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*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)
R: Renal insufficiency (CrCl < 40 mL/min or serum creatinine > 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)
B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET/CT)
100
Smoldering MM
MGUS
80 27% will convert in 15 years
Roughly 2% per year 78
73
Progression (%)
66
60
15% more will convert over next 5 yrs
51 and then 1% per yr thereafter
40
51% will convert in first 5 yrs
~ 10% per yr
20 21
4 16
10
0
0 5 10 15 20 25
Yrs Since Diagnosis
2-Yr
Factor, % Progression
High levels of circulating plasma cells 80
High bone marrow plasma cell proliferative rate 80
Evolution of smoldering multiple myeloma 65
Abnormal plasma cell immunophenotype ≥ 95%
plus immunoparesis 50
Cytogenetic subtypes: t(4;14), 1q amp, or del(17p) 50
Unexplained decrease in creatinine clearance by
≥ 25% accompanied by a rise in urinary monoclonal
protein or serum free light-chain concentrations NA
▪2 important goals
– Counsel: Need to provide pt with realistic expectations
based on currently available treatments
– Therapy: Choose specific therapies based on their
differential effects on high-risk vs standard-risk disease
1.0
Stage Definition
▪ Serum albumin ≥ 3.5 g/dL 0.8
Probability of OS
AND β2-M ≤ 3.5 mg/L
1 ▪ Normal LDH
▪ No t(4;14), t(14;16), or 0.6
del(17p)
2 ▪ Not stage I or III 0.4
▪ β2-M ≥ 5.5 mg/dL PLUS
Median OS, Mos
3 ▪ High LDH, OR
0.2 R-ISS I NR
▪ t(4;14), t(14;16), or del(17p) R-ISS II 83
R-ISS III 43
0
0 12 24 36 48 60 72
Mos
Probability of OS
0.8
0.75
0.6
0.50 P = .0017
0.4
0.25 CR + VGPR (n = 445) 0.2 CR or better PR PD
PR (n = 288) VGPR SD
0 0
0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7
Yrs Since Transplantation Yrs Since Transplantation
▪ Pts with sCR have a significantly better
outcome: estimated 5-yr OS 80% with sCR vs
53% with CR or 47% with nCR
Category 1 Category 2A
▪ Bort/dox/dex ▪ IRd
Initial therapy (induction) ▪ Rd ▪ KRd
for transplantation-eligible ▪ RVd Category 2B
pts (response assessment ▪ VD ▪ Dexamethasone
after cycle 2) ▪ VTD ▪ Liposomal dox/vin/dex
Category 2A ▪ Thal/dex
▪ CyBorD
OS (%)
50 50
25 25
37.4 54.7
21.8 34.2
0 0
0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66
Mos Mos
60 60 ASCT
OS (%)
86
40 40 CRd 71
HR: 0.42 (95% CI: 0.23-0.76;
20 20 P < .004)
Median f/u: 55 mos Median f/u: 55 mos
▪0 Increased grade 3/4 AEs with ASCT vs0 CRd, but similar serious
0hematologic
10 20 (0%
30 vs 2%;
40 50 P60
= .49)
70 and nonhematologic
0 10 20 30 (7%
40 vs5010%;
60
70
P = .393) AEs Mos Mos
75 71 ≥ nCR
60 ≥ CR
sCR
40 32
21 24 22
20 12 8
0
▪ KRd + ASCT produced higher
Induction
ASCT
sCR rate at 8 cycles
Consolidation
End vs historical
of KRd
(n = 48)
controls without (n = 37)
ASCT (71% vs 30%);(nAEs
= 24)similar (n
to =historical
8) controls
Zimmerman TM, et al. ASCO 2015. Abstract 8510. Slide credit: clinicaloptions.com
Duration of Therapy in
Multiple Myeloma
