多发性骨髓瘤药物治疗进展
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摘要
多发性骨髓瘤(MM)是血液系统第三大恶性肿瘤,随着检测手段的不断提高及新药的不断问世,MM的诊断和治疗得以不断完善和改进。高剂量化疗后自体干细胞移植以及沙利度胺、来那度胺、硼替佐米等药物的应用,显著改善了MM患者的预后,但目前仍不能完全治愈,复发、耐药以及治疗相关毒性仍是阻碍患者生存的重要因素,因此寻求新的治疗策略显得尤为重要。近年来,大量新型药物(如三代免疫调节剂、蛋白酶体抑制剂、组蛋白去乙酰化酶抑制剂、单克隆抗体及检查点阻断剂等)均展现出良好的抗骨髓瘤活性。
Multiple myeloma( MM) is the third most common hematologic malignancies. With the continuous improvement of detection methods and the advent of new drugs,the diagnosis and treatment of MM have been continuously improved. The applications of autologous stem cell transplantation after high dose chemotherapy and drugs such as thalidomide,lenalidomide and bortezomib have significantly improved the prognosis of patients with MM,however,complete cure cannot be achieved yet,and relapse,drug resistance and treatment-related toxicity are still important factors that hinder the survival of the patients,so the search for new therapeutic strategies is particularly important. In recent years,a large number of new drugs( such as third generations of immunomodulatory drugs,proteasome inhibitors,histone deacetylase inhibitors,monoclonal antibodies,and checkpoint blockers) have shown good anti-myeloma activity.
Multiple myeloma( MM) is the third most common hematologic malignancies. With the continuous improvement of detection methods and the advent of new drugs,the diagnosis and treatment of MM have been continuously improved. The applications of autologous stem cell transplantation after high dose chemotherapy and drugs such as thalidomide,lenalidomide and bortezomib have significantly improved the prognosis of patients with MM,however,complete cure cannot be achieved yet,and relapse,drug resistance and treatment-related toxicity are still important factors that hinder the survival of the patients,so the search for new therapeutic strategies is particularly important. In recent years,a large number of new drugs( such as third generations of immunomodulatory drugs,proteasome inhibitors,histone deacetylase inhibitors,monoclonal antibodies,and checkpoint blockers) have shown good anti-myeloma activity.
引文
[1]Raza S,Safyan RA,Rosenbaum E,et al.Optimizing current and emerging therapies in multiple myeloma:A guide for the hematologist[J].Ther Adv Hematol,2017,8(2):55-70.
[2]Kumar SK,Dispenzieri A,Lacy MQ,et al.Continued improvement in survival in multiple myeloma:Changes in early mortality and outcomes in older patients[J].Leukemia,2014,28(5):1122-1128.
[3]Dimopoulos MA,Leleu X,Palumbo A,et al.Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma[J].Leukemia,2014,28(8):1573-1585.
[4]Jurczyszyn A,Legie W,Helbig G,et al.New drugs in multiple myeloma-role of carfilzomib and pomalidomide[J].Contemp Oncol(Pozn),2014,18(1):17-21.
[5]Orlowski RZ.Novel agents for multiple myeloma to overcome resistance in phaseⅢclinical trials[J].Semin Oncol,2013,40(5):634-651.
[6]Morgan G,Palumbo A,Dhanasiri S,et al.Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM-003 trial for pomalidomide plus low-dose dexamethasone[J].Br J Haematol,2015,168(6):820-823.
[7]Ramasamy K,Dimopoulos MA,van de Donk NWCJ,et al.Safety of Treatment(Tx)with Pomalidomide(POM)and Low-Dose Dexamethasone(Lo DEX)in Patients(Pts)with Relapsed or Refractory Multiple Myeloma(RRMM)and Renal Impairment(RI),Including Those on Dialysis[J].Blood,2015,126(23):374.
[8]Baz RC,Martin TG 3rd,Lin HY,et al.Randomized multicenter phase 2 study of pomalidomide,cyclophosphamide,and dexamethasone in relapsed refractory myeloma[J].Blood,2016,127(21):2561-2568.
[9]Lacy MQ,Kumar SK,La Plant BR,et al.Pomalidomide Plus LowDose Dexamethasone(Pom/Dex)in Relapsed Myeloma:Long Term Follow up and Factors Predicing Outcome in 345Patients[J].Blood,2012,120:201.
[10]Jakubowiak AJ,Siegel DS,Martin T,et al.Treatment outcomes in patients with relapsed and refractory multiple myeloma and highrisk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study[J].Leukemia,2013,27(12):2351-2356.
