Treating Relapsed Myeloma: Optimizing Therapy

Optimizing treatment for relapsed
myeloma
July 2004 Myeloma “101” M.L.Gray

July 2004 Myeloma “101” M.L.Gray
Current Treatment Goals
 Cures are possible but should not be the
overarching goal
 30% of CR’s can last 10% or more
 Aim for long term complete remission
 Preserve quality of life
 Reduce fatigue
 Control pain
 Protect from infections
 Improve ADLs / Performance Status

Multiple Myeloma Treatment Lines in Transplant-
Eligible Patients
Current Paradigm
Induction Consolidation
Frontline treatment
Risk Stratification?
Maintenance
Maintenance
Rescue
Relapsed
Alkylators
Steroids
Thalidomide
Lenalidomide
Bortezomib
Anthacyclines
e
SCT Thalidomide
Steroids
Bortezomib
Lenalidomide
Alkylators
Steroids
Thalidomide
Bortezomib
Anthacyclines
Carfilzomib
Pomolidomide
Bendamustine
National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology
Multiple Myeloma (Version 1.2011). http://www.nccn.org/. Accessed October 13, 2010.

Patient Case
 65-year-old male presents with anemia
• Initial workup: hemoglobin = 9.5, normal CBC and platelets
 Patient is referred to a local hematologist, an
extensive workup finds
• IgG kappa protein (3.5 g/dL) with reciprocal depression of
the other immunoglobulins, negative UPEP
• 40% plasma cells in the bone marrow with normal
cytogenetics by standard chromosomal analysis and del13
by FISH
• Diffuse lytic disease
• β2-microglobulin = 3.9, albumin = 3.7
UPEP, urine protein electrophoresis.

Patient Case Continued
• He begins induction therapy with thalidomide / bortezomib
/ dex (VTD)
• After 2 cycles he develops paresthesia not interfering with
his function
• After 4 cycles he achieves a PR (75% reduction)
• Stem cells are collected and he receives a single ASCT
• He achieves a CR post-ASCT and declines maintenance
therapy at day 100
• He continues to experience grade 1 peripheral
neuropathy
 15 months after his stem cell transplant, he has a
clinical relapse including new lytic lesions
ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR,
complete response.

Types of Relapse
Alegre A et al. Haematologica 2002;87(6):609-614.

88
Multiple Myeloma
Expectations for Survival After Relapse
Survival as a Function of Era-SCT Patients

Which of the following should NOT be considered
when developing a re-treatment plan?
• Age
• Prior Therapy
• Type of relapse
• Duration of remission
• Comorbidities

Factors in Selecting Salvage Therapy
DISEASE-RELATEDDISEASE-RELATED
DOR to initial therapyDOR to initial therapy
FISH / cytogeneticsFISH / cytogenetics
REGIMEN-RELATEDREGIMEN-RELATED
Prior drug exposurePrior drug exposure
Toxicity of regimenToxicity of regimen
Mode of administrationMode of administration
Previous SCTPrevious SCT
PATIENT-RELATEDPATIENT-RELATED
Pre-existing toxicityPre-existing toxicity
Co-morbiditiesCo-morbidities
AgeAge
Performance statusPerformance status
DOR, duration of response; FISH, fluorescent in situ
hybridization; SCT, stem cell transplant.Lonial S. ASH Education Book. 2010;303-309.
Stage generally does not influence salvage therapy choice.

Relapse Approaches
Lonial S, et al. Clin Cancer Res. 2011;17:1264-1277.
Bz, bortezomib; PN, peripheral neuropathy; len,
lenalidomide; thal, thalidomide; CT, chemotherapy;
SCT, stem cell transplant; PS, performance status.
LENALIDOMIDE-BASEDLENALIDOMIDE-BASED
Initial therapy with bzInitial therapy with bz
Underlying PNUnderlying PN
BORTEZOMIB-BASEDBORTEZOMIB-BASED
Initial therapy len / thalInitial therapy len / thal
Long DOR with prior bzLong DOR with prior bz
Renal dysfunctionRenal dysfunction
TRANSPLANTTRANSPLANT
No previous SCTNo previous SCT
Long remission post-SCTLong remission post-SCT
CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT
EARLY
CT-BASEDCT-BASED
DCEP vs DT-PACEDCEP vs DT-PACE
Oral vs IV CTOral vs IV CT
PS plays an important rolePS plays an important role
CT + NOVEL AGENTCT + NOVEL AGENT
Combinations of lenCombinations of len
and / or bz with otherand / or bz with other
agentsagents
SCT-BASEDSCT-BASED
Likely to be short-livedLikely to be short-lived
Quick disease controlQuick disease control
Reconstitute marrowReconstitute marrow
?
AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE
Consider combination therapy. Don’t wait for symptomatic relapse.

 15 months after his stem cell transplant, he has a
 Treat or not
• Yes, symptomatic relapse
 Single or Combo
• Lets look at the data
 Retransplant?
• Lets look at the data
complete response.

