{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T03:37:24Z","timestamp":1779075444447,"version":"3.51.4"},"reference-count":108,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,18]],"date-time":"2018-07-18T00:00:00Z","timestamp":1531872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients\u2032 survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author\u2019s own experiences\/views.<\/jats:p>","DOI":"10.3390\/ijms19072087","type":"journal-article","created":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T03:50:43Z","timestamp":1531972243000},"page":"2087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies"],"prefix":"10.3390","volume":"19","author":[{"given":"Wolfgang","family":"Willenbacher","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Innsbruck Medical University, 6020 Innsbruck, Austria"},{"name":"Oncotyrol, Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-7824","authenticated-orcid":false,"given":"Andreas","family":"Seeber","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9829-1309","authenticated-orcid":false,"given":"Normann","family":"Steiner","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Willenbacher","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Innsbruck Medical University, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoran","family":"Gatalica","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Swensen","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffery","family":"Kimbrough","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9743-7265","authenticated-orcid":false,"given":"Semir","family":"Vranic","sequence":"additional","affiliation":[{"name":"College of Medicine, Qatar University, Doha 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1053\/j.seminoncol.2016.11.004","article-title":"Multiple myeloma epidemiology and survival: A unique malignancy","volume":"43","author":"Kazandjian","year":"2016","journal-title":"Semin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3322\/caac.21252","article-title":"Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back","volume":"64","author":"Bianchi","year":"2014","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-3-540-85772-3_2","article-title":"Epidemiology of multiple myeloma","volume":"183","author":"Becker","year":"2011","journal-title":"Recent Results Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1002\/cncr.31243","article-title":"Current developments in immunotherapy in the treatment of multiple myeloma","volume":"124","author":"Kohler","year":"2018","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/ajh.24402","article-title":"Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management","volume":"91","author":"Rajkumar","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nrclinonc.2016.122","article-title":"Genomic complexity of multiple myeloma and its clinical implications","volume":"14","author":"Manier","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2217\/imt-2017-0136","article-title":"Emerging immune targets for the treatment of multiple myeloma","volume":"10","author":"Sohail","year":"2018","journal-title":"Immunotherapy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/phar.1671","article-title":"Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat","volume":"35","author":"Afifi","year":"2015","journal-title":"Pharmacotherapy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e431","DOI":"10.1200\/EDBK_159516","article-title":"New Targets and New Agents in High-Risk Multiple Myeloma","volume":"35","author":"Nooka","year":"2016","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1182\/blood.V67.2.529.529","article-title":"Autologous transplantation of blood-derived hemopoietic stem cells after myeloablative therapy in a patient with Burkitt\u2019s lymphoma","volume":"67","author":"Korbling","year":"1986","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1056\/NEJMoa1611750","article-title":"Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma","volume":"376","author":"Attal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1001\/jamaoncol.2017.4600","article-title":"Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis","volume":"4","author":"Dhakal","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1038\/ncomms3997","article-title":"Heterogeneity of genomic evolution and mutational profiles in multiple myeloma","volume":"5","author":"Bolli","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccr.2013.12.015","article-title":"Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy","volume":"25","author":"Lohr","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1038\/leu.2009.174","article-title":"International Myeloma Working Group molecular classification of multiple myeloma: Spotlight review","volume":"23","author":"Fonseca","year":"2009","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1200\/JCO.2016.70.6705","article-title":"Genomics of Multiple Myeloma","volume":"35","author":"Cleynen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/978-3-319-40320-5_3","article-title":"Genomic Aberrations in Multiple Myeloma","volume":"169","author":"Manier","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrc3257","article-title":"The genetic architecture of multiple myeloma","volume":"12","author":"Morgan","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bhutani, M., Landgren, O., and Usmani, S.Z. (2015). Multiple myeloma: Is it time for biomarker-driven therapy?. Am. Soc. Clin. Oncol. Educ. Book, e493\u2013e503.","DOI":"10.14694\/EdBook_AM.2015.35.e493"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1182\/blood-2011-11-390658","article-title":"Trisomies in multiple myeloma: Impact on survival in patients with high-risk cytogenetics","volume":"119","author":"Kumar","year":"2012","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56338","DOI":"10.18632\/oncotarget.17630","article-title":"Identification of precision treatment strategies for relapsed\/refractory multiple myeloma by functional drug sensitivity testing","volume":"8","author":"Majumder","year":"2017","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lin, M., Lee, P.L., Chiu, L., Chua, C., Ban, K.H.K., Lin, A.H.F., Chan, Z.L., Chung, T.H., Yan, B., and Chng, W.J. (2018). Identification of novel fusion