Transcript Slide 1

First-Line Treatment for MM
Patients
Myelomacenter.org
[email protected]
Ruben Niesvizky
Department of Medicine, Division of Hematology/Oncology,
Weill-Cornell Medical College / New York Presbyterian
Hospital, New York, NY, USA
Disclosures
• Speaker’s bureau: Celgene, Millennium, Onyx
LUM
ST5
PAK4
CA3
VIM POT1
JAK2
IFI44
CTTN
GPI
TAC4 CUL7
TMC5
FBN3
RYR2
IBTK
SDF2
POLE BTRC
IFFO2 NRG1 SIAH3
THRB
TJP3
NPR2
NFIA
VSIG1
NCLN GRM8
PICK1
PDIA6
EYS GJD2
MYOF SIPA1
IL4R
SNX15 ATP9A
PTPLA
FLRT2
TXK HES3 SPEG CAPG
LASS3
SKP2
CELA1
HCLS1
HPD
STRN3
MIPEP DISP2
SYTL2
MYO6
IGF1R
HTR1A
CENPJ
RC3H1
UBA2
NBAS CLIC4
FAM5B
OR5P3
FRYL
ADNP
ATG2A
FGFR2
EPHA5
IL1RL2
USP32
ILDR2
EPHB4
TNPO1
TEPP
UBN2
CPSF3 UTP20
RBM5
RTCD1
KCNC1
AP1M1
ASH2L
CETN2
OR1G1
AMT
KIFC1
HDAC9 AUTS2 TUFT1
ALCAM MOXD1
FSCB
CMBL
UGGT1
SRRM1
TOX3
CSPG4
HNF4A
SCN2A
BTLA
ENOX1
FOXP2 LRIG3
APOH RPL10
C9orf85 C1orf64
MYO1C NCAM2
NUMA1
MYO3A
ALMS1
MEF2A KCNT2
PRG4
ZNRF3
ARID1A
CCL2 STAT2
OR1L6
PLA2R1 HMGCL
CNTN5 CRHBP
MTMR1 SRRM2
ZNF830
CUBN TNS4
TSPO2
OR8D1
SETD4
PPAP2A
NRP2
FCGBP
USP26
H2AFY2
CORIN
SYT3
CRIPAK
GPRIN2
STK38L MYSM1
SP100
RBP4
FAM12A
HCFC2 MMP16
KCTD17
OSBP2 OPRL1
RYR1 IDE
MYOM3
CYP2F1
NUP160
C2CD3
LCE3A GRIP1
COL4A3
ELAVL2 CSDE1
PSMC6
ZNF462
MPDZ
NBPF16
GPR158
DNAJA1
TRAFD1 MSL3 PCDH17
IKBIP
CDH19
ODF1
GLP2R
CHRM3
ACTL6A
SCYL2
HSPA8
COL1A1
ZNF569
PCDH20
LRRC41
CLIP1
ANTXR2
CASK
MARK2
SHANK2
PIGK
OVCH1
OR4E2
CLTC
ZNF484
OR4K14 SKIV2L2 POLR3G
DDX23
LINGO2 PTPRD PDZD8 LYPD4
RB1 DLG2 COPG
MOGAT3 CRYBG3
SNAPC3 SETBP1
CNGB3
BICC1 LAMB1
SVIL
SFMBT1 SLITRK6
C17orf46
MCM4 RFX1
GP2
C12orf30
UMODL1
GPR143 IFNAR2
C4orf43
PRKAG2
PLCB4 CNTN3
KCNA4 AGBL4 MDC1 IMP5
BMS1
KCNJ12
KIRREL3 RWDD2A
LRRC36
C11orf61
TXNRD1
NAV3
MELK PPTC7 MAPK4 LINGO4
NOTCH4 OSBPL8 LIPC
GHR
FGA LAMC3 SART1 DSPP
PCDHB1
COL3A1
IPMK FAM155A CPEB4 COL21A1 KIR2DS4
ROPN1 CXorf57
NUP93
ANXA13
TYK2
ALDH1L1 ARRDC1
CD1B
DSTYK VDAC3
C12orf35
