MYELOMA CANADA CONFERENCE
Donna E. Reece, M.D.
Princess Margaret Hospital
Toronto, ON
23 October 2010
Relapsed and Relapsed/Refractory
Multiple Myeloma
 Definitions
 Relapsed disease—myeloma that progresses after a period of
remission
 Relapsed/refractory disease—myeloma that progresses while on
≥ second-line therapy, or within 60 days of the last therapy
 Criteria for progressive myeloma
 Increase in monoclonal protein by 25%
 New bone lesion
 Elevated calcium level
 New plasmacytoma
 Some patients can just be observed
 If the only sign of progression is a rise in monoclonal protein
 No other myeloma-related symptoms
Where We’ve Been
Initial Therapy of Myeloma
<70 years
Patient Age
ASCT
 Overall response rate 80%
 CR/nCR rate 20%
 Median TTP 20-36 months
>70 years
Oral melphalan (alkylator)
and prednisone
 Overall response rate 40-50%
 CR/nCR 5%
 Median TTP 12-15 months
Novel Agents in Multiple Myeloma
Agent
 Thalidomide
 Bortezomib
 Lenalidomide
Main Toxicities
 Teratogenicity, peripheral
neuropathy, constipation,
sedation, rash, VTE
____________________________
 Fatigue, GI toxicity, peripheral
neuropathy, decrease in platelets
and neutrophils
____________________________
 Myelosuppression, VTE
____________________________
VTE= venous thromboembolism
Activity of Novel Agents in
Relapsed/Refractory Myeloma Patients
Agent
CR/nCR
PR
Overall
Thalidomide1
Thalidomide +Dex2
< 5%
< 5%
28%
40-50%
30%
50%
Bortezomib3,4
Bortezomib + Dex5,6
5% / 5%
5% / 5-10%
20-25%
35-55%
30-40%
40-50%
Lenalidomide7
Lenalidomide +
Dex8,9
1Glasmacher A,
6%
15-25%
18%
36-46%
25-40%
61%
et al,Br J Haematol 132: 584-593,2005;2 Palumbo A, et al. Hematol J 2004; 5:31 8-320; 3Richardson PG, et al. N
Engl J Med 352:2487-98, 2005; 4Richardson P, et al. Blood 110:3557-60, 2007; 5Jagannath S et al. Haematologica 91:929-32, 2006;
6Kropff MH, et al. Leuk Res 29:587-90, 2005; 7Richarson PG, et al. Blood 108; 3458-64, 2006; Weber DM, et al. N Engl J Med
357:2133-42, 2007; Dimopoulos M, et al. N Engl J Med 357:2123-32, 2007.
Considerations in the Management of
Relapsed/Refractory Myeloma
 Initial therapy (e.g., use of novel agents, prior ASCT)
 Initial treatment options are changing

Many patients are receiving novel agents as part of initial therapy
 Duration of benefit of initial therapy
 Disease-related features
 Biology of myeloma (e.g., cytogenetics)
 Patient-related features (e.g. diabetes, peripheral
neuropathy, renal failure)
 Treatment-related features (toxicity profile, rapidity of
response)
 Availability of novel agent
“Traditional” Canadian
Approach to Relapsed/Refractory MM
No prior ASCT
(MP)
After ASCT
Time to Progression
 2 years
Second
ASCT
 2 years
< 1 year
Dexamethasone
Cyclophosphamide + prednisone
Thalidomide +/- steroids
Bortezomib
Lenaliomide + dex
Clinical trial
 1 year
Repeat
M+P
Reutilization of Initial Therapy
Relapsed/Refractory Myeloma
 Repeat oral alkylator therapy in elderly patients
 MP if first remission ≥1 year1
 Oral weekly cyclophosphamide (500mg) + alternate day