transcripts in multiple myeloma. J. Clin. Pathol.","DOI":"10.1136\/jclinpath-2017-204961"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/978-1-4939-6703-2_23","article-title":"Recurrent Cytogenetic Abnormalities in Multiple Myeloma","volume":"1541","author":"Chan","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1182\/blood-2005-01-0034","article-title":"Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma","volume":"106","author":"Bergsagel","year":"2005","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.clml.2017.06.021","article-title":"Precision Medicine in Myeloma: Challenges in Defining an Actionable Approach","volume":"17","author":"Keane","year":"2017","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3324\/haematol.2012.066555","article-title":"Standard and novel imaging methods for multiple myeloma: Correlates with prognostic laboratory variables including gene expression profiling data","volume":"98","author":"Waheed","year":"2013","journal-title":"Haematologica"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.soncn.2017.05.001","article-title":"Multiple Myeloma Genomics: A Systematic Review","volume":"33","author":"Weaver","year":"2017","journal-title":"Semin. Oncol. Nurs."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","article-title":"Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma","volume":"33","author":"Walker","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8036","DOI":"10.1200\/JCO.2018.36.15_suppl.8036","article-title":"Molecular underpinnings of clinical disparity patterns in African American (AA) versus Caucasian American (CA) multiple myeloma (MM) patients","volume":"36","author":"Hill","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1158\/2159-8290.CD-13-0014","article-title":"Targeting the BRAF V600E mutation in multiple myeloma","volume":"3","author":"Andrulis","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e337","DOI":"10.1038\/oncsis.2017.36","article-title":"Molecular signaling in multiple myeloma: Association of RAS\/RAF mutations and MEK\/ERK pathway activation","volume":"6","author":"Xu","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1182\/blood-2016-02-698092","article-title":"Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes","volume":"128","author":"Kortum","year":"2016","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1200\/JCO.2003.03.139","article-title":"Thalidomide alone or with dexamethasone for previously untreated multiple myeloma","volume":"21","author":"Weber","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1182\/blood-2007-10-078022","article-title":"Multiple myeloma","volume":"111","author":"Kyle","year":"2008","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0140-6736(16)31594-X","article-title":"Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial","volume":"389","author":"Durie","year":"2017","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.bbamcr.2013.08.012","article-title":"Regulation of proteasome activity in health and disease","volume":"1843","author":"Schmidt","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4420","DOI":"10.1200\/JCO.2002.01.133","article-title":"Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies","volume":"20","author":"Orlowski","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1056\/NEJMoa030288","article-title":"A phase 2 study of bortezomib in relapsed, refractory myeloma","volume":"348","author":"Richardson","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1182\/blood-2006-08-036947","article-title":"Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial","volume":"110","author":"Richardson","year":"2007","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1056\/NEJMoa0801479","article-title":"Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma","volume":"359","author":"Schlag","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"23704","DOI":"10.18632\/oncotarget.25281","article-title":"Efficacy and safety of carfilzomib in relapsed and\/or refractory multiple myeloma: Systematic review and meta-analysis of 14 trials","volume":"9","author":"Shah","year":"2018","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1056\/NEJMoa1411321","article-title":"Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma","volume":"372","author":"Stewart","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1200\/JCO.2017.76.5032","article-title":"Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma","volume":"36","author":"Siegel","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/S1470-2045(17)30578-8","article-title":"Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): An interim overall survival analysis of an open-label, randomised, phase 3 trial","volume":"18","author":"Dimopoulos","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1182\/blood-2014-01-548826","article-title":"Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed\/refractory multiple myeloma patients","volume":"124","author":"Richardson","year":"2014","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1056\/NEJMoa1516282","article-title":"Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"374","author":"Moreau","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1038\/leu.2012.119","article-title":"Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide","volume":"26","author":"Mendy","year":"2012","journal-title":"Leukemia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1056\/NEJM199911183412102","article-title":"Antitumor activity of thalidomide in refractory multiple myeloma","volume":"341","author":"Singhal","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1182\/blood-2002-03-0996","article-title":"Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma","volume":"100","author":"Richardson","year":"2002","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5008","DOI":"10.1200\/JCO.2009.23.6802","article-title":"Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma","volume":"27","author":"Lacy","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/S0140-6736(15)01120-4","article-title":"Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial","volume":"387","author":"Lonial","year":"2016","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1056\/NEJMoa1714678","article-title":"Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma","volume":"378","author":"Mateos","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1505654","article-title":"Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma","volume":"373","author":"Lonial","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34001","DOI":"10.18632\/oncotarget.16987","article-title":"Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed\/refractory