TRAM1L1
FBXL13
MAP2K3
PLA2G2E
INO80
PLEKHA2
ZNF804A
G6PC2 TRIM29 FAM38B
DNM2
AFF1
COL17A1
C6orf146 MRPL15
RNF213 SOCS2
WDR5
FAM153B CTNNAL1
PCDHB13 GPR109B
POLR1C TET1
PRR21 DOLK
RRN3 ESYT1 GSTO2 C2orf61 RNF19A
GALNTL4
C17orf71 HEPHL1 ZC3H14
KIAA0319
C20orf132 C20orf152
EPB41L3
SYNE2
PNLIP BSN
RASGRF1
TTC21A
NEURL4
PTPRG
FLJ43860
IRF8 MUC6 NLRP4
C16orf91
KDM6A FNBP1 MRC2
SLC14A1
SMARCB1 ITGB1BP3
ARNTL2 CTNND2
SCN10A
KIAA0100
RBM9
CNOT6 OBSCN
RYR3
MAB21L2
KIAA0319L
C11orf24
MYOCD
ATM
GABRB3
TSHZ2 TNFRSF1A
SEC63 NBEA
ODZ1 FKBP5
DMXL2
PRSS45
HNRNPUL2
SEMA3A TADA2A
GUCY1A2 FAM116A
ORAOV1 CYP11B2 C20orf117 SPOP
OR2K2 WDR59
RPA4
MT1A
FOXP1
TMPRSS13
SP140 ACAD9
C5orf34 LMBR1L
RETSAT WDR74
LAMA4 HIST1H2AC TSHZ3
CREBBP
BCKDHB
TRAPPC5
CNTNAP2
OSBP
PFAS
EFNA4
TRIM47
PRKG1 COL4A6 CHRNB3
PTDSS1
ANXA2 C1orf14 DNAH9
SLC12A2
METTL2B
ADAMTSL1
SPEF2
CBLN1 GRIK1
PIGZ
MAP1LC3B
TMCC1
TFAP2D
SNAP25
C6orf138
LRRC16A
SPRED1
SIGLEC1
PRR4
ATOH8
VWA2 LRRK2
C1orf26
SHISA6 EMID1 PIGL GPR98
COX11 BCAN SP8
STARD8
SLC10A7 OR5H14
GABRR3 KIAA0125
SLC9A3R1
LMO2 DHX15
DOCK8 KCTD19
ROBO2
FNDC3A DST ZC3H18 NRXN1
SNX19 FNTB
GABRA1 RNF168 NCOA3
FRMPD1 FAM190B
RALGAPA1
ARHGEF3 COL12A1
CD109 EHMT1
FA2H
OLFM3
NPAS3 MLKL
MRE11A
ANK2
ZNF492 C12orf11
ZNF430 SCN11A
C10orf111 RBM33
SENP1
TMPRSS11B HIST1H3A FAM120B
MDN1
IMMP2L
DPY19L2
CKAP5
MAP4K4
FAM18B2 OR5AP2
TAGAP
BRAF
CHD3 KLRC2 MAGED1
HIST1H4D
HLA−A HS3ST4
HECW1
ZKSCAN3
CLRN3 PCCA
C9orf30
WDR66
OR2A14 C11orf90
AFAP1 BRCA1 ZNF483
MLL3
ANKRD57 SFRP4 SIX1 FBXW12
CASC1 NRXN3 PCDH18 CGN RAB3GAP1 NEBL C20orf20 HS6ST3 MCTP2 FCRL2 CBLB
JUND RAB25
NUP214 SAMD13 FLJ20184 VCAN MYH11
UNC5D
ZNF431 HSP90AB1 CD300LG PDGFRL LGALS3
FFAR2
MPHOSPH9
DCHS2
RBM25
RD3
EVI5 ANO6
FXYD6
CSMD3 ABCA13
C10orf72 KIAA1468
MAN1A1
TMEM63B ARHGAP15 PLEKHG2 C13orf30 GAS2L3 TRIM17 N4BP1
EPHB3
CYLD
TOPBP1
OSR2
DOCK4 SNAP47
CSRNP3
C1orf101
KIAA1109
RALGPS1
MTDH
STK17A ERBB3
NLRP7
TRIM6 CDYL
ABCA12
ESR1
C2orf71
