Plsm Cell Disorders ARTICLE Cytogenetics nd long-term survivl of ptients with refrctory or relpsed nd refrctory multiple myelom treted with pomlidomide nd low-dose dexmethsone Meletios A. Dimopoulos, 1 Ktj C. Weisel, 2 Kevin W. Song, 3 Michel Delforge, 4 Lionel Krlin, 5 Hrtmut Goldschmidt, 6 Philippe Moreu, 7 Anne Bnos, 8 Albert Oriol, 9 Lurent Grderet, 10 Michele Cvo, 11 Vlentin Ivnov, 12 Adrin Alegre, 13 Joquin Mrtinez-Lopez, 14 Christine Chen, 15 Andrew Spencer, 16 Stefn Knop, 17 Nizr J. Bhlis, 18 Christoph Renner, 19 Xin Yu, 20 Kevin Hong, 20 Lrs Sterns, 20 Christin Jcques, 20 Mohmed H. Zki, 20 nd Jesus F. Sn Miguel 21 1 Alexndr Hospitl, Athens, Greece; 2 Hemtology & Oncology, Deprtment of Medicine, University Hospitl Tübingen, Germny; 3 Vncouver Generl Hospitl, Vncouver, BC, Cnd; 4 Deprtment of Hemtology, University Hospitl Leuven, Belgium: 5 Centre Hospitlier Lyon Sud/Hospices Civils de Lyon, Pierre-Bénite, Frnce; 6 University Hospitl Heidelberg nd Germn Cncer Reserch Center, Heidelberg, Germny; 7 Hemtology, University Hospitl Hôtel-Dieu, Nntes, Frnce; 8 Hemtology, Centre Hospitlier de l Côte Bsque, Byonne, Frnce; 9 Institut Ctl d Oncologi, HGTiP, Brcelon, Spin; 10 Hopitl Sint Antoine, Pris, Frnce; 11 Seràgnoli Institute of Hemtology, Bologn University School of Medicine, Itly; 12 GUZ Moscow City Clinicl Hospitl S.P. Botkin, Russi; 13 Hospitl Universitrio L Princes, Mdrid, Spin; 14 Hospitl Universitrio 12 de Octubre, Mdrid, Spin; 15 Princess Mrgret Hospitl, Toronto, ON, Cnd; 16 Alfred Hospitl-Monsh University, Melbourne, Austrli; 17 University of Würzburg, Germny; 18 University of Clgry, AB, Cnd; 19 University Hospitl Zurich, Switzerlnd; 20 Celgene Corportion, Summit, NJ, USA; nd 21 Clinic Universidd de Nvrr, CIMA, Pmplon, Spin ABSTRACT Ptients with refrctory or relpsed nd refrctory multiple myelom who no longer receive benefit from novel gents hve limited tretment options nd short expected survivl. del(17p) nd t(4;14) re correlted with shortened survivl. The phse 3 MM-003 tril demonstrted significnt progression-free nd overll survivl benefits from tretment with pomlidomide plus low-dose dexmethsone compred to high-dose dexmethsone mong ptients in whom bortezomib nd lenlidomide tretment hd filed. At n updted medin follow-up of 15.4 months, the progression-free survivl ws 4.0 versus 1.9 months (HR, 0.50; P<0.001), nd medin overll survivl ws 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomlidomide plus low-dose dexmethsone, compred with highdose dexmethsone, improved progression-free survivl in ptients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P <0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), nd in stndrd-risk ptients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the mjority of ptients treted with high-dose dexmethsone took pomlidomide fter discontinution, the overll survivl of ptients treted with pomlidomide plus low-dose dexmethsone or highdose dexmethsone ws 12.6 versus 7.7 months (HR, 0.45; P=0.008) in ptients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), nd 14.0 versus 9.0 months (HR, 0.85; P=0.380) in stndrd-risk subjects. The overll response rte ws higher in ptients treted with pomlidomide plus low-dose dexmethsone thn in those treted with high-dose dexmethsone both mong stndrd-risk ptients (35.2% versus 9.7%) nd those with del(17p) (31.8% versus 4.3%), wheres it ws similr in ptients with t(4;14) (15.9% versus 13.3%). The sfety of pomlidomide plus low-dose dexmethsone ws consistent with initil reports. In conclusion, pomlidomide plus low-dose dexmethsone is efficcious in ptients with relpsed/refrctory multiple myelom nd del(17p) nd/or t(4;14). This study is registered t CliniclTrils.gov s NCT01311687 nd with EudrCT s 2010-019820-30. Introduction The current stndrd of cre for ptients with multiple myelom involves tretment with protesome inhibitors such s bortezomib nd immunomodultory drugs such s lenlidomide. 1,2 With the recent dvnces in tretment, the 5- nd 10-yer reltive survivl rtes for multiple myelom re now 40% nd 21%, respectively. 3 However, most ptients with multiple myelom will relpse severl times during the course of their disese. 4 There re few estblished tretments vilble for those who hve exhusted novel gents. The medin overll survivl for ptients in whom bortezomib or immunomodultory drugs hve filed is only 9 months, demonstrting the cler, unmet need for further tretment options for such ptients. 