Clinical Considerations for
Relapsed/Refractory Disease
• Disease characteristics/prior therapy
– Aggressiveness of relapse
– Relapsed or relapsed and refractory disease
– “High risk disease”
– Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
• Toxicity considerations
– Peripheral neuropathy
– Thrombotic risk
– Myelosuppression
– Impact of prior therapies (eg, SCT, other cumulative toxicity)

How do we treat a patient in first relapse?
Sequencing of therapy is important
Issues
Treat or Not to Treat
Single Agent vs Combinations

Classes of Drugs With Anti-MM Activity
Steroids Immuno-
modulatory
Agents
Proteasome
Inhibitors
Cytotoxic
CT
HDAC
inhibitors
mTOR
inhibitors
mAbs
Prednisone Thalidomide Bortezomib Melphalan Vorinostat Perifosine Elotuzumab
Dexa-
methasone
Lenalidomide Carfilzomib Cyclophos-
phamide
Panobinosta
t
Pomalidomide MLN9708 PLD
ONX 0912 DCEP
Marizomib BCNU
CEP-18770 Benda-
mustine

Novel Agents as Monotherapy
Without Steroids
Regimen Phase n CR + PR CR + nCR Reference
Bortezomib
(APEX)
3 331 43% 16%
Richardson, et al.
Blood. 2005;106
(abstract 2547)
Thalidomide 2
712 28.2% 1.6%
Prince, et al.
Leuk Lymphoma.
2007;48:46
1629 29.4% 1.6%
Glasmacher, et al.
Br J Haematol. 2006;132:584
Lenalidomide 2 102 17% 4%
Richardson, et al.
Blood. 2006;108:3458
Proteasome inhibitor bortezomib has the best single agent activity

Thal + Dex vs. Combination Chemotherapy
PFS median 17 vs.11 months OS at 3 years 60% vs.26%
First Relapse N PFS OS at 3 years
Thalidomide + Dexamethasone 62 17 months 60%
Combination Chemotherapy 82 11 months 26%
Palumbo A, et al. Hematol J. 2004;5:318-324.
THAL 100 mg/day and DEX 40 mg (days 1–4 of each month)
CC: MP, VAD, intermed dose Cytoxan, VMCP-VBAP
Second Relapse N PFS OS at 3 years
Thalidomide + Dexamethasone 58 11 months 19
Combination Chemotherapy 38 9 months 19

Pooled Analysis of MM-009 and MM-010 Data: Response,
TTP and OS According to Number of Prior Therapies
*EBMT Criteria
PR (>50%)
CR (IF-)
PR + CR
ResponseRate(%)
0
20
40
60
65%*
Len/Dex
n=124
26%
Dex
n=124
20%
Dex
58%*
Len/Dex
80
n=229 n=227
1 Prior Therapy ≥ 2 Prior Therapies
4.79.64.714.5*
P<0.05
27.333.333.639.1
Median TTP (months)
Median OS (months)
Weber DM, et al. Presented at: 49th
ASH Annual Meeting; December 8–11, 2007; Atlanta, GA.

Pooled Analysis of MM-009 and
MM-010 Data: Updated OS
0 10 20 30 40 50
0
20
40
60
80
100
Overall Survival (Months)
Patients(%)
*P value from log-rank test (patients analyzed for extended follow-up remained in original groups
despite crossover)
Weber D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:412.
Survival Benefit Retained Despite 47% Crossover
P=0.015*
Plac/Dex
Median, 31 months
Len/Dex
Median, 35 months
(58% remain alive)

Impact of Prior Thalidomide Therapy:
Pooled Analysis of MM-009 and MM-010 Data
7.15020Refractory (PD)
7.04531SD
7.04354Progressed (CR/PR)
8.354127Prior Thal
13.865226Thal Naïve
Median TTP,
months
ORR (≥PR),
%
n
Thal Naïve vs. Thal Exposed
Median Time from Diagnosis: 2.8 years vs. 4.0 years (P<.05)
Median Lines of Prior Therapy: 2 vs. 3 (P<.05)
Weber DM, et al. Presented at 49th
ASH Annual Meeting; December 8-11, 2007; Atlanta, GA.; Weber DM,
et al. N Engl J Med. 2007;357:2133-2142.; Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.

APEX: Bortezomib
Early vs. Late Relapse
Bortezomib
1 prior therapy
n = 132
> 1 prior therapy
n = 200
Median TTP (months) 7.0 4.9
CR (%) 10%* 7%†
CR + PR (%) 51%* 37%†
Median Duration
of Response (months)
8.1 7.8
1-year Survival 89% 73%
* Evaluable patients, response to bortezomib after 1 prior therapy: n = 128
†
Evaluable patients, response to bortezomib after >1 prior therapy: n = 187
Sonneveld P, et al. Haematologica. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium
Pharmaceuticals, Inc.