[11]Dimopoulos MA,Moreau P,Palumbo A,et al.Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma(ENDEAVOR):Arandomised,phase 3,open-label,multicentre study[J].Lancet Oncol,2016,17(1):27-38.
[12]Badros AZ,Vij R,Martin T,et al.PhaseⅡstudy of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency[J].J Clin Oncol,2010,28(15_suppl):8128-8128.
[13]Badros AZ,Vij R,Martin T,et al.Carfilzomib in multiple myeloma patients with renal impairment:Pharmacokinetics and safety[J].Leukemia,2013,27(8):1707-1714.
[14]Stewart AK,Rajkumar SV,Dimopoulos MA,et al.Carfilzomib,lenalidomide,and dexamethasone for relapsed multiple myeloma[J].N Engl J Med,2015,372(2):142-152.
[15]Shah JJ,Stadtmauer EA,Abonour R,et al.Carfilzomib,pomalidomide,and dexamethasone for relapsed or refractory myeloma[J].Blood,2015,126(20):2284-2290.
[16]Gupta N,Hanley MJ,Xia C,et al.Clinical Pharmacology of Ixazomib:The First Oral Proteasome Inhibitor[J/OL].Clin Pharmacokinet,2018[2018-11-10].https://link.springer.com/article/10.1007%2Fs40262-018-0702-1.[published online ahead of Aug 17,2018].
[17]Moreau P,Masszi T,Grzasko N,et al.Oral Ixazomib,Lenalidomide,and Dexamethasone for Multiple Myeloma[J].N Engl JMed,2016,374(17):1621-1634.
[18]Krishnan A,Kapoor P,Palmer JM,et al.PhaseⅠ/Ⅱtrial of the oral regimen ixazomib,pomalidomide,and dexamethasone in relapsed/refractory multiple myeloma[J/OL].Leukemia,2017[2018-11-10].https://www.nature.com/articles/s41375-018-0038-8.[published online ahead of Dec 18,2018].
[19]Gupta N,Hanley MJ,Harvey RD,et al.A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis[J].Br J Haematol,2016,174(5):748-759.
[20]de Weers M,Tai YT,van der Veer MS,et al.Daratumumab,a novel therapeutic human CD38monoclonal antibody,induces killing of multiple myeloma and other hematological tumors[J].J Immunol,2011,186(3):1840-1848.
[21]Afifi S,Michael A,Lesokhin A.Immunotherapy:A New Approach to Treating Multiple Myeloma with Daratumumab and Elotuzumab[J].Ann Pharmacother,2016,50(7):555-568.
[22]Lokhorst HM,Plesner T,Laubach JP,et al.Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma[J].N Engl JMed,2015,373(13):1207-1219.
[23]Lonial S,Weiss BM,Usmani SZ,et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma(SIRIUS):An open-label,randomised,phase 2 trial[J].Lancet,2016,387(10027):1551-1560.
[24]Palumbo A,Chanan-Khan A,Weisel K,et al.Daratumumab,Bortezomib,and Dexamethasone for Multiple Myeloma[J].NEngl J Med,2016,375(8):754-766.
[25]Bahlis NJ,Moreau P,Nahi H,et al.Daratumumab,lenalidomide,and dexamethasone(DRD)vs lenalidomide and dexamethasone(RD)in relapsed or refractory multiple myeloma(RRMM):Efficacy and safety update(POLLUX)[J].Hematol Oncol,2017,35(S2):389-389.
[26]Dimopoulos MA,Lonial S,White D,et al.Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma:ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth[J].Br J Haematol,2017,178(6):896-905.
[27]Zonder JA,Mohrbacher AF,Singhal S,et al.A phase 1,multicenter,open-label,dose escalation study of elotuzumab in patients with advanced multiple myeloma[J].Blood,2012,120(3):552-559.
[28]Lonial S,Dimopoulos M,Palumbo A,et al.Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma[J].N Engl J Med,2015,373(7):621-631.
[29]Dimopoulos MA,Lonial S,Betts KA,et al.Elotuzumab Plus Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma:Extended 4-Year Follow-Up and Analysis of Relative Progression-Free Survival From the Randomized ELOQUENT-2Trial[J].Cancer,2018,124(20):4032-4043.
[30]Wolf JL,Siegel D,Goldschmidt H,et al.PhaseⅡtrial of the pandeacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma[J].Leuk Lymphoma,2012,53(9):1820-1823.
[31]Richardson PG,Schlossman RL,Alsina M,et al.PANORAMA 2:Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma[J].Blood,2013,122(14):2331-2337.
[32]San-Miguel JF,Hungria VT,Yoon SS,et al.Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma:A multicentre,randomised,doubleblind phase 3 trial[J].Lancet Oncol,2014,15(11):1195-1206.