4 The chromosoml berrtions del(17p) nd t(4;14) (found in pproximtely 11% nd 14% of multiple myelom ptients, respectively) re ssocited with n dverse prognosis, reducing medin event-free survivl from dignosis to 20.6 months (versus 36.5 months; P<0.001) nd 15 months (versus 35 months; P<0.001), respectively. 5,6 The presence of t(4;14) ws lso found to predict shorter survivl in ptients with dvnced relpsed or refrctory disese treted with lenlidomide nd dexmethsone (9.4 versus 15.4 months; P=0.005). 7 The (4;14) trnsloction results in incresed expression of the oncogenes fibroblst growth fctor receptor 3 (FGFR3) nd multiple myelom set domin (MMSET). 8-10 The chromosoml bnormlity del(17p) is frequently ssocited with muttions in the TP53 gene or ltertions in the p53 pthwy. 11 Few studies hve nlyzed the impct of these cytogenetic fetures or 2015 Ferrt Storti Foundtion. This is n open-ccess pper. doi:10.3324/hemtol.2014.117077 Mnuscript received on September 23, 2014. Mnuscript ccepted on July 24, 2015 Correspondence: mdimop@med.uo.gr hemtologic 2015; 100(10) 1327
M.A. Dimopoulos et l. other bseline chrcteristics specificlly in dvnced relpsed/refrctory multiple myelom. 4,12,13 Pomlidomide is distinct immunomodultory drug with direct ntimyelom, stroml support inhibitory, nd immunomodultory effects. 14 The open-lbel, rndomized phse 2 MM-002 tril reported n overll response rte of 33% to pomlidomide + low-dose dexmethsone (LoDEX), with medin progression-free survivl of 4.2 months nd medin overll survivl of 16.5 months. These results were consistent even in ptients who were refrctory to lenlidomide s the most recent line of prior therpy. 15 Additionlly, pomlidomide + LoDEX ws effective in ptients presenting with the cytogenetic bnormlities del(17p) nd/or t(4;14). 15 Fvorble results with pomlidomide + LoDEX in ptients with del(17p) were lso seen in the IFM 2010-02 tril. 16 The interntionl, multicenter, open-lbel, rndomized, phse 3 tril MM-003 compred pomlidomide + LoDEX (n=302) with high-dose dex - methsone (HiDEX; n=153) tretment in ptients with multiple myelom refrctory to their lst prior tretment in whom bortezomib nd lenlidomide hd previously filed. Initil results t medin follow-up of 10 months showed significnt improvements in progression-free survivl [(4.0 versus 1.9 months; hzrd rtio (HR), 0.48; P<0.0001)] nd overll survivl (12.7 versus 8.1 months; HR, 0.74; P=0.0285) with pomlidomide + LoDEX, with similr efficcy cross vrious popultions of ptients, including those refrctory to lenlidomide s lst prior tretment. 17 The most common grde 3/4 dverse events reported were hemtologic (neutropeni, nemi, nd thrombocytopeni). This updted nlysis of the MM-003 tril presented here is bsed on medin follow-up of 15.4 months. Anlyses of bseline chrcteristics predictive of long-term benefit nd ssessments of the impct of high-risk cytogenetic bnormlities re lso reported. Methods Study design nd ptients A full description of the study design, inclusion nd exclusion criteri, nd tretment protocol hs been published elsewhere. 17 Briefly, MM-003 ws n open-lbel, rndomized, phse 3 tril conducted in 93 centers in the Europen Union, Russi, Switzerlnd, Austrli, Cnd, nd the USA. Ptients enrolled hd to hve refrctory or relpsed nd refrctory multiple myelom treted with two or more prior ntimyelom regimens, hve been refrctory to their lst prior tretment, filed prior tretment with bortezomib nd lenlidomide (following 2 previous consecutive cycles of ech, lone or in combintion), nd hve received dequte prior lkyltor therpy. Filure of bortezomib nd lenlidomide therpy ws defined s progressive disese on or within 60 dys of completing tretment, progressive disese 6 months fter chieving prtil response, or intolernce when chieving no more thn miniml response (bortezomib only). Additionl detils regrding the selection of ptients hve been described elsewhere. 