increase in CD38 RO of PB-derived immune cells with saturation detected 4 hours after the end of infusion (EOI) at doses ≥ 0.2 mg/kg. The duration of saturation was dose dependent with doses ≥ 0.75 mg/kg saturating CD38 RO through 24 hours. All dose levels tested resulted in increases in the type I IFN gene signature at 24 hours. Consistent with CD38 being an IFN stimulated gene, TAK-573 treatment resulted in CD38 RD increases most notably on NK cells, but also on other CD38+ cells including MM cells. Circulating levels of IFN-associated cytokines were also elevated, with maximal induction 4 hours after the EOI. CD8+ T-cells in BM showed increased CD69 expression in 7 of 9 patients analyzed, 3 of whom also showed increases in both IFNγ and granzyme B positivity suggesting TAK-573 treatment results in increased BM cytolytic CD8+ T-cells, in a subset of patients.Abstract 357 Figure 1Proposed Mechanism of Action of TAK-573ConclusionsThese preliminary biomarker data indicate that TAK-573 is a pharmacologically active molecule that mediates its effect through IFNAR pathway modulation. Additional data are being collected to further refine the mechanism of action (Image 1), which will inform the recommended phase 2 dose and optimal schedule of administration for the development of TAK-573.Trial RegistrationClinicalTrials. gov: NCT03215030Ethics ApprovalThe TAK-573-1501 study is approved by WIRB-Copernicus Group, University of Nebraska Medical Center, Dana Farber Cancer Institute and Advarra IRBs.
Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with ...non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index IPI score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m
intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.
•Conversion from MRD− to MRD+ or from MRD+ to MRD− status during ixazomib or placebo maintenance modulates the risk of disease progression.•Ixazomib prolonged progression-free survival in patients ...who were MRD+ before maintenance and at a 14-month landmark analysis.
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Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival PFS, 38.6 vs 15.6 months in MRD− vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD− status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD− status vs those converting from MRD− to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD−. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single–time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD− status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD− status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.
Measurable residual disease (MRD) status after initial therapy for multiple myeloma is a proven surrogate for progression-free survival (PFS), but its value during maintenance is uncertain. Paiva et al report that serial monitoring of MRD during maintenance treatment captures dynamic conversion between MRD-negative and -positive states and robustly anticipates PFS. This shows the feasibility of longer term MRD monitoring and provides a rationale for trials that investigate intervention prior to frank relapse or shortening of maintenance for those who remain MRD negative.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Modakafusp alfa (moda), a novel immunocytokine, is an innate immunity enhancer comprising two attenuated interferon (IFN) α2b molecules fused to an anti-CD38 IgG4 monoclonal antibody backbone, ...driving preferential IFNα signalling in CD38-expressing innate and adaptive immune cells as well as myeloma cells. Here, we present pharmacodynamic (PD) data from the first-in-human Phase 1/2 study of moda as a monotherapy in patients with RRMM (iinnovate-1; NCT03215030). A total of 37 patients treated with moda at 1.5 or 3 mg/kg every 4 weeks were included in the analysis. Peripheral blood (PB) and bone marrow (BM) samples were collected during screening or pre-dose on cycle 1 day 1 (C1D1) and at multiple timepoints after treatment. BM and PB samples were evaluated by cytometry time of flight (CyTOF) and bulk RNA sequencing (RNAseq) to assess pharmacodynamic changes in immune cell populations, cell activation, and gene expression. Administration of moda led to enhanced innate immune cell activation and cytotoxic function as demonstrated by increased proportions of CD69+ and granzyme B+ in peripheral NK cells analyzed by CyTOF. This was accompanied by a decrease in the proportion of TIGIT+ NK cells, indicating reduced inhibitory signaling. Furthermore, enhanced proliferation (%Ki67+) of NK cells was observed in both BM and PB. Moda also impacted myeloid cell populations in BM and PB. Dendritic cells (DCs) and monocytes in PB showed increased surface expression of the co-stimulatory molecule CD86, suggesting a potential for enhanced antigen presentation and co-stimulation ability. Increased proliferation (%Ki67) of DCs and monocytes was detected in both PB and BM, accompanied by a decrease in numbers of peripheral DCs which may indicate recruitment or homing to secondary lymphoid organs. Additionally, RNAseq analysis revealed that treatment with moda led to upregulation of CD68 expression in both PB and BM, indicating a proinflammatory M1 macrophage type response. Finally, CyTOF analysis also indicated that moda significantly impacted adaptive immunity. We observed enhanced activation (%CD69, %PD1 and %CD40L) and cytotoxic function (%granzyme B) of peripheral CD8 T cells, and increased CD8 T cell proliferation (%Ki67 CD8) in both PB and BM samples. Enhanced activation of peripheral CD4 T cells (%CD69, %CD40L) was also detected. Consistent with activation of the adaptive immune system, there was a reduction in naïve CD8 T cells accompanied by an increase in CD8 T effector memory cells in PB. Analysis of exhaustion markers (TIGIT, PD-1) in cycle 1 (C1D8, C1D15, and C2D1 predose) showed that moda did not induce CD8 T cell exhaustion in either PB or BM, and there was no change in FoxP3+ Treg cells. Moda-induced innate and adaptive immune cell phenotypic changes were evaluated for correlation with clinical response at timepoints with sufficient number of evaluable samples. While none of the associations were statistically significant after correcting for multiplicity testing (using the false discovery rate method), we observed trends warranting further investigation. There was a greater increase of CD40L+ NK cells and PD1+ CD8 cells in responders vs. non-responders at C1D2. Additionally, at C1D15 responders showed a lower increase in proliferation (%Ki67+) of classical monocytes, NK cells, and myeloid DCs in PBas compared to non-responders. A similar trend was also observed in the BM classical monocytes. Even though the peak of Ki67 expression was observed at C1D8, diminished increases of proliferating cells at C1D15 in responders was a surprising observation that needs further consideration. The PD biomarker data from this first-in-human clinical trial demonstrated that treatment with moda enhances both innate and adaptive immune cell activation in PB and BM. Importantly, moda-mediated immune activation did not result in T cell exhaustion during cycle 1, as evaluated in both PB and BM. We have observed interesting trends of immune phenotypic changes that may correlate with response. Follow-up analyses of the correlation of biomarkers with clinical response are in progress and will be presented. Further clinical trials are underway (iinnovate-2, NCT05556616; iinnovate-3, NCT05590377) to evaluate moda's novel immune activating mechanism in combination with standard of care anti-myeloma therapies.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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