Skip to main content
Erschienen in: memo - Magazine of European Medical Oncology 2/2017

01.06.2017 | short review

Is there progress in the treatment of high-risk myeloma?

Novel insights from ASH 2016

verfasst von: DI (FH) Arnold Bolomsky, Univ.Prof.Dr. Heinz Ludwig

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 2/2017

Einloggen, um Zugang zu erhalten

Summary

Treatment of high-risk patients is a major challenge in multiple myeloma (MM). Median survival rates of these patients remain poor at about 2 years and there were no major improvements with the introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). This resulted in a remarkable discrepancy in the treatment results of MM, with a significant proportion of patients achieving long-term progression-free survival of >10 years (or even cure) while in patients with aggressive disease no or only minor improvements have been achieved. Current consensus statements define high-risk based on International Staging System (ISS) stage III plus the presence of cytogenetic aberrations (t(4;14) and/or del17p) and/or high lactate dehydrogenase (LDH). Regarding the treatment of high-risk patients, autologous stem cell transplantation remains the standard of care in transplant-eligible candidates. However, there is an unmet need for novel therapeutic strategies to overcome the limitations of current treatment modalities. Hence, efforts to study high-risk disease in MM were recently intensified. The ongoing search for new treatment strategies and drug targets is also reflected by the growing number of studies investigating high-risk disease. This short review aims to provide an overview about the current research landscape and recent progress in high-risk MM based on selected abstracts of the ASH 2016 meeting.
Literatur
1.
Zurück zum Zitat Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–8.CrossRefPubMed Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–8.CrossRefPubMed
2.
Zurück zum Zitat Chng WJ, Dispenzieri A, Chim C‑S, Fonseca R, Goldschmidt H, Lentzsch S, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014;28(2):269–77.CrossRefPubMed Chng WJ, Dispenzieri A, Chim C‑S, Fonseca R, Goldschmidt H, Lentzsch S, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014;28(2):269–77.CrossRefPubMed
3.
Zurück zum Zitat Ludwig H, Bolejack V, Crowley J, Bladé J, Miguel JS, Kyle RA, et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol. 2010;28(9):1599–605.CrossRefPubMed Ludwig H, Bolejack V, Crowley J, Bladé J, Miguel JS, Kyle RA, et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol. 2010;28(9):1599–605.CrossRefPubMed
4.
Zurück zum Zitat Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98(6):980–7.CrossRefPubMedPubMedCentral Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98(6):980–7.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108(6):2020–8.CrossRefPubMedPubMedCentral Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108(6):2020–8.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62.CrossRefPubMedPubMedCentral Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109(6):2276–84.CrossRefPubMed Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109(6):2276–84.CrossRefPubMed
8.
Zurück zum Zitat Paiva B, Gutiérrez NC, Rosiñol L, Vídriales M‑B, Montalbán M‑Á, Martínez-López J, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687–91.CrossRefPubMed Paiva B, Gutiérrez NC, Rosiñol L, Vídriales M‑B, Montalbán M‑Á, Martínez-López J, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687–91.CrossRefPubMed
9.
Zurück zum Zitat Hose D, Rème T, Hielscher T, Moreaux J, Messner T, Seckinger A, et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica. 2011;96(1):87–95.CrossRefPubMed Hose D, Rème T, Hielscher T, Moreaux J, Messner T, Seckinger A, et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica. 2011;96(1):87–95.CrossRefPubMed
10.
Zurück zum Zitat Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Gertz MA, Lacy MQ, et al. Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood. 2005;106(7):2276–9.CrossRefPubMedPubMedCentral Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Gertz MA, Lacy MQ, et al. Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood. 2005;106(7):2276–9.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067–76.CrossRefPubMedPubMedCentral Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067–76.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Egan J, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060–6.CrossRefPubMedPubMedCentral Egan J, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060–6.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Cavo M, Beksac M, Dimopoulos MA, Pantani L, Gay F, Hájek R, et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):673. Cavo M, Beksac M, Dimopoulos MA, Pantani L, Gay F, Hájek R, et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):673.
14.
Zurück zum Zitat Cavo M, Petrucci MT, Di Raimondo F, Zamagni E, Gamberi B, Crippa C, et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):991. Cavo M, Petrucci MT, Di Raimondo F, Zamagni E, Gamberi B, Crippa C, et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):991.