17 All ptients provided written informed consent to prticipte in the study, which ws pproved by institutionl review bords or independent ethics committees t ll prticipting centers nd performed in ccordnce with the Declrtion of Helsinki nd the Interntionl Conference on Hrmonistion Guidelines on Good Clinicl Prctice. This tril is registered with CliniclTrils.gov (NCT01311687) nd EudrCT (2010-019820-30). All uthors nd the sponsor were involved in the dt collection, nlysis, review, nd interprettion nd writing of the report. A totl of 455 ptients were rndomized in 2:1 rtio to receive 28-dy cycles of pomlidomide (4 mg/dy orlly on dys 1-21) + LoDEX (40 mg/dy orlly on dys 1, 8, 15, nd 22) or HiDEX (40 mg/dy orlly on dys 1-4, 9-12, nd 17-20). In both rms of the study, dexmethsone ws dministered t dose of 20 mg/dy for ptients ged 75 yers. Tretment ws continued until progression or uncceptble toxicity. Thromboprophylxis, consisting of the physicin s choice of low-dose spirin or low-moleculr-weight heprin, ws required for ll ptients who received pomlidomide nd those t high risk of developing thrombosis. Assessments nd sttisticl nlyses The primry endpoint ws progression-free survivl nd secondry endpoints included overll survivl, rte of overll responses defined by Interntionl Myelom Working Group (IMWG) 18 nd Europen Group for Blood nd Mrrow Trnsplnt (EBMT) 19 criteri, time to progression, durtion of response, durtion of tretment, sfety, nd qulity of life. Progression-free survivl nd response were bsed on investigtor ssessment. For cytogenetic nlyses, smples were collected t the time of screening the ptients nd nlyzed by centrl lbortory, s described previously. 20 Briefly, enrichment of CD138 + plsm cells ws followed by interphse fluorescence in situ hybridiztion (FISH) for TP53 deletion [del(17p)] nd/or fibroblst growth fctor receptor 3/immunoglobulin hevy locus gene rerrngement [t(4;14)]. Any detectble presence of muttion ws considered positive result. Progression-free survivl, overll survivl, nd durtion of response were estimted using the Kpln-Meier product-limit method nd compred between tretment groups using log-rnk tests strtified by ge, disese popultion, nd number of prior ntimyelom therpies. Overll response rte ws compred between tretment rms using the Fisher exct test. Progressionfree survivl nd overll survivl for ptients within ech tretment rm were nlyzed by cytogenetic bnormlity sttus using n unstrtified log-rnk test. Ptients in the pomlidomide + LoDEX rm who survived >12 or 12 months were descriptively compred with respect to demogrphics nd bseline chrcteristics to identify potentil fctors tht my contribute to longer survivl. Then, these identified potentil fctors were used in Cox regression model selection process for overll survivl in ll subjects in the pomlidomide + LoDEX rm. The forwrd selection method ws used to identify significnt fctors. Results Ptients chrcteristics The dt cutoff for this report ws September 1, 2013, for medin follow-up of 15.4 months. The tretment rms were well blnced. Ptients were hevily pretreted, with medin of five lines of prior therpy in both rms (Tble 1). A totl of 225 ptients (75%) treted with pomlidomide + LoDEX nd 107 ptients (70%) treted with HiDEX hd evluble cytogenetics. Chromosoml bnormlities were blnced between rms: 15% of ptients in ech tretment rm were positive for del(17p) nd 15% (pomlidomide + LoDEX) nd 10% (HiDEX) were positive for t(4;14). Updted survivl (intent-to-tret popultion) With extended follow-up, the medin progression-free survivl remined significntly longer with pomlidomide + LoDEX versus HiDEX (4.0 versus 1.9 months; HR, 0.50; 1328 hemtologic 2015; 100(10)
Pomlidomide for MM: long-term nd cytogenetic nlyses P<0.001). The medin overll survivl ws lso significntly longer with pomlidomide + LoDEX versus HiDEX (Figure 1; 13.1 versus 8.1 months; HR, 0.72; P=0.009). This overll survivl dvntge ws observed despite 85 ptients (56%) on the HiDEX rm receiving subsequent pomlidomide-bsed tretment. Multivrite nlysis of the pomlidomide + LoDEX tretment rm identified severl bseline chrcteristics significntly ssocited with longer overll survivl: norml lctte dehydrogense level, higher level of hemoglobin or pltelets, lower Estern Coopertive Oncology Group (ECOG) performnce sttus, nd bsence of plsmcytom (Tble 2). Norml lctte dehydrogense level, higher pltelet count, nd lower ECOG performnce sttus were lso significntly ssocited with longer durtion of response. Sfety The updted sfety profile of this nlysis ws consistent with tht reported in the originl publiction (Tble 3). 