Maintenance Therapy for Pts With
Transplantation-Eligible MM
Preferred Regimens Other Regimens
Category 1 Category 2B
▪ Lenalidomide ▪ VP
▪ Thalidomide ▪ VT
Maintenance therapy
Category 2A ▪ Interferon
▪ Bortezomib ▪ Steroids
▪ Thal + pred
PFS
100 ▪ 5-yr PFS (primary endpoint)
superior with Len vs placebo:
75 Len 42% vs 18%, respectively
Placebo (P < .0001)
Pts (%)
50
– PFS benefit independent of
subgroup (eg, β2-M, ORR)
20
HR
▪ Median EFS: 40 mos with Len vs
Len vs placebo: 0.50; P < .001 23 mos for placebo
0
0 6 12 18 24 30 36 42 48 54 60 ▪ Median OS: similar (> 80 mos)
Mos
*Induction with VD or VAD; consolidation with
▪ Grade 3/4 PN: similar in both
lenalidomide. groups
Attal M, et al. ASH 2013. Abstract 406. Slide credit: clinicaloptions.com
CALGB 100104: Lenalidomide vs Placebo
Maintenance Following ASCT for Myeloma
▪ Phase III trial with D-S stage I-III pts; < 71 yrs of age and > 2 cycles of induction with SD
or better (N = 460)
▪ PFS: ITT analysis with median
follow-up from transplant of 34 mos ▪ OS: 35 deaths with lenalidomide and
53 deaths with placebo
– Estimated HR: 0.48 (95% CI: 0.36- 0.63);
– 3-yr OS: 88% vs 80%; HR: 0.62 or a 38%
median TTP: 46 vs 27 mos
reduction in death with the cross over
1.0 1.0
2-sided P < .001
Probability of PFS
Probability of OS
0.6 Lenalidomide 0.6 Placebo
0.4 0.4
2-sided P = .03
0.2 86 of 128 placebo pts Placebo 0.2
crossed over to lenalidomide Median follow-up: 45 mos
0 0
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
Mos Since ASCT Mos Since ASCT
5 5
0 0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
*Median OS for lenalidomide arm extrapolated to be 116 mos based on median of control arm and HR of 0.74.
Singh PP, et al. ASH 2013. Abstract 407. Slide credit: clinicaloptions.com
HOVON-65: Bortezomib in Induction and
Maintenance for Newly Diagnosed MM
▪ CR/nCR superior with PAD induction (30% vs 15% with VAD) and by best
response (35% vs 49% with VAD) (P < .001 for both)[1]
▪ PFS and OS superior with bortezomib-based treatment regimen[1]
Cumulative Percentage
HR: 0.76 (95% CI: 0.64-0.90; HR: 0.78 (95% CI: 0.64-0.90;
P = .001) P = .01)
75 75
50 50
N F N D
VAD 414 311
VAD 414 182
25 PAD 413 284
25
PAD 413 155
Cox LR stratified P = .002 Cox LR stratified P = .05
0 0
▪ Bortezomib
0 12 significantly improved
24 36 48 60 72 84 OS for pts presenting
0 12 24 with
36 renal
48 60failure
72 84
(P < .001)[2] Mos Mos
Discontinuation (%)
Frail
0.75 0.75
OS (%)
0.50 0.50
OS: fit (0) 84%, intermediate (1) 76%
Fit 17%, intermediate 21% (HR: 1.41;
(HR: 1.61; P = .42), frail (≥ 2) 57%
P = .052), frail (≥ 2) 31% (HR: 2.21;
(HR: 3.57; P < .001) P < .001)
CR
CR
0.8 0.8
Probability
VGPR
VGPR
0.6
of OS
All
PR 0.6 PR
PFS
Probability
Pts Older VGPR
VGPR
of OS
0.6 PR 0.6 PR
PFS
Than 75 Yrs
of Age 0.4 0.4
0.2 0.2 P = .004
P = .001
0 0
0 24 48 72 0 24 48 72
Mos Mos
Category 1 Category 2B
▪ Lenalidomide ▪ VP
▪ Thalidomide ▪ VT
Maintenance therapy Category 2A ▪ Interferon