prednisone (50-100 mg)—easier on the blood counts2
 Repeat ASCT3
 PMH policy: Consider if benefit of first ASCT ≥ 2 years4
 NO data on MP—too hard on blood counts
 Oral cyclophosphamide + prednisone can be considered5

1Belch
PR rate 40%; MR rate 20%; stable disease 20%
Median PFS19 months
A, et al. Br J Cancer 57: 94-9, 1988; 352: 2487-98, 2005;2 Wilson K et al. Cancer Treat Rep 71:981-2,1987;
3Abdelkefi A, et al. Blood 111:1805, 2008; 4Mikhael et al. Blood 2007;110:,abstract #110; 5Trieu Y, et al. Mayo Clin Proc
80:1578-82,2005
Second ASCT for Relapsed Myeloma
Princess Margaret Hospital (N=61)
 Median age 56 (35-71) years
 Median time to relapse after first ASCT 33 mos (10-86)
 Overall response rate 88% (8% CR)
 Median PFS from ASCT 15.8 mos, OS 4.2 years
 Results better if PFS after 1st transplant ≥2 years:
Post 2nd ASCT Progression Free Survival
Grouped by =< or > 2 yrs PFS post 1st ASCT
1.0
.8
.6
Cum Survival
= < or > 2 yrs PF S
.4
> 2yrs PFS
.2
=< 2yrs PFS
0.0
0
1
2
3
PF S post ASCT 2 (years)
Mikhael et al. Blood 2007;110:abstract #110
4
5
6
Older Regimens
Relapsed/Refractory Myeloma
Regimen
Alkylator therapy
Dex-based
Thal-based
Response rate
Median TTP
(range) (mos)
MP
57-80%
NA
*Cy+ prednisone
36-40%
NA (19 mos at PMH)
Dexamethasone
18-20%
4.7 (3.5-4.7)
VAD
20-40%
5.4 (4.9-8.0)
Thalidomide alone
28%
10 (6-14)
Thalidomide +
steroids
50%
16 (8.2-30)
Thalidomide +
chemotherapy
64%
12 (9-30)
*Cy=Cyclophosphamide
Glasmacher A, et al,Br J Haematol 132: 584-593,2005; von Lillienfeld-Toal M, et al. Eur J Haematol 2008;
81: 247-252; Reece et al. Leuk Lymphoma 2008; 49: 1471-1485.
Thalidomide Combinations
Relapsed/Refractory Myeloma
 Many combination reported
 CTD,
1,2 DVd-T,3 VTD4,5,
Velcade + Doxil + thal6
 Overview of results
 Overall response rates 60-75% (~20% CRs)
 TTP/PFS ~12 months
 Risk of blood clots increased
 Only one comparative study (Offidani M, et al7)





1D
Case matched study of ThaDD vs thalidomide + dex
Overall response rates 92% vs 63%
CR/nCR rate 30% vs 10%
Median PFS 21 vs 11 months
Median overall survival longer for the 3-drug combination
Roussou M, et . Leuk Lymphoma 2007; 48:754-758; 2Garcia Sanz R, et al. Leukemia 2004; 18: 856-863; 3Hussein MA, et
al. Mayo Clin Proc 2006; 81:889-895; 4Zangari M, et al. Blood 2005;106: abstract #2552; 5Ciolli S, et al. Leuk Lymphoma
2006; 47:171-173; 6Chanan-Khan A, et al. Blood 2006; 108: abstract #3539; 7Offidani M, et al. Eur J Haematol 78: 297-302,
2007
Depth of Response in Multiple Myeloma
Progression
Treatment initiation
MR
PR
VGPR
nCR
CR
sCR
Time
Depth of response usually correlates with TTP
Phase III Trials in Relapsed/Refractory
Multiple Myeloma
 APEX1
 Boretzomib versus dexamethsone
 MMY-30012
 Doxil + bortezomib versus bortezomib alone
 MM090 and MM0103,4
 Lenalidomide + dexamethasone versus
dexamethasone alone
1Richardson
PG, et al. N Engl J Med 2006 ;2 Orlowski RZ, et al. J Clin Oncol 2007; 25: 3892-901; 3 Weber DM, et al. N Engl J
Med 2007; 357: 2133-42. 4Dimopoulos M, et al. N Engl J Med 2007; 357: 21.