Updated APEX Results
OS
ProportionofPatients
23.7 months
0.0
0.2
0.4
0.6
0.8
1.0
• Superior survival despite >62% of HD dexamethasone patients
crossing over to bortezomib
– 1-year survival rate: 80% vs. 67%; P=.0002
P=.0272
Time (Days)
Dexamethasone
Bortezomib
0 180 270 360 45090 540 720 810 900 990630 1080 1170
29.8 months
Richardson PG, et al. Blood. 2007;110:3557-3560.

23
Bortezomib Combination
Therapies in Relapse
Author/Year N Regimen
Overall
Response
Rate (%)
CR/nCR
Rate (%)
Median
PFS
(mos)
Median
OS (mos)
Pineda-Romané/2008 85 BTD 63 22 – 22
Jakubowiak/2005 20 BD + PLD 56 33 – –
Biehn/2007 22 B + PLD 63 36 9.3 (TTP) 38.3
Popat/2005 22 B + Iv Mel +/- D 43 5 6.8 (TTP) –
Palumbo/2007 30 V Mel PT 67 17 61% (1 yr) 84% (1 yr)
Reece/2008 37 B + Cy + P 95 54 >12 >12
B = bortezomib; T = thalidomide; D = dexamethasone; PLD = pegylated liposomal doxorubicin;
Mel = melphalan; P = prednisone; Cy = cyclophosphamide; PFS = progression-free survival; nCR = near
complete response.
Kaufman J et al. Curr Hematol Malig Rep. 2009;4:99-107.

24
Lenalidomide Combination
Therapies in Relapse
Author/Year N Regimen
Overall
Response
Rate (%)
CR/nCR
Rate (%)
Median
PFS
Median
OS
Schey/2009 31 LCD 81 36 (VGPR) – –
Knop/2009 66 LDoD 73 15 40 weeks 88% (1 year)
Reece/2009 15 LCP 74 45 (VGPR) – –
Baz/2006 52 L PLD ViD 75 29 (nCR) 1 year 84% (1 year)
Richardson/2009 35 LBV+/- D 60 >MR 8 7.7 months 37 months
Anderson/2009 62 LBVD 69 26 12 months 29 months
L = lenalidomide; C = cyclophosphamide; D = dexamethasone; DO = doxorubicin; P = prednisone;
PLD = pegylated liposomal doxorubicin; Vi = vincristine; B = bortezomib.
Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood. 2009;113:4137-4143;
Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et al. Ann Oncol. 2006;17:1766-1771;
Richardson PG et al. J Clin Oncol. 2009;27:5713-5719; Anderson KC et al. 2009 ASCO Annual Meeting. Abstract
8536.

Main Randomized Trials of TreatmentMain Randomized Trials of Treatment
of Relapsed/Refractory MMof Relapsed/Refractory MM
ORR = overall response rate; CR = complete response; TTP = time to progression; NR = no response.
Richardson et al, 2007; Orlowski et al, 2007; Weber et al, 2007; Dimopoulos et al, 2007.

Additional Bortezomib and
Lenalidomide Combinations
Study Regimen N Responses Frequent G3/4 AEs
Kropff, et al1
VCD 50
16% CR
66% PR
TCP, leukopenia,
infection, PN, HZV,
fatigue, anemia,
hypotension
Morgan, et al2
CVD 47
31% CR
75% ORR
TCP, neutropenia, PN,
infection
Reece, et al3
VCP 37
>50% CR
95% ORR
Nausea, TCP,
neutropenia
Baz4
Len + PLD 62
29% CR/nCR
75% ORR
Myelosuppression
1
Kropff M, et al. Br J Haematol. 2007;138:330-337. Comment in: Br J Haematol. 2008;140:115-116.
2
Davies FE, et al. Haematologica. 2007;92:1149-1150. 3
Reece DE, et al. J Clin Oncol. 2008;26:4777-
4783. 4
Baz R, et al. Ann Oncol. 2006;12:1766-1771.

PUTTING IT ALL TOGETHERPUTTING IT ALL TOGETHER

28
Indolent, Slow, First Relapse
• Initial Tx with Bz
• May consider single
agent w/o Dex
• Underlying PN
IMiD-Based Salvage
Lenalidomide
Thalidomide
Likely Single-Agent Therapy With Bz or Len/Thal
Bortezomib-Based
Salvage
Transplant-Based
Salvage
• Initial Tx with IMiD
• Previous Bz therapy
but good or long
response
• Renal dysfunction
• Transplant not part
of initial therapy
• Long remission
post transplant
PN = peripheral neuropathy.
Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.

29
Aggressive, Rapid,
Multiple Relapse
• DCEP vs DT-PACE
• Oral vs IV chemo
• PS of patient plays
important role
Chemotherapy-Based
Salvage
Likely Combination Therapy
Do Not Wait for Symptomatic Relapse
Chemotherapy + Novel
Agent
Transplant-Based
Salvage
• Combinations of Len/Bz
and other chemo agents
• Likely to be short lived
• Quick disease control
• Reconstitute marrow
PS = performance status.
Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.