▪ Bortezomib ▪ Steroids
▪ Thalidomide + prednisone
80 80
60
PFS (%)
60
OS (%)
40 40
72 wks
20 20
0 0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Mos Mos
0.9
0.8
0.7 2006-2010
OS (%)
0.6
> 100,000 pts living
0.5 with myeloma
0.4
2001-2005
0.3
0.2
0.1
0
0 1 2 3 4 5 6
Yrs
Kumar SK, et al. Leukemia. 2014;28:1122-1128. Slide credit: clinicaloptions.com
Confronting Disease Relapse in Myeloma
Median, Mos
Median Response Duration (Mos)
Pts (%)
6
40
4
2 20
0 0
First Second Third Fourth Fifth Sixth 0 12 24 36 48 60
Treatment Regimen Mos
Rosenbaum CA, et al. ASCO 2016. Abstract 8007. Slide credit: clinicaloptions.com
SIRIUS: Daratumumab in R/R Myeloma
Lonial S, et al. Lancet. 2016;Jan 6:[E-pub ahead of print]. Slide credit: clinicaloptions.com
CASTOR: Daratumumab/Bortezomib/
Dexamethasone in R/R MM: Efficacy
DVd
Vd
HR
Efficacy Outcome P Value
(n = 251) (n = 247) (95% CI)
Median PFS following 1
NR 7.5 0.31
prior treatment, mos < .0001
77.5 29.4 (0.18-0.52)
▪ 1-yr PFS, %
Median TTP, mos NR 7.3 0.30
< .0001
▪ 1-yr PFS, % 65.4 28.8 (0.21-0.43)
ORR, % 83 63 < .0001
▪ ≥ VGPR 59 29 < .0001
▪ ≥ CR 19 9 .0012
▪ Time
MRD to PR
negative, % occurred 14
early in pts (~2
3 mos), but CR took longer to
develop in many pts (≥ 8 mos)
Ixazomib + Rd Placebo + Rd
Characteristic P Value
(n = 360) (n = 362)
Median PFS, mos 20.6 14.7 .012*
ORR, % 78.3 71.5 .035
▪ CR 11.7 6.6 .019
▪ VGPR 36.4 32.3
▪ PR 66.7 64.9
Median time to response, mos 1.1 1.9
Median DoR, mos 20.5 15.0
Median TTP, mos 21.4 15.7 .007†
*HR: 0.742. †HR: 0.712.
Dimopoulos MA, et al. ASH 2015. Abstract 28. Slide credit: clinicaloptions.com
KEYNOTE-023: Pembrolizumab/
Lenalidomide/Dexamethasone: Response
Len-Refractory
Efficacy Population
Best Overall Response, % Population
(n = 40)
(n = 29)
ORR 50 38
▪ Stringent CR 3 3
▪ VGPR 13 10
▪ PR 35 24
SD 48 59
Disease control rate
98 97
(CR + PR + SD)
▪ 88% of pts showed some decrease in M protein or free light
PD chains from baseline 3 3
Mateos MV, et al. ASCO 2016. Abstract 8010. Slide credit: clinicaloptions.com
Promising Agents in Clinical Trial
▪ Proteasome inhibitors
– Marizomib (NPI0052): orally available, irreversible nonpeptide PI
– Oprozomib (ONX0912): orally available, irreversible carfilzomib derivative
▪ HDAC inhibitors
– Vorinostat + bortezomib
– Rocilinostat (ACY1215): selective HDAC-6 inhibitor
▪ KSP inhibitors
– Filanesib (ARRY-520): inhibits spindle formation during mitosis, inducing
cell death
▪ Monoclonal antibodies
– Isatuximab (SAR650984): humanized anti-CD38 antibody
Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573. Slide credit: clinicaloptions.com
ASCT: Timing of Transplantation
100
80
Survival (%)
60
40
▪Graft-vs-myeloma effect
▪Can potentially provide sustained disease control (aka,
cure)
▪High treatment-related mortality
▪Morbidity from GVHD
▪No definite OS advantage vs autologous SCT
▪Should be offered to high-risk pts in trials
clinicaloptions.com/oncology