multiple myeloma","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/leu.2017.60","article-title":"Monoclonal antibody therapy in multiple myeloma","volume":"31","author":"Touzeau","year":"2017","journal-title":"Leukemia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1002\/ijc.25151","article-title":"Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin","volume":"127","author":"Hayashi","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2217\/epi.15.84","article-title":"Epigenome-based personalized medicine in human cancer","volume":"8","author":"Yan","year":"2016","journal-title":"Epigenomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/S1470-2045(13)70398-X","article-title":"Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study","volume":"14","author":"Dimopoulos","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/S1470-2045(14)70440-1","article-title":"Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial","volume":"15","author":"Hungria","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e506","DOI":"10.1016\/S2352-3026(16)30147-8","article-title":"Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): A randomised, placebo-controlled, phase 3 trial","volume":"3","author":"Hungria","year":"2016","journal-title":"Lancet Haematol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/bjh.14821","article-title":"Panobinostat plus bortezomib and dexamethasone: Impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial","volume":"179","author":"Hungria","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e572","DOI":"10.1016\/S2352-3026(16)30165-X","article-title":"Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): A multicentre, open-label, phase 1\/2 trial","volume":"3","author":"Popat","year":"2016","journal-title":"Lancet Haematol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3324\/haematol.2014.119735","article-title":"Phase I\/II study of the combination of panobinostat and carfilzomib in patients with relapsed\/refractory multiple myeloma","volume":"100","author":"Berdeja","year":"2015","journal-title":"Haematologica"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8567","DOI":"10.1073\/pnas.0503221102","article-title":"Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma","volume":"102","author":"Hideshima","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.1158\/1078-0432.CCR-16-2526","article-title":"Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma","volume":"23","author":"Vogl","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"12293","DOI":"10.1073\/pnas.192461099","article-title":"Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade","volume":"99","author":"Iwai","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1056\/NEJMoa1412082","article-title":"Nivolumab in previously untreated melanoma without BRAF mutation","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0140-6736(16)32517-X","article-title":"Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial","volume":"389","author":"Rittmeyer","year":"2017","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/S0140-6736(15)01281-7","article-title":"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial","volume":"387","author":"Herbst","year":"2016","journal-title":"Lancet"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1056\/NEJMoa1507643","article-title":"Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer","volume":"373","author":"Borghaei","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1016\/S0140-6736(16)00561-4","article-title":"Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial","volume":"387","author":"Rosenberg","year":"2016","journal-title":"Lancet"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1200\/JCO.2016.67.9761","article-title":"Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer","volume":"34","author":"Massard","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1056\/NEJMoa1613683","article-title":"Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma","volume":"376","author":"Bellmunt","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S1470-2045(17)30065-7","article-title":"Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial","volume":"18","author":"Sharma","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed\/Refractory Classic Hodgkin Lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e180013","DOI":"10.1001\/jamaoncol.2018.0013","article-title":"Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial","volume":"4","author":"Fuchs","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1182\/blood-2006-10-051482","article-title":"Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-\u03b3 and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway","volume":"110","author":"Liu","year":"2007","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/leu.2012.213","article-title":"Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma","volume":"27","author":"Tamura","year":"2013","journal-title":"Leukemia"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/leu.2015.11","article-title":"Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells","volume":"29","author":"Ray","year":"2015","journal-title":"Leukemia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4607","DOI":"10.1158\/1078-0432.CCR-15-0200","article-title":"Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma","volume":"21","author":"Gorgun","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1182\/blood-2016-08-731885","article-title":"Targeting the PD-1\/PD-L1 axis in multiple myeloma: A dream or a reality?","volume":"129","author":"Rosenblatt","year":"2017","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e1254856","DOI":"10.1080\/2162402X.2016.1254856","article-title":"PD-1\/PD-L1 inhibitors in multiple myeloma: The present and the