Comparison of the triple (bortezomib-thalidomide-dexamethasone) and dual (thalidomide-
dexamethasone) treatment groups.
Garderet L et al. JCO 2012;30:2475-2482
©2012 by American Society of Clinical Oncology

• 15 months after his stem cell transplant, he has a
• Treat or not
– Yes, symptomatic relapse
• Single or Combo
– I would use combination
• VTD
• VRD
• Carfilzomib based
• DTPace if LDH elevated
• Retransplant
– Difficult question if transplant naïve definitively yes.
complete response.

• Receives VTD x 12 months and is placed on low
dose thalidomide maintenance. Within 2 months
has new lytic lesions and increasing paraprotein
peak.
• Treat or not?
• Single or Combo?
• Retransplant?
complete response.

Response Duration Decreases With
Successive Therapies
• 578 patients; median age 65 years (follow up 55 months)
• Overall survival
– One year 72%
– Two years 55%
– Three years 22%
• 84% died within five years
Figure 3. Duration of response to each treatment
0
2
4
6
8
10
12
1 2 3 4 5 6
Treatment number
Medianresponse
duration(months)
Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.

Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420.
Time to Progression After SCT Correlates
With OS After Initial Relapse

Overall survival from time of relapse after
ASCT- Impact of New Agents as Salvage
Therapy
Kumar SK, et al. Blood. 2008;111:2516-2520.
30.9 months (95% CI; 23.6, 38.2
14.8 months (95% CI; 11.3, 18.4

Recurrent Myeloma
• 45-year-old woman
• κ light chain multiple myeloma diagnosed
January 2001
– Durie-Salmon Stage IIIA, ISS Stage 2
• Laboratory findings
– Total proteinuria 5.82 g/day
– Bence Jones protein (BJP) 3.6 g/day
– Hypogammaglobulinemia
– Albumin 3.9 g/dL
– β2-microglobulin 4.7 mg/L

Recurrent Myeloma
• Bone marrow biopsy
– Cellularity 80% with 25% plasma cells
– Cytogenetics 46, XX, inversion 9 (p11;q13)
• FISH not done
• Skeletal survey: extensive lytic bone disease with
healing fractures of left 7th
and the 8th
ribs
• MRI of the spine: diffuse hyperintense homogenous
signal on STIR sequence
• MRI of the pelvis: diffuse marrow infiltrative changes
due to myeloma

Recurrent Myeloma
• Treatment
– Vincristine 0.4 mg, doxorubicin 9 mg/m2
Days 1-4; dexamethasone 40 mg Days 1-4, 9-12,
17-20; x 4 cycles
– Followed by high-dose melphalan and stem cell
transplant on July 11, 2001
• Achieved complete remission
• Maintained on pamidronate and prednisone
x 1 year

First Relapse Five Years Later
• First relapse January 11, 2006
– Urine total protein 550 mg/day
– Creatinine clearance 84 mL/minute
– BJP 100 mg/day
– Urine IFE free κ light chain
– Serum free κ 750 mg/L
– Free λ 15 mg/L
– κ:λ ratio 50
– Multiple new lytic lesions of the skull
• MRI spine and pelvis January 11, 2006
– New focal lesion at L3 vertebral body

Second Relapse After Failure of IMiDs
• Treated with thalidomide and weekly
dexamethasone for 6 months → stable disease
• Switched to lenalidomide and weekly
dexamethasone x 3 months → stable disease

Third Relapse 18 Months Later
• Treated with bortezomib and dexamethasone x 4 cycles
• Achieved CR
• Painful peripheral neuropathy grade 2
• Discontinued treatment December 2006
• PET/CT June 2008
– 1 cm focal hypermetabolic area in the inferior aspect of the left scapula
– 2.2 cm focal hypermetabolic area in the region of right posterior superior
iliac spine, with associated lytic changes
• Laboratory findings
– Free κ 117 mg/L
– Free λ 15.6 mg/L
– κ:λ ratio 7.5
– Urine total protein 182 mg/day
– BJP 60 mg/day
– Urine immunofixation electrophoresis: free κ
• Treated with VRD with progressive disease
CTC=common toxicity criteria

Definition of Relapsed/Refractory MMDefinition of Relapsed/Refractory MM
 Relapsed
– Relapse off therapy
 Relapsed/Refractory
– Relapse while on, or within 60 days of
discontinuing, therapy
– Unmet medical need
• Lack of drug approval for relapse/refractory to IMiD,
bortezomib, alkylators, anthracyclines, and steroids
IMiD = immunomodulatory drugs.
Anderson et al, 2008.