DAPK1
NSMCE2
C18orf19 ATP6V1C2
RCOR1
KCNH7 ATAD3A MGA
CDH2 B3GALTL
COL5A2
CDON
NBPF3 NOS1
EWSR1
SLC26A4
SLC8A3
STX8
SLC45A4
ADAD1
CCDC123
CIR1
SMC5
ADCY2 GRID1 ZBTB33 C5
RANBP17 SEC14L2 COL6A6 SEMG1
AXIN2
ZNF878
FAM115A
CDH11
AGAP2
NUMB
BAG4
PLA2G2D
CELSR2
LY6H
GPC6 PRDM1 NRG3 COL23A1 ZRANB3 C6orf15
ZFP36L1
C20orf194 DDX11
ZNF329
OR4D5 PODN FGG
ARHGEF15
NID1 DSG1 ZFPM2 PRKDC
HMGCS2
SLC27A5
TRAF3
ERBB2IP
TRAPPC10
HSD17B1 PRUNE2
ZNF527 TECPR1
LYST
TMEM132B
ZNF417 HTR3D ZNF83 PBX2
HNMT USH2A
MAGEL2 KIAA1409 ADAMTS19 TP53
SLCO1B3
ZZEF1
COL7A1 TMEM150A
LRRC4C
CHL1
OR2L8 EXOC6 HS2ST1
ERLIN1 CALR3
RNASEN
GNB3
ADAMTS1
KIAA1467 MRPS27
ALOX15B
PNPLA3
SRD5A3 DKFZp761E198 IARS
DRD3 BTBD7 CADPS
SLC5A12
ZNF667 ACBD5
SLC1A5
IDH3A
EED
C10orf118
PKHD1L1
NCAPD3 SLC1A7 KCNH5
ODZ2 PANK3
GABRG1 F5 TTN TP53AIP1
NT5C3L
GRIA2
MTMR11
KIAA1614
SMAP2
KIAA1024
TNC
TRIO EP400
ASH1L LSM14A
CTNNA3 C3orf38 RAB5B COG5
ZCCHC5
FLNC
ABCC1 PRIMA1
ADAM18 ANKRD30A NCOR1 MUC2 MAP3K14
GPR155
NKAIN3
RIMS2
KIAA1009
SMEK1
BAZ2B CRB1
CCDC144NL
A2M
GRM7 CDH20
C7orf50
PCDHA11 C10orf84
GPATCH8
ALOX12B
CNOT6L
MKRN3
INSR RIPK4
PRPF8 ERC1
PRICKLE2 NALCN LRMP
F3
SLC35C1
MUC17
SAMHD1 NLRP8 SMPDL3A SLC23A2 FAM83H
PFTK2
PLK1S1 SOHLH2
FAM190A
PPP1R12B
DNAJC14
SETX IGSF5 LILRA2
CDC25C FAF1 WHSC1
ALOXE3
CDC42BPB ANKRD50
PPFIA4
USP10 RTN1
PHACTR2
ZNF423 CKM SLC38A9
ST14 DNMT3B
LNP1 ANO3
CEP110 HKDC1
PPFIBP1
CSNK1G3 KRBA2 CARD11
WHSC1L1 NDRG3
USP34 UBN1
MYO18B TUSC3 ADAMTS8 ZCWPW2
DSCAM CAPN12
PTK2
SHOC2
CUL5 ITGB6 PRKD2 ARMC9
RALYL DNAH5 C17orf68 ADAMTS9 FMN1
RORB
PRSS22
ADAMTS20
IL24
SPTBN1 GPRC6A CUX2
RDH16
ANGPTL5 CUEDC2
NUP155
ELF2 SOBP PMP22
SERTAD4 SHROOM2
PCDH10 UBASH3A
CTNND1
CCND1
CDK4 FAM135B TGFBR2 ATP1A4 EPHA6 ITFG1 TLR8
CENPF TTC21B
IVNS1ABP
ITIH5L
DIAPH2
ADAM17
SSX4 ARID2
TTLL6
KIAA0391
SLITRK2
CAMTA1 DCT
CAMK1D FAM73B
ITGA10 HMGCR
MTMR2 UBE3A
DCLK2
CMYA5
IHH
RALGAPB
IPPK
GCET2 ADAMTS18 KIAA0802
IGF2BP1
SPDYE1
