1. What is the Best Induction Therapy in Transplant-Eligible Patients
What is the Best Induction Therapy in Transplant-Eligible Patients? Combination Therapy  
Ajai Chari, MD
Attending Physician
Multiple Myeloma Program
Mount Sinai Medical Center

2. Classes of Agents with Anti-MM Activity: What Is the Best Combination?
off label ―
Steroids
ImIDs
Proteasome Inhibitors
Conventional Chemo
Prednisone
Thalidomide
Bortezomib
Melphalan
Dexamethasone
Lenalidomide
Carfilzomib
Cyclophosphamide
Pomalidomide
Doxil
DCEP/D-PACE
BCNU
Bendamustine

3. Clinical Features at Presentation of Symptomatic MM
Increased plasma cells in the bone marrow (96%)
Monoclonal (M) protein (93%)
Anemia (normochromic normocytic; 73%)
Lytic bone lesions (67%)
Renal failure, serum creatinine >2.0 (19%)
Hypercalcemia (corrected calcium >11) (13%)
Infection
Kyle RA. Mayo Clin Proc 2003;78:21-33

4. Elements of Risk Stratification for MM

5. Doublet Induction Regimens Responses
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Doublet Induction Regimens Responses
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Newly Diagnosed, SCT Eligible
Response to induction D1
N = 235
TD1
VAD2
N = 242
VD2
N = 223
RD3
Rd3
N = 222 CR 3% 8% 6%
15% 5% 4%
> VGPR
16%
44%
38%
50%
40%
ORR
46%
63%
79%
68%
D: dexamethasone
TD: thalidomide, dexamethasone
VAD: vincristine, adriamycin, dexamethasone
VD: bortezomib, dexamethasone;
RD: lenalidomide, dexamethasone;
Rd: lenalidomide, low-dose dexamethasone;
After 4 cycles
1; 2Harousseau JL, et al. J Clin Oncol Oct 20;28(30):4621-9;
3Rajkumar SV, et al. Lancet Oncol. 2010;11(11):29-37.

6. Improved Efficacy with Decreased PN
RVD: 28 vs. 21 Day Regimen –
Improved Efficacy with Decreased PN
21 Day RVD (n=66 all/35 phase 2) 1
28 Day RVD (n=38) 2
Response rate after 4 cycles of RVD
sCR/CR/
nCR
> VGPR
> PR
> MR
> SD
All PN
Dose ↓
For PN
21d RVD 6 11 75 95
100% 80 44
28d RVD 5 63 97
100 37
7.8 .
1 Richardson et al. Blood Aug 5;116(5):
2 Chari et al, Abstract # ASH 2011.

7. Evolution Randomized Phase 2 Study
Induction x 8 3-wk cycles
V 1.3 mg/m2 days 1, 4, 8, 11
D 40 mg days 1, 8, 15
C 500 mg/m2 days 1, 8
R days 1–14
VDCR 
 (15 mg)
VDR
 (25 mg)
VDC
VDC-mod
 (+ day 15)
Maintenance x 4 6-wk cycles
V 1.3 mg/m2 (days 1, 8, 15, 22)
Response, n (%)
VDCR
(n = 48)
VDR
(n = 42)
VDC
(n = 33)
VDC-mod
(n = 17) CR
10 (25)
10 (24)
7 (22)
8 (47)
≥ VGPR
23 (58)
21 (51)
13 (41)
9 (53)
ORR (≥ PR)
35 (88)
35 (85)
24 (75)
17 (100)
Neutropenia
21 (44)
4 (10)
10 (30)
4 (24)
Kumar et al; Blood 2012 May 10;119(19): 7

8. When Cyclophosphamide Might Be Used Preferentially As Proteasome Inhibition Partner
Renal Failure
Poor performance status (e.g. wheelchair bound, paraplegic) due to VTE risk especially if bleeding risk as well
Inpatient
Need to initiate outpatient therapy rapidly (e.g. impending cord compression)
Intolerance of Imids (angioedema)
Washout of lenalidomide pre-stem cell harvest
Oral therapy not dependable (poor compliance, malabsorption)
Inadequate RN/admin support for IMIDs

9. Car + Len + Dex Induction: Efficacy
Independent of ISS and cyto/FISH
Jakubowiak et al; Blood Aug 30;120(9):

10. Car + Len + Dex Induction: Toxicity
During dose escalation, DLTs:
20 mg/m2 (n=4): none
27 mg/m2 (n=13): Gr 3 neutropenia
36 mg/m2 (n=18): Gr 4 pulm edema, Gr 3 dyspnea
Probability: 5.9 vs. 8.1 vs. 12%
Dyspnea due to hydration, methhemoglobinemia (dapsone)
Note: CHF 2/20 in nDMM, 1/8 in sMM with 20/36 mg/m2 CR25D30
Jakubowiak et al; Blood Aug 30;120(9): Korde et al. Abstract #732 ASH Landgren Abstract 06: IMWG 2013.