17 The most common grde 3/4 dverse events were neutropeni (49% versus 17%), nemi (33% versus 39%), nd infections (33% versus 24%) for the pomlidomide + LoDEX versus HiDEX sfety popultions, respectively. The rtes of discontinution due to dverse events were low considering the hevily pretreted condition of this popultion of ptients nd were comprble between the two tretment rms (9% versus 10%). In the 54 pomlidomide + LoDEX ptients who were treted for 1 yer or longer, the most frequent grde 3/4 dverse events were neutropeni (52%) nd infections (43%). These ptients experienced nemi nd thrombocytopeni notbly less frequently (both 9%) compred with the pomlidomide + LoDEX sfety popultion. Cytogenetic subnlyses A significnt progression-free survivl benefit of pomlidomide + LoDEX tretment versus HiDEX ws observed in ll cytogenetic subgroups (Tble 4): del(17p) (4.6 versus 1.1 months; HR, 0.34; P<0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), nd stndrd-risk (4.2 versus 2.3 months; HR, 0.55; P<0.001). The overll survivl of ptients treted with pomlidomide + LoDEX ws longer thn tht of ptients treted with HiDEX in ll groups: the difference ws sttisticlly significnt for ptients with del(17p) (12.6 versus 7.7 months; HR, 0.45; P=0.008) nd showed trend for those with t(4;14) (7.5 versus 4.9 months; HR, 1.12; P=0.761) nd stndrd-risk ptients (14.0 versus 9.0 months; HR, 0.85; P=0.380). The overll survivl benefit ws chieved despite high numbers of HiDEX ptients subsequently receiving pomlidomide: 46% of del(17p)/t(4;14) nd 64% of stndrd-risk ptients. An nlysis of the impct of del(17p) nd t(4;14) within the HiDEX rm showed tht these cytogenetic bnormlities re ssocited with worsened outcomes. The medin progression-free survivl ws reduced from 2.3 months for stndrd-risk ptients to 1.1 months for those with del(17p) or 1.9 months for those with t(4;14) (Figure 2B; Tble 1. Ptients bseline chrcteristics. Chrcteristic POM + LoDEX HiDEX (n = 302) (n = 153) Age, medin yers (rnge) 64 (35-84) 65 (35-87) Time from initil dignosis, 5.3 (0.6-30.0) 6.1 (0.9-21.1) medin, yers (rnge) ECOG performnce sttus, n (%) 0-1 248 (82) 122 (80) 2-3 52 (17) 28 (18) Missing 2 (< 1) 3 (2) ISS stge, n. (%) I-II 196 (65) 92 (60) III 92 (30) 53 (35) Missing 14 (5) 8 (5) Cretinine clernce < 60 ml/min, n (%) 95 (31) 59 (39) N. of previous tretments, medin (rnge) 5 (2-14) 5 (2-17) Refrctory to bortezomib, % 79 79 Refrctory to lenlidomide, % 95 92 Refrctory to lenlidomide 75 74 nd bortezomib, % Evluble for cytogenetics, n (%) 225 (75) 107 (70) del(17p) 44 (15) 23 (15) t(4;14) 44 (15) 15 (10) del(17p) nd t(4;14) 11 (4) 3 (2) ECOG: Estern Coopertive Oncology Group; HiDEX: high-dose dexmethsone; ISS: Interntionl Stging System; LoDEX: low-dose dexmethsone; POM: pomlidomide. Figure 1. Kpln-Meier curve of overll survivl (OS) for the intent-totret popultion. HiDEX: high-dose dexmethsone; HR: hzrd rtio; LoDEX: low-dose dexmethsone; POM: pomlidomide. Tble 2. Multivrite Cox proportionl hzrds nlysis of bseline chrcteristics predictive of overll survivl nd durtion of response in ptients treted with pomlidomide + LoDEX. Model prmeter HR P-vlue Overll survivl Bseline LDH > 1.5 ULN 0.471 0.003 Bseline hemoglobin 10 g/dl 0.611 0.003 ECOG PS 0/1-2 0.668 0.022 Presence of plsmcytom 2.096 0.002 Bseline pltelets 75 10 9 /L 0.538 < 0.001 Durtion of response b Bseline LDH > 1.5 ULN 0.263 0.029 ECOG PS 0/1-2 0.520 0.027 Bseline pltelets 75 10 9 /L 0.313 0.001 Bsed on the Cox proportionl hzrd model compring the hzrd functions ssocited with the model prmeter. b Subjects with t lest prtil response bsed on investigtor ssessment using IMWG criteri. ECOG: Estern Coopertive Oncology Group; HR: hzrd rtio; LDH: lctte dehydrogense; LoDEX: low-dose dexmethsone; PS: performnce sttus; ULN: upper limit of norml. hemtologic 2015; 100(10) 1329
M.A. Dimopoulos et l. P=0.023 nd 0.161, respectively). The medin overll survivl ws similrly reduced, from 9.0 months for stndrdrisk ptients to 7.7 months for those with del(17p) or 4.9 months for ptients with t(4;14) (Figure 3B; P=0.019 nd 0.516, respectively). Among the ptients treted with pomlidomide + LoDEX, the outcomes in those with del(17p) re similr to those in ptients with stndrd-risk, with progressionfree survivl of 4.6 months versus 4.2 months (HR, 0.99; P=0.942) nd overll survivl of 12.6 months versus 14.0 months (HR, 1.22; P=0.358). The presence of t(4;14) ws significnt negtive predictor, shortening progression-free survivl to 2.8 months (HR, 1.50; P=0.023 versus stndrdrisk) nd overll survivl to 7.5 months (HR, 1.72; P=0.008 versus stndrd-risk). Response to pomlidomide + LoDEX tretment differed drmticlly between cytogenetic risk groups (Tble 5). Ptients with del(17p) treted with pomlidomide + LoDEX hd n overll response rte similr to tht in ptients with stndrd cytogenetic risk (31.8% in comprison with 35.1%), wheres the response rte ws much lower in ptients with t(4;14) (15.9%). The rte of response to HiDEX ws somewht lower in ptients with del(17p) (4.3%) thn in ptients with stndrd cytogenetic risk (9.7%), while ptients with t(4;14) were slightly more likely to respond (13.3%). Response to HiDEX ws numericlly lower thn to pomlidomide + LoDEX in ech cytogenetic risk group. Subsequent tretments Approximtely hlf (33/63) of the ptients treted with pomlidomide + LoDEX who progressed following Tble 3. Most commonly reported grde 3/4 dverse events for sfety popultions nd ptients treted with pomlidomide (POM) + LoDEX for 1 yer or more. POM + LoDEX HiDEX POM + LoDEX sfety sfety 1 yer popultion popultion of tretment (n = 300) (n = 150) (n = 54) Grde 3-4 hemtologic AE, n. (%) Neutropeni 146 (49) 26 (17) 28 (52) Febrile neutropeni 28 (9) 0 (0) 9 (17) Anemi 98 (33) 58 (39) 5 (9) Thrombocytopeni 67 (22) 39 (26) 5 (9) Leukopeni 27 (9) 5 (3) 5 (9) Grde 3-4 non-hemtologic AE, n. (%) Infections 98 (33) 37 (24) 23 (43) Pneumoni 42 (14) 12 (8) 11 (20) Bone pin 22 (7) 7 (5) 4 (7) Ftigue 16 (5) 9 (6) 4 (7) Astheni 11 (4) 10 (7) 1 (2) Glucose intolernce 12 (4) 11 (7) 2 (4) Discontinution due to AE, n (%) 28 (9) 16 (11) 2 (4) My hve received POM-bsed tretment following crossover. AE: dverse event; HiDEX: high-dose dexmethsone; LoDEX: low-dose dexmethsone; POM: pomlidomide. Tble 4. Progression-free nd overll survivl by cytogenetic risk group. del(17p) t(4;14) Stndrd risk POM + LoDEX HiDEX POM + LoDEX HiDEX POM + LoDEX HiDEX (n = 44) (n = 23) (n = 44) (n = 15) (n = 148) (n = 72) Medin PFS, months 4.6 1.1 2.8 1.9 4.2 2.3 HR (P-vlue) 0.34 (<0.001) 0.49 (0.028) 0.54 (<0.001) Medin OS, months 12.6 7.7 7.5 4.9 14.0 9.0 HR (P-vlue) 0.45 (0.008) 1.12 (0.761) 0.85 (0.380) HiDEX: high-dose dexmethsone; HR: hzrd rtio; LoDEX: low-dose dexmethsone; OS: overll survivl; PFS: progression-free survivl; POM: pomlidomide. A B Figure 2. Kpln-Meier curves of progression-free survivl by cytogenetic risk groups for ptients treted with (A) POM + LoDEX nd (B) HiDEX. Log-rnk P vs. stndrd risk. HiDEX: high-dose dexmethsone; HR: hzrd rtio; LoDEX: low-dose dexmethsone; PFS: progression-free survivl; POM: pomlidomide. 1330 hemtologic 2015; 100(10)
Pomlidomide for MM: long-term nd cytogenetic nlyses chievement of prtil response or better were treted with t lest one subsequent ntimyelom therpy. The medin time from progression to next therpy ws 1.8 months (rnge, 0.02-7.8 months). The most common tretment regimens were bortezomib (30%), lenlidomide (21%), nd thlidomide (15%); wide vriety of therpies were used demonstrting tht stndrd of cre is not well estblished for these ptients with dvnced disese. Further survivl ws generlly short, with only hlf (32/63) surviving 6 months following progression on pomlidomide + LoDEX. Discussion MM-003 ws the first rndomized phse 3 clinicl tril in refrctory or relpsed nd refrctory multiple myelom ptients who hd filed therpy with bortezomib nd lenlidomide. This updted nlysis with 15.4 months of follow-up confirmed the previously reported overll survivl benefit with pomlidomide + LoDEX compred with HiDEX (medin 13.1 versus 8.1 months; P=0.009). 17 Importntly, with the extended follow-up, the Kpln- Meier overll survivl curves continued to diverge in fvor of pomlidomide + LoDEX, even though 56% of ptients rndomized to the HiDEX rm subsequently received pomlidomide-bsed therpy. These results support erly use of pomlidomide + LoDEX following exhustion of bortezomib- nd lenlidomide-bsed options. 17 In this longterm follow-up, the medin overll survivl of 13.1 months in ptients treted with pomlidomide + LoDEX is consistent with tht recently reported with pomlidomide + LoDEX in the MM-002 tril (16.5 months), 15 compres fvorbly with historicl controls (9 months), 4 nd is similr to tht reported with crfilzomib (15.6 months) 21 in comprble popultions of ptients. The updted sfety profile of pomlidomide + LoDEX is consistent with tht reported in the initil MM-003 publiction nd previous trils. 