A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

Miguel, Jesús F. San; Gutierrez, Maria-Asunción Echeveste; Špıčka, Ivan; Mateos, María‐Victoria; Song, Kevin; Craig, Michael; Bladé, Joan; Hájek, Roman; Chen, Christine; Bacco, Alessandra Di; Estevam, Jose; Gupta, Neeraj; Byrne, Catriona; Lu, Vickie; Velde, Helgi van de; Lonial, Sagar

doi:10.3324/haematol.2017.185991

Cited by 18 publications

(17 citation statements)

References 43 publications

(67 reference statements)

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“…Last, in the time after the study period, the FDA has approved additional chemotherapy agents for MM (eg, carfilzomib, ixazomib, daratumumab). However, in upfront clinical trials, these agents have not been associated with high rates of VTE . In summary, we developed and validated the IMPEDE VTE score, which outperformed the risk stratification in the IMWG/NCCN guidelines.…”

Section: Discussionmentioning

confidence: 99%

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score

et al. 2019

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Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high‐risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time‐to‐event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)‐Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m2; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c‐statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c‐statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c‐statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.

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Section: Discussionmentioning

confidence: 99%

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score

et al. 2019

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“…Similarly, single-agent ixazomib maintenance has been utilized following ixazomib-based induction in four phase 1/2 studies 45,[80][81][82][83] ; a pooled analysis of maintenance patients from these studies reported deepening responses in 23% of patients, as well as a median PFS of 21.4 months and a 3-year OS of 82% from the start of maintenance, with limited new-onset AEs 84 . Ixazomib-daratumumabdexamethasone followed by ixazomib maintenance is being evaluated in unfit and frail patients in the phase 2 HOVON-143 study, which has reported promising safety and response data for the induction phase 85 .…”

Section: Maintenance Therapy Post-induction In the Nontransplant Settingmentioning

confidence: 99%

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma

et al. 2020

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The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

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“…The four trials have been reported in full prev iously. [24][25][26][27][28] Briefly, patients received weekly or twiceweekly ixazomib plus Rd (IRd, C16005, and C16008, respectively), weekly or twice-weekly ixazomib plus melphalan-prednisone (IMP, C16006), or weekly ixazomib plus cyclophosphamide-dexamethasone (ICd, C 16020), as induction treatment, followed by singleagent ixazom ib maintenance. Full details of induction treatment are summariz ed in the Supporting Information section.…”

Section: Included Studiesmentioning

confidence: 99%

“…Among the 59 patients who received ixazomib maintenance at the weekly RP2D of 4.0 mg, the median PFS from start of maintenance was 25.3 months, as determined in two of the original source studies. 24,26 In addition to the TOURMALINE-MM3 study, 23 the TOURMALINE-MM4 (NCT02312258), a phase III, double-blind, placebo-controlled study, is evaluating maintenance treatment in patients with NDMM, who have responded to any induction therapy but have not undergone ASCT. As in TOURMALINE-MM3, an initial weekly dose of 3.0 mg is used, as patients have not been previously exposed to ixazomib; this dose may be escalated to 4.0 mg after 4 cycles in the absence of significant toxicity.…”

Section: Myocardial Infarction 1 (<1)mentioning

confidence: 99%

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Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies

Dimopoulos

Laubach

Gutierrez³

et al. 2019

European J of Haematology

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Objectives:To evaluate the safety and efficacy of maintenance therapy with the oral proteasome i nhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.Methods: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once-or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. Results:A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35;weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drugrelated adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.Conclusions: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing. K E Y W O R D S clinical trials, multiple myeloma | 495 DIMOPOULOS et aL.

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A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

Cited by 18 publications

References 43 publications

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies

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