11. Summary: Efficacy of MM Induction Regimens after 4 cyclesN
(I/II)
sCR/CR/
nCR (%)
> VGPR
(%)
> PR
> MR
> SD
ISS 3
Adverse cyto/FISH
28d RD vs Rd
422 16 46 76 85 91
26% NA
BiRD (after 6 mos) 60 18 57 95
20%
21d RVD
66/35 6 11 75
100 9%
15%
21d RVD (E) 42 7 32 73 19 17
28d RVD 38 5 63 97
11%
8% (18%1q)
28d CRD
49/18 67 88
33%
28d CCTD 35 83
21 d VDCR(E) 48 33 80 21 15
21d VDC (E ) 13 23
21d VDC+ (E) 12 41 82
Rajkumar et al. Lancet Oncol Jan;11(1): Epub 2009 Oct 21.
Guy et al. Am J Hematol Sep;85(9):664-9.
Richardson et al. Blood 2010 Aug 5;116(5):
Chari et al, Blood Abstract #. 2949
Mikhael, J et al. J Clin Oncol 30, 2012 (suppl; abstr 8010)
Jakubowiak et al; Blood Aug 30;120(9):
Kumar et al; Blood May 10;119(19):

12. Bortezomib-Thalidomide-Dexamethasone
VTD (n=236) vs. TD (n=238)
3 cycles of induction
tandem auto SCT
2 cycles of consolidation
Maintenance dex 10 20 30 40 50 60 70 80 %
Induction
First ASCT
Second ASCT
Consolidation
VTD TD
31%
11%
52%
55%
41%
62%
45%
P<0.0001
P=0.0024
P=0.0002
33%
14%
57%
63%
73%
61%
P<0.004
P=0.123
P=0.020
INDUCTION (21-d cycles) Vel 1.3mg/m2 twice weekly, Thal 100200mg/day, Dex 320mg/cycle
CONSOLIDATION (two 35-d cycles): Vel 1.3mg/m2 once weekly, Thal 100mg/day, Dex 320mg/cycle
3 yr PFS: 60 vs 48 % (p 0.043)
3 yr OS: 90 vs 88% (p 0.390)
CR + nCR rates
Cavo et al. Blood Jul 5;120(1):9-19.

13. Summary: Dose Reductions/Toxicity of MM Induction RegimensN
(I/II)
Dose
Reductions
All PN
Dose ↓
For PN
28d RD vs Rd
422
N/A
BIRD 60
21d RVD
66/35
44% (R)
35% (V)
48% (D)
80%
44%
21d RVD (E) 42
55%
17%*
28d RVD 38
8% (R)
8% (V)
37%
7.8%
28d CRD
49/18
33%
23% ?
28d CCTD 17
20%
21 d VDCR(E) 48
56%
13%*
21d VDC (E ) 32
66%
21%*
21d VDC+ (E)
47%
8%*
Cost? Quality of Life?

14. Does Quality of Response Matter After HDM-ASCT?
van de Velde HJ, et al. Haematologica 2007;92(10):

15. > VGPR After 1st Auto SCT Does Not Benefit From Tandem
Does Quality of Response to Induction Therapy Matter?
> VGPR After 1st Auto SCT Does Not Benefit From Tandem
Cavo et al. J Clin Oncol : Attal et al. NEJM Dec 25;349(26):

16. Does Induction Response Quality Matter in Era of Novel Therapies?B1 B2
VAD x 4
Vel
-Dex x 4
Induction
DCEP x 2
Consolidation
Transplant 1: melphalan 200 mg/m2
Transplant 2: second ASCT or RIC allo if < VGPR
PFS post induction
> or < VGPR
PFS post ASCT
PFS post ASCT
> or < VGPR and VAD or VD induction
Moreau P. et al. Blood 2011;117(11):

17. Combination Therapy: The Future
Steroids
ImIDs
Proteasome Inhibitors
Conventional Chemo
Prednisone
Thalidomide
Bortezomib
Melphalan
Dexamethasone
Lenalidomide
Carfilzomib
Cyclophosphamide
Pomalidomide
MLN9708/Ixazomib
Doxil
Oprozomib
DCEP/D-PACE
Marizomib
BCNU
Bendamustine
off label/
investgational ―
Epigenetics/
Chaperoning
Signal Transduction
Inhibitors
Cell Cycle/
Apoptosis
Monoclonal Antibodies
Vorinostat
mTOR
KSP Inhibitor
Anti-CD138
Panobinostat
AKT
CDK inhibitor
Anti-CD38
Romidepsin
BTK
Aurora Kinase Inhibitor
Anti-CS1
HSP90 inhib
PIM
Bcl2 Inhibitor
IGF-R
CRM1 inhibitor
TRAIL agonist
Bone Targeted Agents
Bisphosphonates
RANKL inhibitors
DKK1 antibody
Activin A receptor

18. Combination Therapy Preferable: Conclusions
Symptomatic MM patients benefit from rapid & deep resolution of symptoms
Multidrug regimens are associated with higher response rates
If no overlapping toxicity of individual drugs, combination regimens are very well tolerated
Since induction therapy is not continued until PD, resistance is unlikely and retreatment is feasible
MM is very hetereogeneous - to date, so called “risk-stratified treatment algorithms” are not based on prospective phase 3 studies with the precision of differential therapies for NHL subtypes: FL vs DLBCL vs. BL. Rather,
Risk definitions keep evolving: 13q -> t(4;14) -> ch 1q -> ?
Risk is dependent on therapy eg. t(4;14)
Improved depth of response pre SCT: 1) improves likelihood of adequate SCH 2) decreases likelihood of second SCT with attendant hospitalization/morbidity/cost and 3) may increase PFS