Phase III Trial: Bortezomib + DOXIL®
vs Bortezomib (MMY-3001)
Time to progression
Overall survival
http://www.emea.europa.eu
PLD, pegylated liposomal doxorubicin
Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901
Lenalidomide + Dex vs Dex Alone for
Relapsed/Refractory MM
Results of 2 Phase III Studies (MM-009, MM-010)
Relapsed or refractory MM
Lenalidomide 25 mg/day, days 1-21
Dex 40 mg/day, days 1-4, 9-12, 17-20*
>1 prior lines of tx
No dex resistance
Creatinine <2.5 mg/dL
LFTs 3 x normal
Placebo on days 1-21
Dex 40 mg, d 1-4, 9-12, 17-20*
Treatment continued until disease progression
* Dex reduced to 40mg on day 1- 4 only after cycle 4 until PD
Weber M et al. Dimopoulos M et al. N Engl J Med, 2007
Lenalidomide + Dex vs Dex + Placebo in
Relapsed MM
75
50
Len/Dex
25
0
100
MM-009
Placebo/Dex
0
5
10
15
20
25
Time to progression (months)
Patients (%)
Patients (%)
100
30
MM-010
75
Len/Dex
50
25
0
0
Placebo/Dex
5
10
15
20
25
Time to progression (months)
Median time to progression (months)
Len/Dex
Placebo/Dex
P-value*
MM-009
11.1
4.7
<0.001
MM-010
11.3
4.7
<0.001
Weber D, et al. NEJM 2007;357:2133
Dimopoulos M, et al. NEJM 2007;357:2123
*`P-value from log-rank test
Subset Analysis of Phase III Trials
Relapsed/Refractory Myeloma
Number of Prior Regimens
1 prior
regimen
> 2 prior
regimens
Trial
Rx
Overall
Response
Rate (%)
Median TTP
(months)
APEX
Btz
Dex
45%
26%
7.0
5.6
MM 009/010
Len/Dex
Dex
69%
22-30%
17.1
4.7-5.1
APEX
Btz
Dex
34%
13%
4.9
2.9
MM 009/010
Len/Dex
Dex
57%
18-21%
10.6
4.6-4.7
Richardson PG, et al. N Engl J Med 2005; 352: 2487-2498; Stadtmauer EA, et al. Eur J Haematol Mar 19
2009. [Epub ahead of print]
Subset Analysis of Phase III Trials
Relapsed/Refractory Myeloma
Prior Thalidomide
No prior
thal
Prior thal
Trial
Rx
ORR (%)
Median TTP
(months)
MM 009/010
Len/Dex
Dex
65%
27%
13.9
4.7
DOXIL-MMY-3001
Btz/PLD
Btz
47%
43%
9.8
6.3
MM 009/010
Len/Dex
Dex
54%
14%
8.4
4.6
DOXIL-MMY-3001
Btz/PLD
Btz
48%
4.3%
9.0
6.8
Wang M, et al. Blood 2008 112; 4445-445; Sonneveld P, et al. Cancer 2008; 112: 1529-1537.