[33]Sanmiguel JF,Hungria VT,Yoon SS,et al.Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone(the PANORAMA1 trial):A randomised,placebo-controlled,phase 3 trial[J].Lancet Haematol,2016,3(11):e506-515.
[34]Moore D.Panobinostat(Farydak):A Novel Option for the Treatment of Relapsed Or Relapsed and Refractory Multiple Myeloma[J].P T,2016,41(5):296-300.
[35]Chhabra S.Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors:Progress in Myeloma Therapeutics[J].Pharmaceuticals(Basel),2017,10(2).pii:E40.
[36]Richardson P,Mitsiades C,Colson K,et al.PhaseⅠtrial of oral vorinostat(suberoylanilide hydroxamic acid,SAHA)in patients with advanced multiple myeloma[J].Leuk Lymphoma,2008,49(3):502-507.
[37]Siegel DS,Dimopoulos M,Jagannath S,et al.VANTAGE 095:An International,Multicenter,Open-Label Study of Vorinostat(MK-0683)in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma[J].Clin Lymphhoma Myeloma Leuk,2016,16(6):329-334.e1.
[38]Dimopoulos M,Siegel DS,Lonial S,et al.Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma(VANTAGE 088):A multicentre,randomised,double-blind study[J].Lancet Oncol,2013,14(11):1129-1140.
[39]Richardson PG,Moreau P,Laubach JP,et al.Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma[J].Pharmacol Res,2017,117:185-191.
[40]Laubach JP,San-Miguel JF,Hungria V,et al.Deacetylase inhibitors:An advance in myeloma therapy?[J].Expert Rev Hematol,2017,10(3):229-237.
[41]Vogl DT,Raje NS,Jagannath S,et al.Ricolinostat,the First Selective Histone Deacetylase 6 Inhibitor,in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma[J].Clin Cancer Res,2017,23(13):3307-3315.
[42]Mishima Y,Santo L,Eda H,et al.Ricolinostat(ACY-1215)induced inhibition of aggresome formation accelerates carfilzomibinduced multiple myeloma cell death[J].Br J Haematol,2015,169(3):423-434.
[43]Yee AJ,Bensinger WI,Supko JG,et al.Ricolinostat plus lenalidomide,and dexamethasone in relapsed or refractory multiple myeloma:A multicentre phase 1b trial[J].Lancet Oncol,2016,17(11):1569-1578.
[44]Rosenblatt J,Avigan D.Targeting the PD-1/PD-L1 axis in multiple myeloma:A dream or a reality?[J].Blood,2017,129(3):275-279.
[45]Lesokhin AM,Ansell SM,Armand P,et al.Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy:Preliminary Results of a PhaseⅠb Study[J].J Clin Oncol,2016,34(23):2698-2704.
[46]Ocio EM,Mateos MV,Orlowski R,et al.Pembrolizumab(Pembro)plus lenalidomide(Len)and low-dose dexamethasone(Dex)for relapsed/refractory multiple myeloma(RRMM):Efficacy and biomarker analyses[J].J Clin Oncol,2017,35(15_suppl):8015-8015.
[47]Badros A,Hyjek E,Ma N,et al.Pembrolizumab,pomalidomide,and low-dose dexamethasone for relapsed/refractory multiple myeloma[J].Blood,2017,130(10):1189-1197.
[48]Pianko MJ,Goldberg AD,Lesokhin AM.Clinical Development of PD-1 Blockade in Hematologic Malignancies[J].Cancer J,2018,24(1):31-35.
[2]Kumar SK,Dispenzieri A,Lacy MQ,et al.Continued improvement in survival in multiple myeloma:Changes in early mortality and outcomes in older patients[J].Leukemia,2014,28(5):1122-1128.
[3]Dimopoulos MA,Leleu X,Palumbo A,et al.Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma[J].Leukemia,2014,28(8):1573-1585.
[4]Jurczyszyn A,Legie W,Helbig G,et al.New drugs in multiple myeloma-role of carfilzomib and pomalidomide[J].Contemp Oncol(Pozn),2014,18(1):17-21.
[5]Orlowski RZ.Novel agents for multiple myeloma to overcome resistance in phaseⅢclinical trials[J].Semin Oncol,2013,40(5):634-651.
[6]Morgan G,Palumbo A,Dhanasiri S,et al.Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM-003 trial for pomalidomide plus low-dose dexamethasone[J].Br J Haematol,2015,168(6):820-823.