15,17,22 The extended dt demonstrte tht dverse events re mngeble fter long-term tretment with pomlidomide + LoDEX. Ptients who continue tretment for 1 yer or longer exhibit notbly lower rtes of grde 3/4 nemi nd thrombocytopeni, which is consistent with the finding tht higher hemoglobin nd pltelet levels were ssocited with longer survivl in multivrite nlysis. A B Figure 3. Kpln-Meier curves of overll survivl (OS) by cytogenetic risk groups for ptients treted with (A) POM + LoDEX nd (B) HiDEX. Logrnk P vs. stndrd risk. HiDEX: high-dose dexmethsone; HR: hzrd rtio; LoDEX: low-dose dexmethsone; POM: pomlidomide. Tble 5. Response to tretment (IMWG criteri). POM + LoDEX HiDEX Stndrd risk del(17p) t(4;14) Stndrd risk del(17p) t(4;14) (n = 148) (n = 44) (n = 44) (n = 72) (n = 23) (n = 15) ORR ( PR), % 35.2 31.8 15.9 9.7 4.3 13.3 Stringent complete response 0.7 0 0 0 0 0 Complete response 0.7 0 0 0 0 0 VGPR 5.4 6.8 2.3 1.4 0 0 Prtil response 28.4 25.0 13.6 8.3 4.3 13.3 Stble disese 51.4 50.0 63.6 63.9 34.8 33.3 Medin DOR, months 7.5 4.2 3.7 9.4 4.4 NE Subjects with t lest prtil response bsed on investigtor ssessment using IMWG criteri. DOR: durtion of response; HiDEX: high-dose dexmethsone; IMWG: Interntionl Myelom Working Group; LoDEX: low-dose dexmethsone; NE: not estimble; ORR: overll response rte; POM: pomlidomide; PR: prtil response; VGPR: very good prtil response. hemtologic 2015; 100(10) 1331
M.A. Dimopoulos et l. Fetures ssocited with worse prognosis hve not been thoroughly evluted in dvnced relpsed/refrctory multiple myelom. A study conducted by the IMWG found tht higher β 2 -microglobulin nd lower serum lbumin levels correlted with poorer prognosis in multivrite model. 4 Multivrite nlysis of ptients treted with pomlidomide + LoDEX within MM-003 showed tht norml lctte dehydrogense level, higher hemoglobin nd pltelet levels, lower ECOG performnce sttus, nd bsence of plsmcytom were significntly ssocited with longer survivl nd tht norml lctte dehydrogense level, higher pltelet count, nd lower ECOG performnce sttus were lso significntly ssocited with longer durtion of response. These results confirmed tht ptients chrcteristics cn significntly predict outcomes even in hevily pretreted ptients. The importnce of high-risk cytogenetic fetures in dvnced relpsed/refrctory multiple myelom hs not been clerly defined. In ptients in whom novel gent therpy filed, the IMWG found tht t(4;14) t dignosis contributed to shorter overll survivl (HR, 2.14; P=0.086) but did not find tht del(17p) ws specificlly ssocited with shorter overll survivl or event-free survivl. 4 It is importnt to note tht limited dt regrding cytogenetic sttus nd FISH results were vilble for the IMWG study. 4 In prticulr, informtion regrding the prognostic vlue of cytogenetic sttus t the time of relpse is currently lcking. The lrge dvnced relpsed/refrctory multiple myelom popultion included in MM-003 mkes it vluble source to ssess the impct of cytogenetic bnormlities. By Kpln-Meier nlysis, del(17p) ws found here to be significnt negtive predictor of progression-free survivl nd overll survivl in ptients treted without newer gents (ie, HiDEX); t(4;14) lso ppered to predict shortened progression-free survivl nd overll survivl in these ptients, lthough the effect ws not sttisticlly significnt. This nlysis hs shown tht pomlidomide + LoDEX ws of benefit to ptients in the in MM-003 tril regrdless of their cytogenetic risk profile. The progression-free survivl dvntges observed with pomlidomide + LoDEX versus HiDEX in ptients with del(17p) or t(4;14) (HR, 0.34 nd 0.49, respectively) were similr to those for ptients with stndrd-risk cytogenetics (HR, 0.55) nd the overll study popultion (HR, 0.49). The benefits of pomlidomide + LoDEX tretment were prticulrly drmtic in ptients with del(17p), who chieved outcomes sttisticlly indistinguishble from stndrd-risk ptients (progression-free survivl: 4.6 versus 4.2 months; P=0.942; overll survivl: 12.6 versus 14.0 months; P=0.358). The French IFM 2010-02 tril of pomlidomide + LoDEX in ptients with del(17p) nd/or t(4;14) reported similr findings. 16 In this study, the medin time to progression (7.3 versus 2.8 months) nd overll survivl (12 versus 9.2 months) ppered longer for ptients with del(17p) thn in those with t(4;14). 16 However, 75% of the ptients in the MM-003 tril were refrctory to both bortezomib nd lenlidomide, wheres 54% were so in the French tril. 17,23 Clinicl trils of newer gents suggest tht these my overcome the poor prognosis ssocited with specific cytogenetic bnormlities. A recent single-rm tril of crfilzomib nlyzed ptients with relpsed/refrctory multiple myelom nd high-risk cytogenetic bnormlities [defined s del(13) or hypodiploidy by metphse cytogenetic nlysis nd/or del(17p13), t(4;14), or t(14;16) by interphse FISH]. In this study, progression-free survivl ws not significntly reduced compred with tht for stndrd-risk ptients (medin 3.5 versus 4.6 months; P=0.06). 12 It is notble tht the cytogenetic profile predictive of benefiting from crfilzomib differs from tht reported for pomlidomide + LoDEX. 