PDE11A PRSS16
CLIP4 KCTD1
UNC5B CD163
HHIPL2 PCYT1B
LOH12CR1 PNRC1
MYT1
CHRNA6 PARN
TNPO2 SERPINE2 CCDC158 C6orf170
ZNF761 GPR83
CSMD2
GMCL1
PCDHGA7
ZP3 KIF1A SFTPD
LOXL2
C10orf96
CNBD1
TNRC6B
GTF2F2
USP7
NEDD1
CACNA1B FHDC1
LRRN3 TNKS1BP1 HCN1 GPATCH2
PPRC1
OBFC2A AKR1B15
VGLL3
ZNF416
RANBP9
AQP7 IFT122
NR3C2 AKAP6
EPHA7
IL10RA
ZBTB45 CAPZA1
BCAS4
MLL2 CCDC147 IGSF3
NEFM FIG4
SERPINB3
ZKSCAN5 TAS2R38
ZNF646 TRPM3
B4GALNT4 ARHGEF10 ADAMTSL3 NOM1
PHC1
LRRIQ3
C6orf125 KIAA1755
ADAM22
OR8J3 NPY2R
ATP4B
GLIPR1L2 COL19A1
OSBPL6
SERPINH1
ADAMTS2
SLC25A13
SNTG2 ZNF530
GNMT PKP1
NPFFR2 CMTM2 OR8K3
LRP2
MCART1 XBP1
KIAA0182
DCAF12L1
SORCS2
JMJD4
SERPINB6
SCGB1A1
CYP8B1 SPOCK1 S100PBP
LIX1L
ZNF700
MUC21
USP19
CEP290
DENND4C
SLC6A12
CCDC153
C9orf93
LAMA2
RAG2
C20orf107
EFCAB3
TBC1D9
MAGEC1 KIAA1486
TMCO6 KRT31 ASPM
SI KHDRBS3 TCERG1L CCDC157 C22orf43 PCDH15
MPL
USP6 SETD2 MED26 ZNF319
ELOVL3
ZSCAN4 GABRB2
RAD54L2 PCDHA12
TIMP2 UPF1
AXL
RANBP3L GAL3ST3 NPLOC4 PLA2G6 WDR25
EPYC
PCDHB10
CEP170 DHRS11
TMEM195
ALDH1L2 RPS6KA1
SPTA1 UBTF
PFTK1 FANCB HIVEP3
LRP6
SULT2B1 MFSD6L
ZFYVE1
DOCK10
NUP210L EGR1 KIAA1279 MLPH GPR109A
ZMYM4 PDE3A
EFHC1 SEL1L3
BTBD11
ASNS
FLG2
USP9X VAT1L
FRK
PRPF38B
ZC3H11A CHRNB2
QRICH2
WDR54
TRIM10 NUP210 SHKBP1 CHIA DONSON ARPP−21
RBM39
KIF3C
TMX3 CTCFL
OR12D2
FAM135A
SLITRK4
JAKMIP3
SLC16A9
NDST4
FOXK1
MATK
METAP2 TMEM19
ZNF193
PTPN11
KCNH4
ZNF749 MCTS1
C19orf33
ADAM29
DOPEY2
SEMA3E
C1orf163
TSHR
RABL3
SACM1L
ATP8B4 PRKCZ
RXFP2 MDM4 NAV2
MYO10
RGNEF ZC3H15 RAB27B THSD7B
EXOSC2
IRGC
GTF3C1
CMKLR1
ISPD UBE2G1
CD14
AIM1L
CANT1 GRIA4
PIWIL1
POLR3C
POLR3A
PPFIA1
CCDC46
HOXD13 ACTRT1 CXorf22
LMOD3
ARID4A
METTL9
BLMH
VAV3
EYA4
RRM1 DDX25
NDUFA5 OR5D16 SH2D2A
ACAD11
FAM47B
RAG1
ZNF148
GLB1L2
MEGF9 FAM5C AADAT
DMXL1 SMOC2
TLN2
GPR112
SLC4A5
BCAP29
GPR115 LUC7L3
MRVI1
FMO1
NEFH
USP22
EHBP1
PSEN1 MYO9A C3orf64
PSMD1
TUBAL3
FBXL19 AFG3L2
SLC9A6 ZNF630
KLK9
IRF4
14−Sep
SYNJ1