[7]Ramasamy K,Dimopoulos MA,van de Donk NWCJ,et al.Safety of Treatment(Tx)with Pomalidomide(POM)and Low-Dose Dexamethasone(Lo DEX)in Patients(Pts)with Relapsed or Refractory Multiple Myeloma(RRMM)and Renal Impairment(RI),Including Those on Dialysis[J].Blood,2015,126(23):374.
[8]Baz RC,Martin TG 3rd,Lin HY,et al.Randomized multicenter phase 2 study of pomalidomide,cyclophosphamide,and dexamethasone in relapsed refractory myeloma[J].Blood,2016,127(21):2561-2568.
[9]Lacy MQ,Kumar SK,La Plant BR,et al.Pomalidomide Plus LowDose Dexamethasone(Pom/Dex)in Relapsed Myeloma:Long Term Follow up and Factors Predicing Outcome in 345Patients[J].Blood,2012,120:201.
[10]Jakubowiak AJ,Siegel DS,Martin T,et al.Treatment outcomes in patients with relapsed and refractory multiple myeloma and highrisk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study[J].Leukemia,2013,27(12):2351-2356.
[11]Dimopoulos MA,Moreau P,Palumbo A,et al.Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma(ENDEAVOR):Arandomised,phase 3,open-label,multicentre study[J].Lancet Oncol,2016,17(1):27-38.
[12]Badros AZ,Vij R,Martin T,et al.PhaseⅡstudy of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency[J].J Clin Oncol,2010,28(15_suppl):8128-8128.
[13]Badros AZ,Vij R,Martin T,et al.Carfilzomib in multiple myeloma patients with renal impairment:Pharmacokinetics and safety[J].Leukemia,2013,27(8):1707-1714.
[14]Stewart AK,Rajkumar SV,Dimopoulos MA,et al.Carfilzomib,lenalidomide,and dexamethasone for relapsed multiple myeloma[J].N Engl J Med,2015,372(2):142-152.
[15]Shah JJ,Stadtmauer EA,Abonour R,et al.Carfilzomib,pomalidomide,and dexamethasone for relapsed or refractory myeloma[J].Blood,2015,126(20):2284-2290.
[16]Gupta N,Hanley MJ,Xia C,et al.Clinical Pharmacology of Ixazomib:The First Oral Proteasome Inhibitor[J/OL].Clin Pharmacokinet,2018[2018-11-10].https://link.springer.com/article/10.1007%2Fs40262-018-0702-1.[published online ahead of Aug 17,2018].
[17]Moreau P,Masszi T,Grzasko N,et al.Oral Ixazomib,Lenalidomide,and Dexamethasone for Multiple Myeloma[J].N Engl JMed,2016,374(17):1621-1634.
[18]Krishnan A,Kapoor P,Palmer JM,et al.PhaseⅠ/Ⅱtrial of the oral regimen ixazomib,pomalidomide,and dexamethasone in relapsed/refractory multiple myeloma[J/OL].Leukemia,2017[2018-11-10].https://www.nature.com/articles/s41375-018-0038-8.[published online ahead of Dec 18,2018].
[19]Gupta N,Hanley MJ,Harvey RD,et al.A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis[J].Br J Haematol,2016,174(5):748-759.
[20]de Weers M,Tai YT,van der Veer MS,et al.Daratumumab,a novel therapeutic human CD38monoclonal antibody,induces killing of multiple myeloma and other hematological tumors[J].J Immunol,2011,186(3):1840-1848.
[21]Afifi S,Michael A,Lesokhin A.Immunotherapy:A New Approach to Treating Multiple Myeloma with Daratumumab and Elotuzumab[J].Ann Pharmacother,2016,50(7):555-568.
[22]Lokhorst HM,Plesner T,Laubach JP,et al.Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma[J].N Engl JMed,2015,373(13):1207-1219.
[23]Lonial S,Weiss BM,Usmani SZ,et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma(SIRIUS):An open-label,randomised,phase 2 trial[J].Lancet,2016,387(10027):1551-1560.
[24]Palumbo A,Chanan-Khan A,Weisel K,et al.Daratumumab,Bortezomib,and Dexamethasone for Multiple Myeloma[J].NEngl J Med,2016,375(8):754-766.
[25]Bahlis NJ,Moreau P,Nahi H,et al.Daratumumab,lenalidomide,and dexamethasone(DRD)vs lenalidomide and dexamethasone(RD)in relapsed or refractory multiple myeloma(RRMM):Efficacy and safety update(POLLUX)[J].Hematol Oncol,2017,35(S2):389-389.
[26]Dimopoulos MA,Lonial S,White D,et al.Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma:ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth[J].Br J Haematol,2017,178(6):896-905.