12 The medin progression-free survivl nd overll survivl were shorter in crfilzomibtreted ptients with del(17p) thn in ptients with t(4;14) (medin progression-free survivl, 2.8 versus 4.1 months; overll survivl, 7.0 versus 11.8 months), 12 wheres pomlidomide + LoDEX treted ptients with del(17p) fred better thn those with t(4;14). The percentges of ptients in the crfilzomib tril positive for del(17p) nd t(4;14) (18% nd 11%, respectively) were similr to those in the MM-003 tril. 12 Dt regrding the interctions of del(17p) or t(4;14) with bortezomib tretment re inconsistent. In smll pilot study of ptients with erly relpsed or refrctory multiple myelom, t(4;14) hd no impct on response to bortezomib tretment, but the effect of del(17p) ws not exmined. 24 In newly dignosed multiple myelom, bortezomibcontining induction regimens were shown to significntly improve prognosis nd survivl for ptients with t(4;14) but not those with del(17p) in IFM 2005-01; 25 however, the HOVON-65 tril showed tht the ddition of bortezomib to induction ws beneficil in the presence of del(17p) but not t(4;14). 26 The lndmrk GIMEMA tril of bortezomibthlidomide-dexmethsone induction found tht ptients with t(4;14) benefited from the ddition of bortezomib, but the tril did not contin enough del(17p) ptients for nlysis. 27 In contrst, in the Totl Therpy 3 protocol, the ddition of bortezomib to thlidomide nd dexmethsone negted the dverse consequences of del(17p) in newly dignosed multiple myelom ptients who were low-risk ccording to their gene expression profile. 28 By comprison, results from MM-003 nd IFM 2010-02 re consistent in demonstrting tht pomlidomide my overcome the poor outcomes typiclly ssocited with del(17p). 16 In conclusion, these updted results for MM-003 confirm the previous observtions tht pomlidomide + LoDEX significntly improved progression-free survivl, overll survivl, nd response compred with HiDEX in ptients with refrctory or relpsed nd refrctory multiple myelom. Ptients with stndrd-risk cytogenetic profiles or those with del(17p) or t(4;14) ll gin significntly extended progression-free survivl nd some degree of overll survivl benefit from pomlidomide + LoDEX vs HiDEX. These results support the use of pomlidomide + LoDEX s stndrd of cre in ptients with relpsed/refrctory multiple myelom following exhustion of tretment options with bortezomib nd lenlidomide, including ptients with the high-risk cytogenetic bnormlities del(17p) nd t(4;14). Acknowledgments This study ws funded by Celgene Corportion. The uthors would like to thnk the ptients who volunteered to prticipte in this study, stff members t the study sites who cred for them, nd the representtives of the sponsors who were involved in dt gthering nd nlyses. We lso thnk Richrd Blzer, PhD, nd Nicol Hnson, PhD, from MediTech Medi for writing ssistnce, which ws funded by Celgene Corportion. Authorship nd Disclosures Informtion on uthorship, contributions, nd finncil & other disclosures ws provided by the uthors nd is vilble with the online version of this rticle t www.hemtologic.org. 1332 hemtologic 2015; 100(10)
Pomlidomide for MM: long-term nd cytogenetic nlyses References 1. Plumbo A, Rjkumr SV, Sn Miguel JF, et l. Interntionl Myelom Working Group consensus sttement for the mngement, tretment, nd supportive cre of ptients with myelom not eligible for stndrd utologous stem-cell trnsplnttion. J Clin Oncol. 2014;32(6):587-600. 2. Engelhrdt M, Terpos E, Kleber M, et l. Europen Myelom Network recommendtions on the evlution nd tretment of newly dignosed ptients with multiple myelom. Hemtologic. 2014;99(2):232-242. 3. Pulte D, Gondos A, Brenner H. Improvement in survivl of older dults with multiple myelom: results of n updted period nlysis of SEER dt. Oncologist. 2011;16(11):1600-1603. 4. Kumr SK, Lee JH, Lhuert JJ, et l. Risk of progression nd survivl in multiple myelom relpsing fter therpy with IMiDs nd bortezomib: multicenter Interntionl Myelom Working Group study. Leukemi. 2012;26(1):149-157. 5. Avet-Loiseu H, Attl M, Moreu P, et l. Genetic bnormlities nd survivl in multiple myelom: the experience of the Intergroupe Frncophone du Myélome. Blood. 2007;109(8):3489-3495. 6. Avet-Loiseu H, Hulin C, Cmpion L, et l. Chromosoml bnormlities re mjor prognostic fctors in elderly ptients with multiple myelom: the Intergroupe Frncophone du Myélome experience. J Clin Oncol. 2013;31(22):2806-2809. 7. Avet-Loiseu H, Soulier J, Fermnd JP, et l. Impct of high-risk cytogenetics nd prior therpy on outcomes in ptients with dvnced relpsed or refrctory multiple myelom treted with lenlidomide plus dexmethsone. Leukemi. 