future","volume":"5","author":"Jelinek","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2698","DOI":"10.1200\/JCO.2015.65.9789","article-title":"Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study","volume":"34","author":"Lesokhin","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Jatin, J., Shah, S.J., Mar\u00eda-Victoria, M., Antonio, P., Uma, K., Patricia, M.M., and Jesus, S.M. (2016). KEYNOTE-183: A randomized, open-label phase 3 study of pembrolizumab in combination with pomalidomide and low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma (rrMM). J. Clin. Oncol., 34.","DOI":"10.1200\/JCO.2016.34.15_suppl.TPS8070"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"TPS8069","DOI":"10.1200\/JCO.2016.34.15_suppl.TPS8069","article-title":"KEYNOTE-185: A randomized, open-label phase 3 study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM)","volume":"34","author":"Palumbo","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8008","DOI":"10.1200\/JCO.2018.36.15_suppl.8008","article-title":"FDA analysis of pembrolizumab trials in multiple myeloma: Immune related adverse events (irAEs) and response","volume":"36","author":"Krauss","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8010","DOI":"10.1200\/JCO.2018.36.15_suppl.8010","article-title":"A phase 3 randomized study of pembrolizumab (pembro) plus lenalidomide (len) and low-dose dexamethasone (Rd) versus Rd for newly diagnosed and treatment-naive multiple myeloma (MM): KEYNOTE-185","volume":"36","author":"Usmani","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_90","first-page":"8084","article-title":"T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma","volume":"77","author":"Brudno","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1182\/blood-2012-01-405985","article-title":"Clonal competition with alternating dominance in multiple myeloma","volume":"120","author":"Keats","year":"2012","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/hon.2353","article-title":"Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation","volume":"35","author":"Mey","year":"2017","journal-title":"Hematol. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1158\/2159-8290.CD-16-1396","article-title":"High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial","volume":"7","author":"Massard","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Steiner, N., Hajek, R., Sevcikova, S., Borjan, B., Johrer, K., Gobel, G., Untergasser, G., and Gunsilius, E. (2017). High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181487"},{"key":"ref_95","first-page":"2877","article-title":"Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma","volume":"28","author":"Hao","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Rastgoo, N., Pourabdollah, M., Abdi, J., Reece, D., and Chang, H. (2018). Dysregulation of EZH2\/miR-138 axis contributes to drug resistance in multiple myeloma by downregulating RBPMS. Leukemia.","DOI":"10.1038\/s41375-018-0140-y"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.18632\/oncotarget.3075","article-title":"Molecular chaperone GRP78 enhances aggresome delivery to autophagosomes to promote drug resistance in multiple myeloma","volume":"6","author":"Jagannathan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/bjh.15210","article-title":"Resistance to proteasome inhibitors and other targeted therapies in myeloma","volume":"182","author":"Kuss","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1182\/blood-2007-08-104950","article-title":"Molecular basis of bortezomib resistance: Proteasome subunit \u03b25 (PSMB5) gene mutation and overexpression of PSMB5 protein","volume":"112","author":"Oerlemans","year":"2008","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a primary target of thalidomide teratogenicity","volume":"327","author":"Ito","year":"2010","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"301","DOI":"10.18632\/genesandcancer.121","article-title":"Treatment of patients with refractory metastatic cancer according to molecular profiling on tumor tissue in the clinical routine: An interim-analysis of the ONCO-T-PROFILE project","volume":"7","author":"Seeber","year":"2016","journal-title":"Genes Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejca.2018.02.021","article-title":"Comprehensive analysis of cancers of unknown primary for the biomarkers of response to immune checkpoint blockade therapy","volume":"94","author":"Gatalica","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Topcagic, J., Feldman, R., Ghazalpour, A., Swensen, J., Gatalica, Z., and Vranic, S. (2018). Comprehensive molecular profiling of advanced\/metastatic olfactory neuroblastomas. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191244"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/cam4.1372","article-title":"Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients","volume":"7","author":"Vanderwalde","year":"2018","journal-title":"Cancer Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4877","DOI":"10.1200\/JCO.2009.26.5983","article-title":"Pilot study using molecular profiling of patients\u2032 tumors to find potential targets and select treatments for their refractory cancers","volume":"28","author":"Stephenson","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1111\/j.1365-2141.2007.06921.x","article-title":"Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: Comparison with total therapy 2","volume":"140","author":"Zangari","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1182\/blood.V124.21.195.195","article-title":"Curing Multiple Myeloma (MM) with Total Therapy (TT)","volume":"124","author":"Barlogie","year":"2014","journal-title":"Blood"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41408-018-0065-8","article-title":"Defining cure in multiple myeloma: A comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies","volume":"8","author":"Ravi","year":"2018","journal-title":"Blood Cancer J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2087\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:12:45Z","timestamp":1760195565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,18]]},"references-count":108,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["ijms19072087"],"URL":"https:\/\/doi.org\/10.3390\/ijms19072087","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,18]]}}}