[27]Zonder JA,Mohrbacher AF,Singhal S,et al.A phase 1,multicenter,open-label,dose escalation study of elotuzumab in patients with advanced multiple myeloma[J].Blood,2012,120(3):552-559.
[28]Lonial S,Dimopoulos M,Palumbo A,et al.Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma[J].N Engl J Med,2015,373(7):621-631.
[29]Dimopoulos MA,Lonial S,Betts KA,et al.Elotuzumab Plus Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma:Extended 4-Year Follow-Up and Analysis of Relative Progression-Free Survival From the Randomized ELOQUENT-2Trial[J].Cancer,2018,124(20):4032-4043.
[30]Wolf JL,Siegel D,Goldschmidt H,et al.PhaseⅡtrial of the pandeacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma[J].Leuk Lymphoma,2012,53(9):1820-1823.
[31]Richardson PG,Schlossman RL,Alsina M,et al.PANORAMA 2:Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma[J].Blood,2013,122(14):2331-2337.
[32]San-Miguel JF,Hungria VT,Yoon SS,et al.Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma:A multicentre,randomised,doubleblind phase 3 trial[J].Lancet Oncol,2014,15(11):1195-1206.
[33]Sanmiguel JF,Hungria VT,Yoon SS,et al.Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone(the PANORAMA1 trial):A randomised,placebo-controlled,phase 3 trial[J].Lancet Haematol,2016,3(11):e506-515.
[34]Moore D.Panobinostat(Farydak):A Novel Option for the Treatment of Relapsed Or Relapsed and Refractory Multiple Myeloma[J].P T,2016,41(5):296-300.
[35]Chhabra S.Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors:Progress in Myeloma Therapeutics[J].Pharmaceuticals(Basel),2017,10(2).pii:E40.
[36]Richardson P,Mitsiades C,Colson K,et al.PhaseⅠtrial of oral vorinostat(suberoylanilide hydroxamic acid,SAHA)in patients with advanced multiple myeloma[J].Leuk Lymphoma,2008,49(3):502-507.
[37]Siegel DS,Dimopoulos M,Jagannath S,et al.VANTAGE 095:An International,Multicenter,Open-Label Study of Vorinostat(MK-0683)in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma[J].Clin Lymphhoma Myeloma Leuk,2016,16(6):329-334.e1.
[38]Dimopoulos M,Siegel DS,Lonial S,et al.Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma(VANTAGE 088):A multicentre,randomised,double-blind study[J].Lancet Oncol,2013,14(11):1129-1140.
[39]Richardson PG,Moreau P,Laubach JP,et al.Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma[J].Pharmacol Res,2017,117:185-191.
[40]Laubach JP,San-Miguel JF,Hungria V,et al.Deacetylase inhibitors:An advance in myeloma therapy?[J].Expert Rev Hematol,2017,10(3):229-237.
[41]Vogl DT,Raje NS,Jagannath S,et al.Ricolinostat,the First Selective Histone Deacetylase 6 Inhibitor,in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma[J].Clin Cancer Res,2017,23(13):3307-3315.
[42]Mishima Y,Santo L,Eda H,et al.Ricolinostat(ACY-1215)induced inhibition of aggresome formation accelerates carfilzomibinduced multiple myeloma cell death[J].Br J Haematol,2015,169(3):423-434.
[43]Yee AJ,Bensinger WI,Supko JG,et al.Ricolinostat plus lenalidomide,and dexamethasone in relapsed or refractory multiple myeloma:A multicentre phase 1b trial[J].Lancet Oncol,2016,17(11):1569-1578.
[44]Rosenblatt J,Avigan D.Targeting the PD-1/PD-L1 axis in multiple myeloma:A dream or a reality?[J].Blood,2017,129(3):275-279.
[45]Lesokhin AM,Ansell SM,Armand P,et al.Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy:Preliminary Results of a PhaseⅠb Study[J].J Clin Oncol,2016,34(23):2698-2704.
[46]Ocio EM,Mateos MV,Orlowski R,et al.Pembrolizumab(Pembro)plus lenalidomide(Len)and low-dose dexamethasone(Dex)for relapsed/refractory multiple myeloma(RRMM):Efficacy and biomarker analyses[J].J Clin Oncol,2017,35(15_suppl):8015-8015.
[47]Badros A,Hyjek E,Ma N,et al.Pembrolizumab,pomalidomide,and low-dose dexamethasone for relapsed/refractory multiple myeloma[J].Blood,2017,130(10):1189-1197.
[48]Pianko MJ,Goldberg AD,Lesokhin AM.Clinical Development of PD-1 Blockade in Hematologic Malignancies[J].Cancer J,2018,24(1):31-35.