Carfilzomib–dexamethasone vs bortezomib–dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR

Wj, Chng; Goldschmidt, Hartmut; Dimopoulos, Meletios Α.; Moreau, Philippe; Joshua, Douglas; Palumbo, Antônio; Façon, Thierry; Ludwig, Heinz; Pour, Luděk; Niesvizky, Rubén; Oriol, Albert; Rosiñol, Laura; Suvorov, Aleksandr; Gaïdano, Gianluca; Pika, Tomáš; Weisel, Katja; Goranova-Marinova, Vesselina; Gillenwater, HH; Mohamed, Nehal; Feng, Shibao; Aggarwal, Shivani; Hájek, Roman

doi:10.1038/leu.2016.390

Cited by 51 publications

(38 citation statements)

References 24 publications

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“…6-10 "High-risk" abnormalities on fluorescence in situ hybridization (FISH) have typically been considered to comprise the translocations t(4;14) and t (14;16) and chromosome 17p deletion [del(17p)], 7,9,[11][12][13][14][15] each of which has been shown to be an independent poor prognostic marker in MM. [16][17][18][19] Additionally, gain of 1q21 on FISH has been shown to confer poor prognosis 17,20,21 ; in some reports, 1q21 amplification is considered a high-risk abnormality, 21,22 including in a 2016 consensus paper from the International Myeloma Working Group, 10 whereas other reports classify it as conferring intermediate or standard risk.…”

Section: Introductionmentioning

confidence: 99%

“…25 This is consistent with the FISH abnormalities used to define "high risk" in other phase 3 studies and analyses [with or without the rare t(14;20) translocation] in patients with MM. 7,9,[11][12][13][14][15] The presence of these abnormalities has previously been shown to be associated with poor outcomes, including poor PFS and OS, relative to outcomes seen in patients without these abnormalities. 7,9,14 Consequently, there remains an ongoing unmet need in patients with MM not only to improve absolute outcomes in high-risk patients but also to provide long-term disease control and overcome the poor prognosis associated with these cytogenetic abnormalities.…”

Section: Org Frommentioning

confidence: 99%

“…[11][12][13]15 The International Myeloma Working Group recently advised that newly diagnosed MM patients with high-risk cytogenetics should receive a combination of a proteasome inhibitor with lenalidomide or pomalidomide and dexamethasone, 10 noting the positive impact of these regimens on outcomes in patients with specific poor-prognosis abnormalities. Nevertheless, there remains a need for additional active therapeutic options for patients with high-risk cytogenetics, including regimens that allow for prolonged treatment and thus may offer extended disease control.…”

Section: Introductionmentioning

confidence: 99%

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Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

Avet-Loiseau¹,

Bahlis

Chng

et al. 2017

Blood

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• IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standardrisk cytogenetics. • The addition of ixazomib toRd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P 5 .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P 5 .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI,, and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI,. IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537. (Blood. 2017;130(24):2610-2618

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Section: Introductionmentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

Avet-Loiseau¹,

Bahlis

Chng

et al. 2017

Blood

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“…In patients with high-risk CAs, there was a trend for increased PFS with carfilzomib compared with lenalidomide and dexamethasone alone by 9 months (P = 0.083) (vs. an increased PFS of 10 months for patients with standard-risk cytogenetics; P = 0.003) (Avet-Loiseau et al, 2016). However, it must be noted that in both ENDEAVOR and ASPIRE carfilzomib treatment did not completely overcome the poor prognosis associated with high-risk CAs (Stewart et al, 2015;Chng et al, 2017;Avet-Loiseau et al, 2016).…”