43
Kumar SK et al. Leukemia. 2012;26:149-157.
Once Treatment Fails,
Trouble Begins
Kumar S. Mayo Clin Proc. 2004;79:867-874.
Overall Survival From Start of Therapy
by Regimen Number
00.20.40.60.81.0
0 2 4 6 8 10
CumulativeProbability(%)
Years From Start of Regimen
Regimen 1
Regimen 2
Regimen 3
Regimen 4
Regimen 5
Regimen 6
0
20
40
60
80
100
0 12 24 36 48 60
Months From Time Zero
Survival with Bz/Len Refractory Ds
Overall Survival 173/231 9 (7, 11)
Event-Free Survival 222/291 5 (4, 6)
Events/N
Median
(Months)
Survival(%)

45
Bortezomib (reversible)
Carfilzomib (irreversible)
CEP 18770 (reversible)
MLN9708 (reversible)
NPI-0052 (irreversible)
β1 Post-
glutamyl Tryptic
Chymo-
tryptic
NP
I
β2
β3
β4
β5
β6
β7
NP
I
NP
IPost-
glutamyl
Tryptic
Chymo-
tryptic
β3
β4
β5
β6
β7
Bortezomib
β1
Comparison of
Proteasome Inhibitors

46
Study 004: Phase 2 Trial of
Single-Agent Carfilzomib in
Relapsed/Refractory Multiple Myeloma
• Primary endpoint: ORR (CR + IVGPR + PR [IMWG criteria])
• Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety
– OS, TTP, response rate (EBMT criteria), safety
*Results for bortezomib (BOR)-treated cohort have been reported previously (Vij R et al.
J Clin Oncol. 2010. Abstract 8000).
†
Subjects who enrolled under amended protocol allowing dose increase to 27 mg/m2
or who
re-consented before Cycle 4 start were grouped in Cohort 2.
Study population (N = 165)
• Measurable disease
• Responsive to ≥1 prior therapy
• Relapsed and/or refractory MM
following 1-3 prior treatment
regimens
• ECOG PS 0-2
Carfilzomib IV
qd x 2 for 3 weeks (28-day cycle for up to 12 cycles)
Cohort 1
20 mg/m2
Cohort 2†
20 mg/m2
cycle 1
Escalation to 27 mg/m2
in all subsequent cycles
BOR-treated*
(n = 35)
BOR-naive
(n = 59)
BOR-naive
(n = 70)
Vij R et al. ASH 2011 Annual Meeting. Abstract 813.

Bortezomib-naïve
patients (Wang, et al)
N = 59
Bortezomib-treated
patients (Siegel, et al)
N = 35
Evaluable patients 54 33
Complete response 1 (2%) 1 (3%)
Very good partial response 5 (9%) 1 (3%)
PR/MR/SD 35%/15%/22% 12%/12%/39%
Duration of response (≥ PR) 8.4 months 10.6 months
Treatment-emergent
peripheral neuropathy
Grade 1/2: 12%
Grade 3: 2%
Grade 1/2: n = 3 (9%)
Grade 3: n = 1 (3%)
Results of the PX-171-004 Phase II Trial –
Carfilzomib in Relapsed and/or Refractory MM
Wang L, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:302.
Siegel D, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:303.

48
Median, months
Cohort 1
20 mg/m2
(n = 59)
Cohort 2
20/27 mg/m2
(n = 67)*
Duration of response n = 25 n = 35
Median, (95% CI) 13.1 (7.2-NE) NR (NE-NE)
Duration of clinical benefit response n = 35 n = 43
Median, (95% CI) 11.5 (6.2-NE) NR (NE-NE)
Time to progression n = 59 n = 67
Median, (95% CI) 8.3 (6.0-12.3) NR (11.3-NE)
Time to response n = 25 n = 35
Median, (min, max) 1.0 (0.5, 3.7) 1.9 (0.5, 3.7)
Time to clinical benefit response n = 35 n = 43
Median, (min, max) 0.5 (0.5, 6.5) 0.5 (0.5, 5.9)
Single-Agent Anti-Tumor Activity:
Bortezomib-Naive Response-Evaluable
Population by Cohorts
*3 patients were not evaluable for response as they did not have either baseline or post-baseline
assessment.
NE = not estimable; NR = not reached.

49
Progression-Free Survival:
Response Evaluable Population

50
Overall Survival:
Response Evaluable Population

51
Pomalidomide Summary
Study N Regimen
Median Prior
Therapies
ORR
(%)
MR
(%)
Richardson et al1
38
Pom (2-5 mg daily for
21/28 days) ± dex
6 25 50
120
Pom (4 mg daily for
21/28 days) ± dex
5 25 38
Lacy et al2
35
Pom (2 mg daily) +
low-dose dex
6 26 49
35
Pom (4 mg daily) +
low-dose dex
6 28 43
Leleu et al3
43
Pom (4 mg 21/28
days) + low-dose dex
4 18 NR
41
Pom (4 mg 21/28
days) + low-dose dex
4 16 NR
Pom = pomalidomide; dex = low-dose dexamethasone; ORR = overall response rate;
MR = marginal response.
1. Richardson P et al. ASH 2010 Annual Meeting. Abstract 864.
2. Lacy MQ et al. Blood. 2011;118;2970-2975.
3. Leleu X et al. ASH 2010 Annual Meeting. Abstract 859.