15.
Zurück zum Zitat Sonneveld P, Beksac M, van der Holt B, Dimopoulos MA, Carella AM, Ludwig H, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): a randomized phase 3 study of the european myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):242. Sonneveld P, Beksac M, van der Holt B, Dimopoulos MA, Carella AM, Ludwig H, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): a randomized phase 3 study of the european myeloma network (EMN02/HO95 MM trial). Blood. 2016;128(22):242.
16.
Zurück zum Zitat Straka C, Knop S, Vogel M, Müller J, Kropff M, Metzner B, et al. Bortezomib consolidation following autologous transplant equalizes the outcome for older patients with less intensive pretreatment compared to younger patients with newly diagnosed multiple myeloma. Blood. 2016;128(22):516. Straka C, Knop S, Vogel M, Müller J, Kropff M, Metzner B, et al. Bortezomib consolidation following autologous transplant equalizes the outcome for older patients with less intensive pretreatment compared to younger patients with newly diagnosed multiple myeloma. Blood. 2016;128(22):516.
17.
Zurück zum Zitat Silvennoinen R, Anttila P, Säily M, Lundan T, Heiskanen J, Siitonen T, et al. RVD + ASCT + lenalidomide maintenance benefits patients without high-risk cytogenetics and results in recovery of the normal plasma cell composition in bone marrow. Blood. 2016;128(22):676. Silvennoinen R, Anttila P, Säily M, Lundan T, Heiskanen J, Siitonen T, et al. RVD + ASCT + lenalidomide maintenance benefits patients without high-risk cytogenetics and results in recovery of the normal plasma cell composition in bone marrow. Blood. 2016;128(22):676.
18.
Zurück zum Zitat Wester R, van der Holt B, Asselbergs E, van Duin M, Zweegman S, Kersten MJ, et al. Phase 2 study of carfilzomib, thalidomide, and low-dose dexamethasone as induction/consolidation in newly diagnosed, transplant eligible patients with multiple myeloma, the carthadex trial. Blood. 2016;128(22):1141. Wester R, van der Holt B, Asselbergs E, van Duin M, Zweegman S, Kersten MJ, et al. Phase 2 study of carfilzomib, thalidomide, and low-dose dexamethasone as induction/consolidation in newly diagnosed, transplant eligible patients with multiple myeloma, the carthadex trial. Blood. 2016;128(22):1141.
19.
Zurück zum Zitat Zimmermann T, Raje NS, Vij R, Reece D, Berdeja JG, Stephens LA, et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Krd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Blood. 2016;128(22):675. Zimmermann T, Raje NS, Vij R, Reece D, Berdeja JG, Stephens LA, et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Krd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Blood. 2016;128(22):675.
20.
Zurück zum Zitat Mateos MV, Estell J, Barreto W, Corradini P, Min CK, Medvedova E, et al. Efficacy of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory myeloma based on prior lines of therapy: updated analysis of castor. Blood. 2016;128(22):1150. Mateos MV, Estell J, Barreto W, Corradini P, Min CK, Medvedova E, et al. Efficacy of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory myeloma based on prior lines of therapy: updated analysis of castor. Blood. 2016;128(22):1150.
21.
Zurück zum Zitat Usmani SZ, Dimopoulos MA, Belch A, White D, Benboubker L, Cook G, et al. Efficacy of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients with 1 to 3 prior lines of therapy: updated analysis of pollux. Blood. 2016;128(22):1151. Usmani SZ, Dimopoulos MA, Belch A, White D, Benboubker L, Cook G, et al. Efficacy of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients with 1 to 3 prior lines of therapy: updated analysis of pollux. Blood. 2016;128(22):1151.
22.
Zurück zum Zitat Branca A, Buros A, Yoon D, Suva LJ, Weinhold N, Rasche L, et al. Daratumumab single agent and daratumumab plus pomalidomide and dexametasone in relapsed/refractory multiple myeloma: a real life retrospective evaluation. Blood. 2016;128(22):4516. Branca A, Buros A, Yoon D, Suva LJ, Weinhold N, Rasche L, et al. Daratumumab single agent and daratumumab plus pomalidomide and dexametasone in relapsed/refractory multiple myeloma: a real life retrospective evaluation. Blood. 2016;128(22):4516.
23.
Zurück zum Zitat Driessen C, Müller R, Novak U, Cantoni N, Betticher D, Mach N, et al. The HIV protease inhibitor Nelfinavir in combination with bortezomib and dexamethasone (NVd) has excellent activity in patients with advanced, proteasome inhibitor-refractory multiple myeloma: a multicenter phase II trial (SAKK 39/13). Blood. 2016;128(22):487. Driessen C, Müller R, Novak U, Cantoni N, Betticher D, Mach N, et al. The HIV protease inhibitor Nelfinavir in combination with bortezomib and dexamethasone (NVd) has excellent activity in patients with advanced, proteasome inhibitor-refractory multiple myeloma: a multicenter phase II trial (SAKK 39/13). Blood. 2016;128(22):487.
24.