Section: Patients With High-risk Cytogenetic Abnormalitiesmentioning

confidence: 87%

“…In pre-planned subgroup analyses of ENDEAVOR, carfilzomib improved outcomes compared with bortezomib regardless of cytogenetic risk category. Carfilzomib prolonged PFS compared with bortezomib in patients with high-risk CAs (8.8 months vs. 6.0 months; HR, 0.65; P = 0.0075) and in those with standard-risk cytogenetics (not estimable vs. 10.2 months; HR, 0.44; P < 0.0001); however, it must be noted that outcomes for patients with high-risk CAs were worse than for those with standard-risk CAs (Chng et al, 2017). Carfilzomib has also shown efficacy in this patient population in combination with lenalidomide and dexamethasone.…”

Section: Patients With High-risk Cytogenetic Abnormalitiesmentioning

confidence: 92%

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

Cook

Mateos

Suzan

et al. 2018

Critical Reviews in Oncology/Hematology

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A B S T R A C TMultiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM), including immunomodulatory agents, proteasome inhibitors, histone deacetylase inhibitors and monoclonal antibodies. Additionally, several different drugs may be available within each agent class, each with their own specific efficacy and safety profile. This expansion of the treatment landscape has dramatically improved outcomes for patients. However, as the treatment options for RRMM become more complex, choosing the class of agent or combination of agents to use in the relapsed setting becomes increasingly challenging. Furthermore, treatment options for specific patient populations such as the elderly, those with high-risk cytogenetic abnormalities and those with refractory disease are yet to be defined in the current treatment landscape. When choosing an appropriate treatment approach, physicians must consider multiple criteria including both patient-related and disease-related factors. The aim should be to provide patientspecific treatment in order to gain a clinical benefit while minimizing toxicity. This review provides an overview of the mechanism of action and efficacy and safety profiles of each class of agent and of treatment regimens that combine different classes of agent, with a special focus on treating specific patient populations.

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Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

et al. 2020

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IMPORTANCEThe addition of daratumumab to backbone multiple myeloma (MM) regimens is associated with improved response rates and progression-free survival (PFS). Whether improved outcomes are also associated with this regimen among patients with cytogenetically defined high-risk MM (HRMM) remains unclear.OBJECTIVE To measure PFS associated with adding daratumumab to backbone MM regimens among patients with HRMM.DATA SOURCES For this systematic review and meta-analysis, MEDLINE, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and meeting libraries were searched from inception to January 2, 2020, using terms reflecting multiple myeloma and daratumumab.STUDY SELECTION Included studies were phase 3 randomized clinical trials that compared backbone MM regimens with the same regimen plus daratumumab in newly diagnosed or relapsed or refractory MM, such that the only difference between the intervention and control groups was use of daratumumab and reported outcomes by cytogenetic risk. High-risk MM was defined as the presence of t(4;14), t(14;16), or del(17p).DATA EXTRACTION AND SYNTHESIS Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 investigators independently extracted study data, with disagreements resolved by a third investigator. Quality was assessed by the Cochrane risk-of-bias method.MAIN OUTCOMES AND MEASURES Data on effectiveness were extracted using hazard ratios (HRs) for PFS. Relative log-HRs were pooled using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran Q and the I 2 statistic. RESULTSOf 5194 studies screened, 6 phase 3 trials were eligible, including 3 trials for newly diagnosed MM (2528 patients; 358 with HRMM) and 3 trials for relapsed or refractory MM (1533 patients; 222 with HRMM). Among patients with newly diagnosed HRMM, the addition of daratumumab to backbone regimens was associated with improved PFS (pooled HR, 0.67; 95% CI, 0.47-0.95; P = .02), with little evidence of heterogeneity (Cochran Q, P = .77; I 2 = 0%). Similar results were seen among patients with relapsed or refractory HRMM (pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity (Cochran Q, P = .63; I 2 = 0%).CONCLUSIONS AND RELEVANCE This study suggests that incorporating daratumumab to backbone regimens may be associated with improved PFS among patients with newly diagnosed HRMM or relapsed or refractory HRMM.

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Carfilzomib–dexamethasone vs bortezomib–dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR

Cited by 51 publications

References 24 publications

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

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