Bortezomib Combinations in
Relapsed/Refractory Myeloma
 Bortezomib is attractive agent to use in combination




Predictable and reversible drop in platelets and neutrophils
No cumulative myelosuppression
No increased risk of blood clots
Many 3- and 4-drug combinations reported
 One Phase III trial shows superiority of combination Rx1
 DOXIL- MMY- 3001: Bortezomib + DOXIL vs bortezomib alone
 Not much information on bortezomib + dex
 Many bortezomib combinations under investigation






*
Bortezomib + lenalidomide + dex2
Bortezomib + tipifarnib (MMRC)*
Bortezomib + MoAb (HuLUC 63, anti-IL6)
Bortezomib + histone deacetylase inhibitors (vorinostat*, panobinostat)*
Bortezomib + mTor inhibitors
Bortezomib + perifosine (Akt inhibitor)
PMH trials
RZ, et al. J Clin Oncol 2007;25:3892–3901; 2Richardson P, et al. Blood 2008;112:abstract #1742
1Orlowski
“CYBOR-P”
Weekly Bortezomib 1.5 mg/m2 + CY + P
 Weekly bortezomib + weekly cyclophosphamide 300 mg/m2 +
prednisone 100 mg q 2 days
 N=13
 Overall RR 85% (CR/nCR rate 54%)
 Only 2 progression events
pfs :

1-year PFS 83% and OS 100%
 76 cycles evaluable for toxicity
1.00
0.75
 Gr 4  ANC 1.3%
 Gr 4  pl 2.6%
 Gr 3  pl 1.3%
 Gr 1 PN in 7 patients (55%)
 Shingles in 4 patients
0.50
0.25
0.00
0
100
200
300
400
pfs day
Legend:
Produc t-Limit Es tim ate Curv e
Censored Obs erv ations
Progression-free survival
Reece D, et al. J Clin Oncol 2008; 10: 4778-4783
500
Lenalidomide Combinations in
Relapsed/Refractory MM
 Anthracyclines
 DVd-R – PLD, vincristine, DEX, lenalidomide
 RAD – lenalidomide, adriamycin, DEX*
 Alkylators
 RCD – lenalidomide, cyclophosphamide, DEX*
 CPR – cyclophosphamide, lenalidomide, prednisone*
 Novel agents
 Lenalidomide, bortezomib (+/- DEX)*
 Lenalidomide, perifosine, DEX
 Lenalidomide, bevacizumab, DEX
 Lenalidomide ,vorinostat, DEX*
 Lenalidomide, melphalan, prednisone, thalidomide (RMPT)*
*ASH abstracts 2008
“CPR”: Phase I-II Trial Dose Levels
28-day Cycle (N=31)
CY mg/m2 Lenalidomide Prednisone
(Revlimid)
mg
on Days
mg per day
1,8,15
Q 2 days
on Days 1-21
Dose
Level
N
Median #
cycles given
(range)
# on
Rx
1
3
150
15
100
12
(12-34+)
1
2
3
300
25
100
10
(9-23)
0
3
26
300
25
100
17
(5-28+)
12
*All patients received ASA 81 mg
DLT not identified
Overall response rate is 94% (≥69%) at dose level 3
1-year PFS 78% and OS 93%
Reece, et al. IMW 2009, abstract; personal communications
Lenalidomide, Bortezomib and Dex (Rev/Vel/Dex) in
Relapsed/Refractory MM
Phase II Study (N=64)
 Regimen
 Revlimid 15mg daily x 14 days
 Bortezomib 1.0 mg/m2 days 1,4,8,11
 Dex 20 mg day on and after bortezomib
 amended to 10mg
 Daily ASA; G-CSF permitted
 Patients
 Relapsed 38(59%), refractory 26(41%)
 Prior ASCT 36%
 Prior btz 55%, len 8%, thal 77%, ASCT
 Toxicities




Responses (n=62)
CR/nCR PR
Total
21%
47%
68%
Prior 17%
btz
40%
57%
Prior 15%
IMiD
40%
57%
All
Most heme toxicity Gr 1-2
2 atrial fibrillation
2 VTE
1 death fungal pneumonia
 Median TTP and PFS 12 months
Richardson PG, et al Blood 2008: 112: abstract 1742; Anderson K, et al. Proc ASCO 2009: abstract 8536.
Newer Regimens for Relapsed/Refractory
Myeloma: Phase I-II Trials
Regimen # Cycles
N
Response rate
(CR rate)
1-year
PFS†
1-year
Overall
Survival†
VMPT1
6
30
67% (17%)
61%
84%
CyBor-P2
8
37
85% (54%)*
56%
89%
VCD3
11
50
82% (16%)
50%
~75%
RVD4
8+
33
68% (21%)
50%
--
RAD5
6
69
76% (10%)*
~40%
88%
*At MTD
1 Palumbo
A et al. Blood 2007; 109: 2767-272; 2 Reece D, et al. J Clin Oncol 2008. 229: 4777-4783; 3Kropff M,
et al. Br J Haematol 2007; 138: 330-337; 4 Anderson K, et al. Proc ASCO 2009: abstract 8536.; 5Knop S, et al.