Zurück zum Zitat Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, et al. Selinexor and low dose dexamethasone (sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Blood. 2016;128(22):491. Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, et al. Selinexor and low dose dexamethasone (sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Blood. 2016;128(22):491.
25.
Zurück zum Zitat Jakubowiak A, Jasielec J, Rosenbaum CA, Cole CE, Chari A, Nam J, et al. Final results of phase 1 MMRC trial of selinexor, carfilzomib, and dexamethasone in relapsed/refractory multiple myeloma (RRMM). Blood. 2016;128(22):973. Jakubowiak A, Jasielec J, Rosenbaum CA, Cole CE, Chari A, Nam J, et al. Final results of phase 1 MMRC trial of selinexor, carfilzomib, and dexamethasone in relapsed/refractory multiple myeloma (RRMM). Blood. 2016;128(22):973.
26.
Zurück zum Zitat Kumar S, Vij R, Kaufman JL, Mikhael J, Facon T, Pegourie B, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Blood. 2016;128(22):488. Kumar S, Vij R, Kaufman JL, Mikhael J, Facon T, Pegourie B, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Blood. 2016;128(22):488.
27.
Zurück zum Zitat Moreau P, Chanan-Khan AA, Roberts AW, Agarwal AB, Facon T, Kumar S, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Blood. 2016;128(22):975. Moreau P, Chanan-Khan AA, Roberts AW, Agarwal AB, Facon T, Kumar S, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Blood. 2016;128(22):975.
28.
Zurück zum Zitat Spencer A, Harrison S, Laubach JP, Zonder J, Badros AZ, Bergin K, et al. Pmd-107: marizomib, pomalidomide and low dose-dexamethasone combination study in relapsed/refractory multiple myeloma (NCT02103335): full enrollment results from a phase-1 multicenter, open label study. Blood. 2016;128(22):3326. Spencer A, Harrison S, Laubach JP, Zonder J, Badros AZ, Bergin K, et al. Pmd-107: marizomib, pomalidomide and low dose-dexamethasone combination study in relapsed/refractory multiple myeloma (NCT02103335): full enrollment results from a phase-1 multicenter, open label study. Blood. 2016;128(22):3326.
29.
Zurück zum Zitat Yaccoby S, Qu P, Mehdi S, Hoering A, Epstein J, Johnson SK, et al. Signatures of mesenchymal cell lineages and microenvironment factors are dysregulated in high risk myeloma. Blood. 2016;128(22):2065. Yaccoby S, Qu P, Mehdi S, Hoering A, Epstein J, Johnson SK, et al. Signatures of mesenchymal cell lineages and microenvironment factors are dysregulated in high risk myeloma. Blood. 2016;128(22):2065.
30.
Zurück zum Zitat Mehdi S, Khan S, Ling W, Shelton RS, Epstein J, Edmondson RD, et al. Mesenchymal stem cells preconditioned with myeloma cells from high-risk patients support the growth of myeloma cells from low-risk patients. Blood. 2016;128(22):3304. Mehdi S, Khan S, Ling W, Shelton RS, Epstein J, Edmondson RD, et al. Mesenchymal stem cells preconditioned with myeloma cells from high-risk patients support the growth of myeloma cells from low-risk patients. Blood. 2016;128(22):3304.
31.
Zurück zum Zitat Gruber F, Keats JJ, McBride K, Runge K, Wuest D, Hadzi T, et al. Bayesian network models of multiple myeloma: drivers of high risk and durable response. Blood. 2016;128(22):4406. Gruber F, Keats JJ, McBride K, Runge K, Wuest D, Hadzi T, et al. Bayesian network models of multiple myeloma: drivers of high risk and durable response. Blood. 2016;128(22):4406.
32.
Zurück zum Zitat Gu C, Chen R, Jing X, Janz S, Yang Y. FOXM1, CDK6 and Rb dependent drug resistance and senescence in myeloma. Blood. 2016;128(22):4456. Gu C, Chen R, Jing X, Janz S, Yang Y. FOXM1, CDK6 and Rb dependent drug resistance and senescence in myeloma. Blood. 2016;128(22):4456.
33.
Zurück zum Zitat Bolomsky A, Heusschen R, Schlangen K, Schönfelder K, Muller J, Schreiner W, et al. Maternal embryonic leucine zipper Kinase (MELK) drives a high-risk gene network and represents an attractive novel drug target in multiple myeloma. Blood. 2016;128(22):309. Bolomsky A, Heusschen R, Schlangen K, Schönfelder K, Muller J, Schreiner W, et al. Maternal embryonic leucine zipper Kinase (MELK) drives a high-risk gene network and represents an attractive novel drug target in multiple myeloma. Blood. 2016;128(22):309.
34.
Zurück zum Zitat Pawlyn C, Bright M, Buros A, Stein CK, Walters Z, Aronson L, et al. Inhibition of the epigenetic modifier EZH2 Upregulates cell cycle control genes to inhibit myeloma cell growth and overcome high-risk disease features. Blood. 2016;128(22):3289. Pawlyn C, Bright M, Buros A, Stein CK, Walters Z, Aronson L, et al. Inhibition of the epigenetic modifier EZH2 Upregulates cell cycle control genes to inhibit myeloma cell growth and overcome high-risk disease features. Blood. 2016;128(22):3289.
Metadaten
Titel
Is there progress in the treatment of high-risk myeloma?
Novel insights from ASH 2016
verfasst von
DI (FH) Arnold Bolomsky
Univ.Prof.Dr. Heinz Ludwig
Publikationsdatum
01.06.2017
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 2/2017
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-017-0338-0

Weitere Artikel der Ausgabe 2/2017

memo - Magazine of European Medical Oncology 2/2017 Zur Ausgabe