2010;24(3):623-628. 8. Chesi M, Nrdini E, Brents LA, et l. Frequent trnsloction t(4;14)(p16.3;q32.3) in multiple myelom is ssocited with incresed expression nd ctivting muttions of fibroblst growth fctor receptor 3. Nt Genet. 1997;16(3):260-264. 9. Chesi M, Nrdini E, Lim RS, Smith KD, Kuehl WM, Bergsgel PL. The t(4;14) trnsloction in myelom dysregultes both FGFR3 nd novel gene, MMSET, resulting in IgH/MMSET hybrid trnscripts. Blood. 1998;92(9):3025-3034. 10. Chesi M, Brents LA, Ely SA, et l. Activted fibroblst growth fctor receptor 3 is n oncogene tht contributes to tumor progression in multiple myelom. Blood. 2001;97(3):729-736. 11. Lode L, Eveillrd M, Trichet V, et l. Muttions in TP53 re exclusively ssocited with del(17p) in multiple myelom. Hemtologic. 2010;95(11):1973-1976. 12. Jkubowik AJ, Siegel DS, Mrtin T, et l. Tretment outcomes in ptients with relpsed nd refrctory multiple myelom nd high-risk cytogenetics receiving singlegent crfilzomib in the PX-171-003-A1 study. Leukemi. 2013;27(12):2351-2356. 13. Klein U, Juch A, Hielscher T, et l. Chromosoml berrtions +1q21 nd del(17p13) predict survivl in ptients with recurrent multiple myelom treted with lenlidomide nd dexmethsone. Cncer. 2011;117(10):2136-2144. 14. Quch H, Ritchie D, Stewrt AK, et l. Mechnism of ction of immunomodultory drugs (IMiDs) in multiple myelom. Leukemi. 2010;24(1):22-32. 15. Richrdson PG, Siegel DS, Vij R, et l. Pomlidomide lone or in combintion with low-dose dexmethsone in relpsed nd refrctory multiple myelom: rndomized phse 2 study. Blood. 2014;123(12):1826-1832. 16. Leleu X, Krlin L, Mcro M, et l. Pomlidomide plus low-dose dexmethsone in multiple myelom with deletion 17p nd/or trnsloction (4;14): IFM 2010-02 tril results. Blood. 2015;125(9):1411-1417. 17. Sn Miguel J, Weisel K, Moreu P, et l. Pomlidomide plus low-dose dexmethsone versus high-dose dexmethsone lone for ptients with relpsed nd refrctory multiple myelom (MM-003): rndomised, open-lbel, phse 3 tril. Lncet Oncol. 2013;14(11):1055-1066. 18. Durie BG, Hrousseu J, Miguel JS, et l. Interntionl uniform response criteri for multiple myelom. Leukemi. 2006;20(9): 1467-1473. 19. Bldé J, Smson D, Reece D, et l. Criteri for evluting disese response nd progression in ptients with multiple myelom treted by high-dose therpy nd hemopoietic stem cell trnsplnttion. Myelom Subcommittee of the EBMT. Europen Group for Blood nd Mrrow Trnsplnt. Br J Hemtol. 1998;102(5): 1115-1123. 20. Hrtmnn L, Biggerstff JS, Chpmn DB, et l. Detection of genomic bnormlities in multiple myelom: the ppliction of FISH nlysis in combintion with vrious plsm cell enrichment techniques. Am J Clin Pthol. 2011;136(5):712-720. 21. Siegel DS, Mrtin T, Singhl S, et l. Response rtes to single-gent crfilzomib in ptients refrctory or intolernt to both bortezomib nd immunomodultors in tril PX-171-003-A1. J Clin Oncol. 2012;30(15 suppl):518s. Abstrct 8035. 22. Leleu X, Attl M, Arnulf B, et l. Pomlidomide plus low dose dexmethsone is ctive nd well tolerted in bortezomib nd lenlidomide-refrctory multiple myelom: Intergroupe Frncophone du Myélome 2009-02. Blood. 2013;121(11): 1968-1975. 23. Leleu X, Krlin L, Mcro M, et l. Pomlidomide plus low-dose dexmethsone in relpsed or refrctory multiple myelom (RRMM) with deletion (del)17p nd/or trnsloction t(4;14). Blood. 2013;122(21):Abstrct 689. 24. Chng H, Trieu Y, Qi X, Xu W, Stewrt KA, Reece D. Bortezomib therpy response is independent of cytogenetic bnormlities in relpsed/refrctory multiple myelom. Leuk Res. 2007;31(6):779-782. 25. Avet-Loiseu H, Leleu X, Roussel M, et l. Bortezomib plus dexmethsone induction improves outcome of ptients with t(4;14) myelom but not outcome of ptients with del(17p). J Clin Oncol. 2010;28(30):4630-4634. 26. Neben K, Lokhorst HM, Juch A, et l. Administrtion of bortezomib before nd fter utologous stem cell trnsplnttion improves outcome in multiple myelom ptients with deletion 17p. Blood. 2012;119(4):940-948. 27. Cvo M, Tcchetti P, Ptrirc F, et l. Bortezomib with thlidomide plus dexmethsone compred with thlidomide plus dexmethsone s induction therpy before, nd consolidtion therpy fter, double utologous stem-cell trnsplnttion in newly dignosed multiple myelom: rndomised phse 3 study. Lncet. 2010;376(9758):2075-2085. 28. Shughnessy JD, Zhou Y, Hessler J, et l. TP53 deletion is not n dverse feture in multiple myelom treted with totl therpy 3. Br J Hemtol. 2009;147(3):347-351. hemtologic 2015; 100(10) 1333