Blood 2009 Jan 30 [Epub ahead of print]
Impact of Novel Agents on the Outcome
in Relapsed/Refractory Disease (n=387)
1.0
Relapsed before 1998
Relapsed 1998–1999
Relapsed 2000–2001
Relapsed 2002–2003
Relapsed 2004–2005
Survival
0.8
0.6
0.4
P<0.001
Introduction of novel agents for
relapsed myeloma have greatly
improved survival
0.2
0.0
0
20
40
60
Time (months)
80
100
Kumar et al. ASH 2007 (Abstract 3594)
Important Questions
Management of Relapsed/Refractory Myeloma
 What is the best therapy for recurrent myeloma in
patients given novel agents at diagnosis?
 Can alkylating agents like MP or cyclophosphamide +
prednisone be used after MPT, VMP or lenalidomide +
dex given as first line therapy?
 How effective is repeating the same novel agent?
 How well does lenalidomide work after bortezomib and
vice versa?
 If lenalidomide is used as maintenance, can the dose
be increased and dex added at relapse
 Should novel agents be used in combination or
sequentially in relapsed/refractory myeloma?
What is the Optimal Strategy for
Relapsed Myeloma?
Novel Agent Combination
(e.g.,RVD, CyBorP) x 6-8 cycles
+/- maintenance
Bortezomib +/- steroids
Len + Dex
Len + Dex
Bortezomib-based therapy
? Comparative Overall Survival ?
ASCT in t(4;14) Myeloma
• Translocation between heavy Ig
gene locus and MMSET + FGFR3
• Found in 15% of patients
• Associated with IgA myeloma
Study
N
# ASCT
Chang/2004
Gertz/2005
16
26
1
1
Median PFS
(mos)
9.9
8.2
Moreau/2007
100
2
21
Chang et al. Bone Marrow Transplant 2005;36:793; Gertz et al. Blood 2005;106:2837;Moreau et al.
Leukemia 2007 2007;21:2024
Treatment of Progressive t(4;14) MM
1Jaksic
Regimen
N
Response
Median
rate
TTP (mos)
Cyclophosphamide +
prednisone/MP1
11
0 (63% SD)
--
Thalidomide or dex1
17
41%
4.7
Bortezomib +/steroids2
6
67%
10.5
Lenalidomide +
Dexamethasone3
28
77%
8.0
W, et al. J Clin Oncol 2003; 23:7069; 2Chang H, et al. Leuk Res 2007; 31:779-782; 3 Reece D, et al.
Blood 2009; Mar 30 [Epub ahead of print].
The t(4;14) translocation
4
4
14
14
FGFR3 and MMSET under the
control of the IgH enhancer
DNA break in IgH
Dysregulated expression of
FGFR3 and MMSET
DNA break in proximity
of FGFR3 and MMSET
Oncogenic transformation
IgH FGFR3
IgH
der(14)
Chr. 14
der(4)
Chr. 4
MMSET
FGFR3
MMSET IgH
CHIR258 is a Potent Inhibitor of Class III, IV & V
Receptor Tyrosine Kinases
I
II
III
IV
V
F
N
N
N
N
N
IGFR1
CHIR258 IC50 >2 mM
Adapted from Grassot et al. Nucleic Acids Res. 2003 Jan 1; 31(1): 353-8.