52
Pomalidomide: Previous Phase 2
Studies in RRMM
Study Phase N
Pom.
schedule
Treatment Population
Prior
Lines*
ORR
(≥ PR)
(%)
Richardson et al1
2 221 21/28
Pom: 4 mg vs
Pom 4 mg + Dex
Len & Bort
refractory
5 13 vs 34
Lacy et al2
2 34 28/28# Pom: 2 mg
Dex: 40 mg/week
Len refractory 4 32
Lacy et al3
2 70 28/28* Pom: 2 and 4 mg
Dex: 40 mg/week
Len & Bort
refractory
6 25 and 29
Len = lenalidomide; bort = bortezomib; Pom = pomalidomide; RRMM = relapsed/refractory
multiple myeloma.
*Median prior therapies; †
continuous.
1. Richardson P et al. ASH 2011 Annual Meeting. Abstract 634.
2. Lacy MQ et al. Leukemia. 2010;24:1934-1939.
3. Lacy MQ et al. Blood. 2011;118:2970-2975.

53
Arm A – Cycle 21 days
• Pomalidomide 4 mg oral/d, Days 1–21
Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22
• Aspirin/LMWH continue
Primary objective:
Response rate (PR and
better) according to
IMWG in either arm
Arm B – Cycle 28 days
• Pomalidomide 4 mg oral/d, Days 1–28
Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22
• Aspirin/LMWH continue
Key inclusion criteria:
• Relapsed MM
• Resistant or refractory to both
lenalidomide and bortezomib
• Measurable disease (central lab)
• ANC >1 x109
/L; Platelets ≥ 75 x109
/L;
Hb ≥ 8 g/dL
• Creatinine clearance ≥50 mL/min
N = 84 randomized
Pomalidomide: IFM 2009-2012
Study Design
Until progression
(relapse or refractory)
17 patients per arm
40 patients per arm
6 patients per arm
DMC – TOLERANCE
Rule: no difference
DMC – EFFICACY
Rule: 4 ≥ PR /arm
LMWH = low molecular weight heparin; IMWG = International Myeloma Working Group.
Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.

54
Time to Events
00.20.40.60.81.0
0 2 4 6 8 15
SurvivalDistributionFunctionEstimate
Time From First Intake (months)
HR = 1.18 [0.65]
Log-rank P = 0.5875
KM median: A = 9.23 [5.42]
KM median: B = 7.36 [4.60, 9.96]
Events: A = 21, B = 23
Time to Progression
Median 9.1 months
(95%CI, 5.8-10.0)
121 3 5 7 1410 139 11
A
B
43 32 23 20 17 0636 30 22 19 011 215 8
41 32 23 20 16 0237 27 21 18 07 214 6
No. at Risk
A
B
Overall Survival
Median 13.4 months
(95%CI, 9.8-)
00.20.40.60.81.0
0 2 4 6 8
SurvivalDistributionFunctionEstimate
Time From First Intake (months)
HR = 0.90 [0.46, 1.73]
Log-rank P = 0.7453
KM median: A = 13.44 [8.90, 13.93]
KM median: B = 15.26 [9.17]
Events: A = 19, B = 18
121 3 5 7 109 11
A
B
43 40 36 31 29 942 38 32 30 2126 14
41 39 32 30 27 840 34 32 29 1926 15
No. at Risk
A
B

55
≥ PR
21/28
N = 43
28/28
N = 41
Total
All patients % 35 34 34.5
Refractory to* %
Lenalidomide 36 36 36
Bortezomib 32 26.5 29
Both lenalidomide and bortezomib 34 28 31
Last prior therapy 33 31 32
Del17p and/or t(4;14) 25 31 30
Response by Prior Therapy:
ITT, IRC
*Refractory to as per IMWG criteria.

56
AEs, %
21/28
N = 43
28/28
N = 41
Total
Serious AEs 33 41.5 37
Any grade 3 and 4 AEs 91 83 87
Blood and lymphatic system disorders 72 71 71
Anemia 33 32 32
Neutropenia 63 56 59.5
Thrombocytopenia 28 24 26
General disorders and administration site
conditions 23 27 25
Asthenia 14 5 9.5
Discontinued due to drug-related AE, n = 2.
Adverse Events

57
Tai YT et al. Cancer Res. 2005;65:5898-5906; Hideshima T et al. Clin Cancer Res. 2005;11:8530-8533.
Permission requested; Catley L et al. Blood. 2006;108:3441-3449.
Blockade of Ubiquitinated
Protein Catabolism
HDAC6
HDAC6
HDAC6
Protein
Protein aggregates
(toxic)
Ub
26S Proteasome
Ub Ub
Ub
Aggresome
Tubacin
LBH, vorinostat
Dynein
Dynein
Microtubule
Autophagy
Bortezomib
Ub Ub
Ub
Lysosome
Ub
Ub
Ub
Ub
UbUb
Ub
Ub Ub

