Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma

Avet-Loiseau, Hervé; Fonseca, Rafaël; Siegel, David S.; Dimopoulos, Meletios Α.; Špıčka, Ivan; Masszi, Tamás; Hájek, Roman; Rosiñol, Laura; Goranova-Marinova, Vesselina; Mihaylov, Georgi; Maisnar, Vladimír; Mateos, María Victoria; Wang, Michael; Niesvizky, Rubén; Oriol, Albert; Jakubowiak, Andrzej; Minařík, Jiří; Palumbo, Antônio; Bensinger, William I.; Kukreti, Vishal; Ben‐Yehuda, Dina; Stewart, A. Keith; Obreja, Mihaela; Moreau, Philippe

doi:10.1182/blood-2016-03-707596

Cited by 112 publications

(92 citation statements)

References 22 publications

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“…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%

“…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%

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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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100

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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: Org Frommentioning

confidence: 99%

Section: Introductionmentioning

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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100

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“…In ASPIRE, a significant increase in PFS was observed with carfilzomib regardless of patients' cytogenetic risk, where a 60% cut-off was used to define high-risk patients for t(4;14), t(14;16) and del(17p). 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: 83%

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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“…При исполь-зовании карфилзомиба в монорежиме ОО достигнут у 52 % бортезомиб-наивных больных с рецидивами [6], а у рефрактерных к бортезомибу -приблизительно у 20 % [7]. Карфил зомиб показал преимущество в те-рапии ММ, ассо циированной с высоким цитогенети-ческим риском: транслокации (4;14), (14;16) и делеция хромосомы 17, что было продемонстрировано в III фа-зе клинического исследования [8]. Пациенты (n = 417) были стратифицированы на 2 группы: высокий риск (n = 100) и стандартный риск (n = 317).…”

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Proteasome inhibitors: situation and prospects (literature review and own data)

Rukavitsyn¹,

Рукавицын²

2016

Onkogematologiâ

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Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma

Abstract: Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

Cited by 112 publications

References 22 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

Proteasome inhibitors: situation and prospects (literature review and own data)

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