TLR4 MON2 RAB28
MBD1
MCF2L
ATP10B
GLT6D1
INTS12
ZNF559 MYO1E
ABCE1
ARID3C
UMOD CYC1 TFPI
NEB CHRND
DCHS1 CHRM2
VEPH1
EIF3B
RMI1
ATOH1
UVRAG KLHL6 TRABD
GPD1 TSC1
MYOM2
LAMB2
ADAM9
CAMK4
SF3A3
TMED6
JAM3 SCG5
NR2F2
CALCR
EGLN3 NLRP2
OR2G2
CLCN1
POLH TTF1
MASP1
ADNP2
SLMAP
GRIK2
TAAR8
PRKD3
KIF6
RNF26
PDE8B
NSUN2
GNPAT EPHB1
CFTR
KCNH1
CDH8
PARVG
MAOA ACTN3
STAG1 CDC2
RPGR WDR1
CNTN4 NKAPL
HSPA4 CHST5 SYDE2
TLE4
ST18
ASB15
LAMA5 UBE2K
INTS4
DYSF
HAO1
LRTM2
CD3G
ZBTB3
PBK
RXFP1
WDR7
PLK4
ETNK1
DOT1L
OCM
PUS7L
LZTR1
AASS SMOX
RELN
HRH4
ALPK2
TACR3
FLG
CD200
MLL MID2
KLK15
RGL1
MYH8
LRP8
POLQ HIPK1
MFN1
ITGAE
HEXB
UPP1
EGFR IKBKB
HAS2 PLD2
XPO4
STK4
DKK2
ODZ4
SGCZ
TFAM
GJB4
NBN PUS7
JAG2
FEN1 FGF6
STAC
TLL1
GAA
GIT1 IRX5 ZP1
MTR
DIS3
PKHD1
MAP2K4
MSRB3
NRAS
KRAS
LRP1B
FAT3 MUC16
NTN1
FAM46C
MYH10
Egan et al. Blood vol. 120 no. 5
Gompertzian Growth
1012
Precursor
Disorders
MGUS
Smoldering
Renal Failure
Myelosuppression
Bone disease Hypercalcemia
109
Mol CR, IF CR: MRD
105
Surviving
clone
Surviving
clone
Criteria for Diagnosis of Myeloma
MGUS
Smoldering MM
• <3 g M-spike
• <10% PC
• 3 g M-spike
• OR 10% PC
AND
Active MM
• Increased PC
• Any M-spike +
AND
YES
NO
C - High calcium
R - Renal dysfunction
A - Anemia
B - Bone lesions
(also hyperviscosity,
amyloidosis, recurrent
infections)
Kyle RA, et al. N Engl J Med. 2002;346:564-569.
Smoldering Myeloma
Smoldering Myeloma
Probability of
Progression (%)
100
p < 0.001
Gr 1:TTP 1.9 y
80
Gr 2: TTP: 5 y
60
Gr 3: TTP 10 y
40
No. of
risk factors
1
2
3
20
No.
81
114
78
Rel risk
1
1.9 (1.2–2.9)
4.0 (2.6–6.1)
0
0
• PCsBM Infiltration ≥ 10%
• Serum M protein ≥ 3 g/dL
• Serum FLC ratio < 1/8 or > 8
5
10
15
Years
Kyle RA, et al. N Engl J Med. 2007; 356:2582-90
Dispenzieri A, et al. Blood. 2008;111:785-9.
ORIGINAL ARTICLE
Lenalidomide plus Dexamethasone for High-Risk
Smoldering Multiple Myeloma
María-Victoria Mateos et al.
N Engl J Med. 2013; 369:438-447.