58
VANTAGE PN088:
Phase 3 Trial Design
• Primary endpoint
– PFS†
• Secondary endpoints
– OS, TTP, response rate†
(EBMT criteria), safety
*
Constitutes patients who received treatment after randomization.
†
Assessed by an Independent Adjudication Committee.
EBMT = European Group for Blood and Marrow Transplantation.
Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
Patients enrolled
(N = 637)
• Progressive disease after
the most recent treatment
• 1 to 3 prior treatment
regimens
• Bortezomib-sensitive
patients
Dosing schedule
Bortezomib
1.3 mg/m2
IV on Days 1, 4, 8, 11
in combination with
Vorinostat 400 mg OR placebo
Once daily on Days 1-14
(21-day treatment cycle)
Analysis populations
Intent-to-treat (ITT)
PFS, TTP, OS
Bortezomib + Vorinostat
(N = 317)
Bortezomib + Placebo (N = 320)
Full analysis set (FAS)*
ORR, safety
Bortezomib + Vorinostat
(N = 315)
Bortezomib + Placebo (N = 320)

59
EBMT Response Assessment (IAC):
Response-Evaluable Population
ORR = 56% vs 41%, P<0.0001
CBR = 71% vs 54%, P<0.0001
Bortezomib + vorinostat (N = 315) Bortezomib + placebo (N = 320)
IAC = Independent Adjudication Committee; SD = stable disease.

60
0 5 10 15 20 25
Time (months)
0
10
20
30
40
50
60
70
80
90
100
PFS(%)
BTZ + Placebo
BTZ + Vorinostat
320 157 58 12 4 0
317 196 75 14 3 0
BTZ + Placebo
No. at Risk:
BTZ + Vorinostat
Progression-Free Survival (IAC)
Events Median PFS (95% CI) HR (95% CI) P value
BTZ + Vorinostat
BTZ + Placebo
201/317
216/320
7.63 months (6.9-8.4)
6.83 months (5.7-7.7)
0.774 (0.64-0.94) 0.01

61
Overall Survival
0 5 10 15 20 25 30
Time (months)
0
10
20
30
40
50
60
70
80
90
100
OS(%)
320 286 235 124 48 16 0
317 291 238 120 43 12 1
BTZ + Placebo
No. at Risk:
BTZ + Vorinostat
Events Median OS (95% CI) HR (95% CI) P value
BTZ + Vorinostat
BTZ + Placebo
71/317
80/320
NA
28.1 months (28.1 – NA)
0.86 (0.62 – 01.18) 0.35
NA = not available.
BTZ + Placebo
BTZ + Vorinostat

Second Salvage ASCT for Relapsed Myeloma
Princess Margaret Hospital (N=79)
Mikhael J, et al. Blood 2009; 114: abstract #1217
• Median 60 years (39-72)
• Median TTP after 1st
transplant 2.72 years (0.81-8.26)
• Median interval between transplants 3.61 years (1.63-9.59)
• NRM 2.5%
• Response after 2nd
transplant: 15% CR/nCR, 78% PR, 8% MR/SD
• Results after 2nd
transplant based on TTP after 1st
transplant
Group N Median PFS (mos) Median OS (mos)
All 79 18.5 52.8
<24 mos 15 12.7 42.2
24-36 mos 30 17.0 52.7
>36 mos 34 32.6 NYR

Second Salvage AlloSCT for
Myeloma
Study N Median FU
(mo)
Response
rate (CR) (%)
Median
PFS (mos)
Median
OS (mos)
Gerull/20051
52 19 -- ~6 ~16
Quazilbash/20062
26 30 69 (31) 7.3 13
Majolino/20073
41 -- -- ~28 ~30
van Dorp/20074
23 -- --(4) 12 --
de Lavallade/20085
18 36 61 ~24 ~36
Kroger/20096
96 43 95 (46) 10.6 22.6
1
Gerull S, et al. Bone Marrow Transplant 2005; 36: 963-939; 2
Quazilbash MH, et al. Cancer 2006; 106; 1084-1089;
3
MajolinoI et al. Leuk Lymphoma 2007; 48: 759-766; 4
van Dorp S, et al. Neth J Med 2007; 65: 178-184; 5
de Lavallade
H, et al. Bone Marrow Transplant 2008; 41: 953-960; 6
Kroger N, et al. Br J Haematol 2010; 148: 323-331.

65
Antibodies
• BT-062 (CD138 + maytansinoids)
• CD40
• CD200
• CD56
Bortezomib combinations have activity:
Bz + CNTO 328 (anti IL6 ab)1
: ORR of 57% with TTP of
8.7 months (1-3 prior lines)
Bz + Elotuzumab (anti CS1 ab)2
: ORR of 48% TTP of 9.4 months
(median of 2 prior lines)
1. Rossi JF et al. ASH 2008 Annual Meeting. Abstract 1867.
2. Jakubowiak AJ et al. 2010 ASCO Annual Meeting. Abstract 8003.

