NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018

Kumar, Shaji; Callander, Natalie S.; Alsina, Melissa; Atanackovic, Djordje; Biermann, J. Sybil; Castillo, Jorge; Chandler, Jason C.; Costello, Caitlin; Faiman, Matthew; Fung, Henry C.; Godby, Kelly N.; Hofmeister, Craig C.; Holmberg, Leona; Holstein, Sarah A.; Huff, Carol Ann; Kang, Yubin; Kassim, Adetola A.; Liedtke, Michaela; Malek, Ehsan; Martin, Thomas G.; Neppalli, Vishala T.; Omel, James; Raje, Noopur; Singhal, Seema; Somlo, George; Stockerl-Goldstein, Keith; Weber, Donna M.; Yahalom, Joachim; Kumar, Rashmi; Shead, Dorothy A.

doi:10.6004/jnccn.2018.0002

Cited by 149 publications

(83 citation statements)

References 33 publications

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“…However, nearly all patients require multiple lines of therapy as they relapse or develop disease refractory to treatment. First‐line and subsequent therapies usually involve IMiDs and PIs in doublet or triplet combinations with corticosteroids and other systemic therapies (Kumar et al , ). As use of these combinations have become new standards of care, the treatment challenges in the relapsed/refractory (RR) setting have evolved, with increasing numbers of patients being quad‐refractory to bortezomib, lenalidomide, pomalidomide and carfilzomib or penta‐refractory to these four drugs and the anti‐CD38 monoclonal antibody daratumumab.…”

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confidence: 99%

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

et al. 2019

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Summary Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients. Registered at ClinicalTrials.gov (NCT02199665)

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confidence: 99%

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

et al. 2019

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“…Diese über mehrere Jahre belegte Wirksamkeit von ELd nahmen nationale und internationale Fachgesellschaften zum Anlass, Elotuzumab in ihren Leitlinien als Standardtherapie für das rezidivierte und/oder refraktäre Myelom zu empfehlen [12][13][14]. Die Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie verweist in ihrer kürzlich aktualisierten Leitlinie (Stand Mai 2018) auf ELd als wichtige Immunmodulator-basierte Dreifachkombination in der Zweitlinie [12].…”

Section: Elotuzumab Als Zweitlinienstandard Empfohlenunclassified

“…Das US-amerikanische National Comprehensive Cancer Network (NCCN) spricht sich in seiner Leitlinie (Stand Februar 2018) ebenfalls für die Kombination ELd als bevorzugte Therapieoption in der Zweitlinie aus. Das NCCN unterstreicht den Stellenwert von Elotuzumab zusätzlich, indem es ELd in die Empfehlungskategorie 1 mit höchstem Evidenz-und Konsenslevel einordnet [13]. Die European Society for Medical Oncology listet Elotuzumab in Kombination mit Ld bereits seit 2017 als empfohlene Therapie beim rezidivierten und/oder refraktä-ren Multiplen Myelom [14].…”

Section: Elotuzumab Als Zweitlinienstandard Empfohlenunclassified

OnkoImmun 6

2018

Oncol Res Treat

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“…8 The reason for the improved outcomes is a series of therapeutic advances that include the introduction of autologous stem cell transplants (ASCT), immunomodulatory drugs (IMiDs), and proteasome inhibitors (PIs), all of which are now first-line therapies. 7–9 Despite the success of these treatments in extending the overall survival (OS) by 6-10 years, depending upon age at diagnosis, most patients eventually relapse and become refractory to the therapies that they had received. 10–12 The mechanisms by which patients develop resistance to these therapies are only partially understood and are thought to depend critically upon the BM microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

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38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

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NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018

Cited by 149 publications

References 33 publications

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

OnkoImmun 6

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

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