Objectives
QuiRedex
Primary objective
 Time to progression to symptomatic MM
Secondary objectives
 Response rates
 Duration of response
 Safety and tolerability
 Progression-free survival, overall survival
External CRO: monitorization of data
Independent Data Monitoring Committee: Inclusion criteria & primary endpoint
Schedule of Therapy (n:126 pts)
Treatment arm
(n = 60)
Control arm
(n = 66)
Lenalidomide
Induction
Nine 4-week cycles
Maintenance
25 mg/daily during 21d every 28 d
Dexamethasone
Therapeutic abstention
20 mg D1-D4 and D12-D15 every 28 d
Lenalidomide
10 mg/daily during 21 d
every month*
Therapeutic abstention
Ammendment on August 2011: Stop treatment at 2 years of treatment
* Low-dose Dex will be added at the moment of biological progression
Len-dex vs. No Treatment: TTP to Active Disease (n = 119)
ITT analysis
Median follow-up: 32 months (range 12–49)
Lenalidomide + dex
1.0
Median TTP: NR
Proportion of patients alive
9 Progressions (15%)
0.8
5 pts:early disc followed by DP
4 pts:symptomatic DP
0.6
0.4
No treatment
Median TTP: 23m
0.2
37 Progressions (59%)
20 patients: bone disease
HR: 6.0; 95% IC (2.9–12.6); p < 0.0001
7 patients: renal failure
0.0
0
5
10
15
20
25
Time from inclusion
30
35
40
45
50
Len-dex vs. No Treatment: OS From Inclusion
(n = 119)
Median follow-up: 32 months (range 12–49)
Lenalidomide + Dex
Proportion of patients alive
1.0
No treatment
0.8
0.6
p=0.04
0.4
0.2
Lenalidomide + Dex: 93% at 3 years
No treatment: 76% at 3 years
0.0
0
5
10
15
20
25
30
Time from inclusion
35
40
45
50
• Carfilzomib, Lenalidomide, and Dexamethasone for
Smoldering Multiple Myeloma
• Biomarker Study of Elotuzumab in High Risk Smoldering
Myeloma
Myeloma Treatment
Younger
Induction
Transplant
Consolidation
Maintenance
Older
Induction
Consolidation
Maintenance
Quality of Response: Survival
Niesvizky et al. Br J Haematol. 2008 Oct;143(1):46-53
CR in Transplant Setting
• Outcomes of 4990 HDT/SCT
patients (21 studies) according
to best response were
reported
• Majority of these studies show
correlation between maximal
response (CR/nCR/VGPR) and
long-term outcomes (OS &
EFS/PFS)
• Two meta-analyses: both show
highly significant associations
–One based on p-values
reported
–One based on primary
response and outcome data
van de Velde et al. Haematologica 2007
Impact of CR + VGPR on Outcome
IFM99 Double ASCT
100
75
≥ 90% (n = 51)
50
≥ 50% (n = 81)
25
< 50% (n = 46)
0
0
22
44
66
88
Survival
Survival
Distribution Function (%) Distribution Function (%)
IFM90
1.00
p = .0007
0.75
p = 7 x 10-5
0.50
PR: 290
CR + VGPR: 440
0.25
0.00
0
250 500 750 1,000 1,250 1,500 1,750 2,000 2,250
EFS
1.00
0.75
0.50
PR: 290
CR + VGPR: 440
0.25
0.00
0
250 500 750 1,000 1,250 1,500 1,750 2,000 2,250
OS
EFS = event-free survival.
Moreau et al, 2008; Attal et al. 1996, 2006.
p = 7 x 10-5
Hematologic CR Correlates With Long-Term PFS and OS in
Elderly Patients Treated With Novel Agents
• Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON
groups (N=1175)
• First-line treatment
MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)
OS
PFS
CR
VGPR
PR
P<0.001
VGPR
Probability
Probability
CR
PR
P<0.001
•Significant benefit also seen when analysis is restricted to patients >75 years old
Gay et al. Blood 2011; 117(11):3025-31
The Better the Quality of the Response the Longer the
Survival (Immunophenotypic CR): GEM2005>65y
PFS
100
80
Immunophenotypic CR
90% at 3y
“Stringent CR”
38% at 3y
Conventional CR
57% at 3y
PR (≥70% reduction)
28% at 3y
60
40
20
0
P =0.001
0
10
20
30
Months
40
50
60
Paiva et al; J Clin Oncol. 2011;29(12):1627-33.
Abstract
Martinez-Lopez et al. Blood. 2011;118(3):529-534
Abstract
Martinez-Lopez et al. Blood. 2011;118(3):529-534
CR vs. nCR/VGPR/PR vs. Less
Martinez-Lopez et al. Blood. 2011;118(3):529-534
Advancing Outcomes With Total Therapy
Years from date of first complete response
Barlogie Leukemia, 22:1633 –1636; 2008
Combinations in the Upfront Treatment of MM
Stewart et al, 2009.
BiRD (Clarithromycin/lenalidomide/dexamethasone)
combination therapy results in high complete- and
overall-response rates in treatment-naive
symptomatic multiple myeloma.
2008; 111: 1101-1109
Prepublished online Nov 7, 2007; doi:10.1182/blood-2007-05-090258
Ruben Niesvizky, David S. Jayabalan, Paul J. Christos, Jessica R. Furst, Tara
Naib, Scott Ely, Jessica Jalbrzikowski, Roger N. Pearse, Faiza Zafar, Karen
Pekle, April LaRow, Richard Lent, Tomer Mark, Hearn J. Cho, Tsiporah Shore,
Jeffrey Tepler, John Harpel, Michael W. Schuster, Susan Mathew, John P.