CHIR258 IC50 < 210 nM
O
CHIR258
RTK
FLT3
c-KIT
CSFR1/c-fms
FGFR1
FGFR3
VEGFR1/Flt1
VEGFR2/Flk1
VEGFR3/Flt4
PDGFR
PDGFR
INSR
EGFR1
c-MET
EphA2
TIE2
IGFR1
HER2
IC50 in uM
<0.001
0.002
0.036
0.008
0.009
0.01
0.013
0.008
0.027
0.21
2
2
>3
4
4
>10
>20
N
CHIR258 Inhibits Tumor Growth in a
Xenograft Model of FGFR3 Myeloma
Placebo
Trudel S, 2004
60mg/kg
30mg/kg
R3Mab Antibody against FGFR3
 Unique anti-FGFR3
monoclonal antibody
(Genentech)
 Advantage of selectivity
 Anti-tumor activity
mediated in part via ADCC
 PMH is lead site for phase
I-II trial in t(4;14) myeloma
(S. Trudel)
Qing J, el al. J Clin Invest 2009; 119: 1216-1229
ASCT in 17p Del
• Loss of p53 gene
• Found in 10% of patients
at diagnosis and up to
30% at relapse
Author/Year
N
#
ASCT
Median PFS
(mos)
Chang/2005
10
1
7.9
Gertz/2005
18
1
8.7
Chang et al. Bone Marrow Transplant 2005;36:793; Gertz et al. Blood 2005;106:2837
Treatment or Relapsed/Refractory Myeloma
Patients with p53 Deletion (N=31)
Agent
N
ORR(%)
Median PFS
(mos)
Thalidomide
15
20%
5.0
Bortezomib
12
50%
5.6
Lenalidomide
11
60%
4.8
Alkylating agents
9
11%
5.1
Steroids
5
20%
1.9
Other
7
43%
6.3
Reece D, et al. Blood 2008; 112: abstract 1724
What is the optimal therapy in patients relapsing
after more effective induction regimens?
 Minimal data available for treatment of relapse after VMP, MPT
or lenalidomide + dexamethasone in transplant ineligible
patients
 No data on second salvage transplants after novel agents
integrated into induction therapy + ASCT
 No data on the efficacy of ASCT deferred to the time of first
relapse after first-line therapy with lenalidomide + dex or novel
3- and 4-drug regimens
 Upcoming new drugs/combinations likely will be key to
prolonging survival
 Drugs under evaluation for “unmet medical need”
 Pomalidomide + dex
 Bortezomib + HDAC inhibitors
Responses after Subsequent Therapy in
VISTA Trial of VMP versus MP
Subsequent
therapy*
VMP
(N=129)
MP
N=(194)
N (%)
Response rate (CR)
N (%)
Response rate (CR)
Bortezomib-based
(N=105)**
21(16%)
39% (6%)
84 (43%)
55% (10%)
Thalidomide-based
(N=149)**
63 (46%)
48% (4%)
86 (44%)
55% (3%)
Lenalidomide-based
(N=37)**
25 (16%)
56% (4%)
12 (6%)
55% (0)
*Other agents were used as subsequent therapy, including dexamethasone; patients could receive
multiple-agent regimens.
** Single-agent use: 36% bortezomib, 37% thalidomide, 14% lenalidomide
Patients relapsing after VMP are not intrinsically more resistant than after using MP
San Miguel JF, et al. Blood 2008;112: abstract 650.
PMH Approach to Progressive Myeloma
No prior ASCT
After ASCT
≥ 1 year benefit
≥ 2 year benefit
Second
ASCT
Trial Candidate
no
Lenalidomide + dex +/-CY
Bortezomib +/- steroids +/- CY
Thalidomide +/- steroids
Cyclophosphamide + prednisone
Repeat M+P
yes
Bortezomib + dex + panobinostat
Bortezomib + Geminex (Mayo)
Bortezomib + Vorinistat (MMRC)
Lenalidomide + carfilzomib + dex
Lenalidomide + dex + HuLuc MoAb
(Pomalidomide +/- dex) [MMRC])
Akt inhibitor (GSK)
TKI 258 (t[4;14])
Genentech MoAb (t[4;14])
Treatment of Relpased/Refractory
Multiple Myeloma-(1)
 Many options/combinations
 May repeat initial therapy in selected patients
 Combinations with novel agents produce high
overall and complete response rates—effect on
PFS awaited
 Bortezomib and lenalidomide/dex can be
effective in patients with t(4;14)
 New targeted agents available in phase I-II trials
 Most people eventually receive all of the
effective drugs for different relapses
Treatment of Relapsed/Refractory
Multiple Myeloma-(2)
 Selection of therapy depends on many factors
 Therapy can be optimized for patients with renal
impairment/failure



Rapid anti-tumor responses observed with bortezomib
regimens
Good safety profile for bortezomib and thalidomide
Growing experience with lenalidomide
 Therapy can be individualized for patients with
peripheral neuropathy, decreased marrow reserve and
steroid intolerance
 Use of novel agents has improved survival after
myeloma relapse