66
Elotuzumab Background
ADCC = antibody-dependent cellular cytotoxicity; DMSO = dimethyl sulfoxide; mAb = monoclonal antibody;
MED = maximum efficacious dose; MoA = mechanism of action; NK = natural killer.
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. Permission requested; 2. Tai YT et al. Blood. 2008;112:1329-1337;
3. Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; 4. Lonial S et al. ASH 2009 Annual Meeting. Abstract 432.
• Elotuzumab is a humanized IgG1 mAb targeting
human CS1, a cell surface glycoprotein1,2
• CS1 is highly expressed on >95% of MM cells1-3
– Lower expression on NK cells
– Little to no expression on normal tissues
TumorVolume(mm3
)
Study Day
600
400
300
200
100
0
500
14 28 35 4221
Lenalidomide dosing (50 mg/kg)
Elotuzumab (1 mg/kg) or control
IgG1 dosing
Control IgG1 + DMSO
Elotuzumab + DMSO
Lenalidomide + control IgG1
Elotuzumab + lenalidomide
• MoA of elotuzumab is primarily through NK cell-
mediated ADCC against myeloma cells1,2
• In a MM xenograft mouse model, the combination of
elotuzumab + lenalidomide significantly reduced
tumor volume compared with either agent alone4
Normal plasma cells Plasmacytoma
Lymphoplasmacytic
lymphoma
Myeloma cells in bone
marrow

67
Elotuzumab + Lenalidomide + Low-Dose
Dexamethasone: Phase 1 Results
• Elotuzumab tested at 5, 10, and 20 mg/kg
– Elotuzumab-related AEs were primarily infusion-related
– 89% experienced at least 1 infusion reaction AE, no DLTs observed
and MTD not reached
VGPR = very good partial response; DLT = dose-limiting toxicity.
Lonial S et al. ASCO 2010 Annual Meeting. Abstract 8020; Lonial S et al. ASH 2010 Annual Meeting. Abstract
1936.
• Median TTP not reached at a median 12.7 months’ follow-up
• Elotuzumab saturation of CS1 binding sites in BM MM cells >80%
at both 10 (n = 1) and 20 mg/kg (n = 4)
Total
Lenalidomide-
Naive Prior Thalidomide
Refractory to Most
Recent Therapy
Total Patients, n 28 22 16 12
≥ PR, n (%) 23 (82) 21 (95) 15 (94) 10 (83)
CR/VGPR, n (%) 11 (39) 10 (45) 7 (44) 5 (42)
PR, n (%) 12 (43) 11 (50) 8 (50) 5 (42)

68
Elotuzumab
10 mg/kg
Elotuzumab
20 mg/kg Total
Patients, n 36 37 73
ORR (≥PR), n (%) 33 (92) 27 (73) 60 (82)
CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)
VGPR, n (%) 14 (39) 12 (32) 26 (36)
PR, n (%) 14 (39) 11 (30) 25 (34)
<PR, n (%) 3 (8) 10 (27) 13 (18)
Efficacy
Best Response (IMWG Criteria)
• Median time to response: 1 month (range, 0.7-5.8)
• Median time to best response: 2.2 months (range, 0.7-17.5)
Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.

69
Progression-Free Survival
No. at Risk:
10 mg/kg
20 mg/kg
36 32 30 29 21
37 29 26 23 19
13 4 1 0
14 4 0 0
Months
100
Proportionof
Progression-FreePatients(%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Median Time to Progression/Death:
10 mg/kg (n = 36): NA
20 mg/kg (n = 37): NA
14 15 16 17 18 19 20 21 22
90
80
70
60
50
40
30
20
10
0
Median Follow-Up:
10 mg/kg: 14.0 mo (range 2.6-21.2 mo)
20 mg/kg: 14.3 mo (range 2.1-20.5 mo)
At a median follow-up of 14.1 months, the median PFS was not reached
– PFS rate was 75% (10 mg/kg) and 65% (20 mg/kg)

70
Investigator-Designated
Infusion Reactions
Elotuzumab
Total
N = 73
Parameter, n (%)
10 mg/kg
n = 36
20 mg/kg
n = 37
Any AE 5 (14) 4 (11) 9 (12)
Grade 1 3 (8) 2 (5) 5 (7)
Grade 2 1 (3) 2 (5) 3 (4)
Grade 3* 1 (3) Rash 0 1(1)
• Investigator-designated infusion reactions are AEs identified by
the investigator as a sign or symptom of an elotuzumab-related
infusion reaction
• AEs that occurred in ≥ 2 subjects included nausea, pyrexia, and rash
*There were no Grade 4 infusion reaction AEs.

71
Summary
• New options and combinations are active in
relapsed/refractory disease
• Novel targets help to improve outcomes perhaps
even better than the historical use of alkylators
• Proteasome inhibitors, IMiDs, HDACs, and
antibodies will help to improve outcomes in
relapse and induction

72
Conclusion
• THERE IS NO EASY ALGORITHM FOR
MANAGING RELAPSED/REFRACTORY
MULTIPLE MYELOMA
• Patient-specific issues and prior therapy should
be used to determine choice of agents
• Use of FISH and cytogenetics can guide single-
agent vs combo decision and prognosis
• New targets and agents are being explored.
Phase 3 trials are in progress

Treating Relapsed Myeloma: Optimizing Therapy

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