Leonard, Madhu Mazumdar, Selina Chen-Kiang and Morton Coleman
Maximum Response to BiRD
(n = 72, 69 evaluable)
Median time on treatment: 368 days (29-944)
Niesvizky et al. Blood. 2008;111:1101-1109.
Sustained Responses to BiRD Over Time
100
90
80
70
60
50
40
30
20
10
0
1
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53
PR%
VGPR%
CR%
SCR%
UPDATE BiRD
PFS for Patients Receiving BiRD
OS for Patients Receiving BiRD
1.00
Pro p ortion of Pa tie n ts
Proportion of Patients
Proportion of Pa tie nts
1.00
0.75
0.50
0.25
Median PFS: 70.8 months (range, 47.6-NR)
5-year PFS rate: 54.5% (95% CI: 40.5%-66.4%)
0.75
0.50
0.25
4-year OS rate: 82.2% (95% CI: 70.7%-89.5%)
Median 5-year OS has not been reached
0.00
0.00
0
100
200
300
0
100
68
53
300
Time
(Weeks)
Time
(We
e k s)
Time (Weeks)
Time (Weeks)
umber at risk
200
39
Num ber at risk
8
68
63
55
BiRD, clarithromycin, lenalidomide, dexamethasone; CI, confidence interval;
EFS, event-free survival; SPM, second primary malignancy; NR, not reached;
PFS, progression-free survival.
Rossi et al. Blood 2013 Jan 8 Epub
11
Progression-Free Survival is not Affected by
Transplant After Lenalidomide
Proportion of Patients
1.00
0.75
0.50
P=0.61 by log-rank test
0.25
No Transplant
Transplant
0.00
0
No Transplant:
N=36 patients, 15 progressions
Median PFS = 307.9 weeks (95% CI 207 - NR)
5-year PFS = 60.7% (95% CI = 41.5% - 75.2%)
100
Time (weeks)
200
300
Transplant:
N=32 patients, 15 progressions
Median PFS = 259.4 weeks (95% CI 146.9 - NR)
5-year PFS = 48.0% (95% CI = 27.5% - 65.8%)
Rossi et al. Blood 2013 Jan 8 Epub
Complete Remission in pts with BiRD therapy detected by the
disappearance of paraprotein (CR), Negative IHC(sCR) & Negative
PCR(Mol CR)
PCR Analysis
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
5
10
15
20
25
30
35
Pt. #15
Pt. #40
Pt. #43 Pt. #59
pre
pre
pre
post
post
post
pre
No new clones were identified and the primary
clone was
undetectable in 5/7 tested pairs
CR
sCR
Cycles
Mol CR
MRD
post
CyBORD3
N=35
39
CR
BCD + BDT4
N=65
28
61
VRD2
N=65
38.9
76
73
NA
VGPR
22
30
20.8
30
PR
27
NA
16.7
25
MR
1
NA
5.6
NA
Refractory
1
NA
0
0
Overall
88
100
90.3
100
Niesvizky et al Blood. 111, 1101-1109; 2008.
Richardson et al. ASH 2008, Abstract 92
13.9
26
nCR
1.
2.
18
BiRD1
N=72
3. Reeder et al. Leukemia 2009, 23:1337-41
4. Bensinger et al. ASH 2008, Abstract 94
18
74
A phase 1/2 study of carfilzomib in
combination with lenalidomide
and low-dose dexamethasone as a
frontline treatment for multiple
myeloma
CR 42%
>VGPR 62%
Jakubowiak, et al. Blood, 2013
Summary / Conclusions
• Novel agents can increase CR/VGPR
• CR should be the goal, but…..
• Improvement in induction reached top numbers….what’s next
– Consolidation post transplant
– Transplant as salvage, improve on conditioning regimens
Car Dex
20-27-45-52
BiRd
? Other IMiDs
SC collection
?MRD
MyelomaCenter. org
Morton Coleman
NCI K23 Award: CA109260-01
Faiza Zafar
Selina Chen-Kiang
Roger N Pearse
Monica Guzman
Tomer Mark
Adriana C Rossi
Karen Pekle
Arthur Perry
Tsiporah Shore
Koen Van Besien
Linda Tangenstam
Kathleen Pogonowski
Scott Ely
Yashpal Agrawal
David S. Jayabalan
Stanley Goldsmith
Maureen Lane
Paul Christos
Susan Mathew