donna e. reece, m.d. princess margaret hospital toronto, on 23 october 2010 myeloma canada...
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Donna E. Reece, M.D.
Princess Margaret Hospital
Toronto, ON
23 October 2010
MYELOMA CANADA CONFERENCE
Relapsed and Relapsed/Refractory Multiple Myeloma
DefinitionsRelapsed disease—myeloma that progresses after a period of
remissionRelapsed/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 lesionElevated calcium levelNew plasmacytoma
Some patients can just be observed If the only sign of progression is a rise in monoclonal proteinNo other myeloma-related symptoms
Where We’ve Been Initial Therapy of Myeloma
Overall response rate 80% CR/nCR rate 20%
Median TTP 20-36 months
Overall response rate 40-50% CR/nCR 5%
Median TTP 12-15 months
ASCT
Patient Age
Oral melphalan (alkylator)and prednisone
>70 years<70 years
Novel Agents in Multiple Myeloma
Main Toxicities
Thalidomide
Bortezomib
Lenalidomide
Teratogenicity, peripheral neuropathy, constipation, sedation, rash, VTE
____________________________ Fatigue, GI toxicity, peripheral
neuropathy, decrease in platelets and neutrophils
____________________________ Myelosuppression, VTE
____________________________
Agent
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
6%
15-25%
18%
36-46%
25-40%
61%
1Glasmacher A, 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 therapyDisease-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
After ASCT No prior ASCT(MP)
Time to Progression
2 years 2 years
Second ASCT
< 1 year 1 year
RepeatM + P
DexamethasoneCyclophosphamide + prednisone
Thalidomide +/- steroidsBortezomib
Lenaliomide + dexClinical trial
Reutilization of Initial Therapy Relapsed/Refractory Myeloma
Repeat oral alkylator therapy in elderly patientsMP 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 countsOral cyclophosphamide + prednisone can be considered5
PR rate 40%; MR rate 20%; stable disease 20%
Median PFS19 months
1Belch 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 MyelomaPrincess Margaret Hospital (N=61)
Median age 56 (35-71) yearsMedian 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 yearsResults better if PFS after 1st transplant ≥2 years:
Mikhael et al. Blood 2007;110:abstract #110
Post 2nd ASCT Progression Free Survival
Grouped by =< or > 2 yrs PFS post 1st ASCT
PFS post ASCT2 (years)
6543210
Cu
m S
urv
iva
l
1.0
.8
.6
.4
.2
0.0
=< or > 2 yrs PFS
> 2yrs PFS
=< 2yrs PFS
Older Regimens Relapsed/Refractory Myeloma
Regimen 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.
Alkylator therapy
Dex-based
Thal-based
Thalidomide Combinations Relapsed/Refractory Myeloma
Many combination reportedCTD, 1,2 DVd-T,3 VTD4,5, Velcade + Doxil + thal6
Overview of resultsOverall response rates 60-75% (~20% CRs)TTP/PFS ~12 monthsRisk of blood clots increased
Only one comparative study (Offidani M, et al7)Case matched study of ThaDD vs thalidomide + dexOverall response rates 92% vs 63%CR/nCR rate 30% vs 10%Median PFS 21 vs 11 monthsMedian overall survival longer for the 3-drug combination
1D 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
MR
PR
VGPRnCRCR
sCR
Treatment initiation
Progression
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
Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901PLD, pegylated liposomal doxorubicin
http://www.emea.europa.eu
Lenalidomide 25 mg/day, days 1-21Dex 40 mg/day, days 1-4, 9-12, 17-20*
Placebo on days 1-21Dex 40 mg, d 1-4, 9-12, 17-20*
Relapsed or refractory MM
>1 prior lines of tx
No dex resistance
Creatinine <2.5 mg/dL
LFTs 3 x normal
Lenalidomide + Dex vs Dex Alone for Relapsed/Refractory MM
Results of 2 Phase III Studies (MM-009, MM-010)
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
Time to progression (months)
0 10 20 300
25
50
75
100
Placebo/Dex
Len/Dex
Pat
ien
ts (
%)
5 15 25
100MM-009
0 5 10 15 20 250
25
50
75
Placebo/Dex
Len/Dex
Time to progression (months)
Pat
ien
ts (
%)
MM-010
Median time to progression (months)Median time to progression (months)
Len/DexLen/Dex Placebo/DexPlacebo/Dex P-value*P-value*
MM-009MM-009 11.111.1 4.74.7 <0.001<0.001
MM-010MM-010 11.311.3 4.74.7 <0.001<0.001
*`P-value from log-rank testWeber D, et al. NEJM 2007;357:2133Dimopoulos M, et al. NEJM 2007;357:2123
Subset Analysis of Phase III TrialsRelapsed/Refractory Myeloma
Number of Prior Regimens
Trial Rx Overall Response Rate (%)
Median TTP (months)
1 prior regimen
APEX BtzDex
45%26%
7.05.6
MM 009/010 Len/DexDex
69%22-30%
17.14.7-5.1
> 2 prior regimens
APEX BtzDex
34%13%
4.92.9
MM 009/010 Len/DexDex
57%18-21%
10.64.6-4.7
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
Trial Rx ORR (%) Median TTP (months)
No prior thal
MM 009/010 Len/DexDex
65%27%
13.94.7
DOXIL-MMY-3001 Btz/PLDBtz
47%43%
9.86.3
Prior thal MM 009/010 Len/DexDex
54%14%
8.44.6
DOXIL-MMY-3001 Btz/PLDBtz
48%4.3%
9.06.8
Wang M, et al. Blood 2008 112; 4445-445; Sonneveld P, et al. Cancer 2008; 112: 1529-1537.
Bortezomib Combinations inRelapsed/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 trials1Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901; 2Richardson P, et al. Blood 2008;112:abstract #1742
“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 1-year PFS 83% and OS 100%
76 cycles evaluable for toxicity 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
Reece D, et al. J Clin Oncol 2008; 10: 4778-4783
pfs:
0.00
0.25
0.50
0.75
1.00
pfsday
0 100 200 300 400 500
Legend: Product-Limit Estimate Curve Censored Observations
Progression-free survival
Lenalidomide Combinations in Relapsed/Refractory MM
AnthracyclinesDVd-R – PLD, vincristine, DEX, lenalidomideRAD – lenalidomide, adriamycin, DEX*
AlkylatorsRCD – lenalidomide, cyclophosphamide, DEX*CPR – cyclophosphamide, lenalidomide, prednisone*
Novel agentsLenalidomide, bortezomib (+/- DEX)* Lenalidomide, perifosine, DEX Lenalidomide, bevacizumab, DEXLenalidomide ,vorinostat, DEX*Lenalidomide, melphalan, prednisone, thalidomide (RMPT)*
*ASH abstracts 2008
“CPR”: Phase I-II Trial Dose Levels28-day Cycle (N=31)
Dose Level
N CY mg/m2
on Days 1,8,15
Lenalidomide (Revlimid)
mg per day
on Days 1-21
Prednisone mg
Q 2 days
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
Reece, et al. IMW 2009, abstract; personal communications
DLT not identifiedOverall response rate is 94% (≥69%) at dose level 3
1-year PFS 78% and OS 93%
*All patients received ASA 81 mg
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 Responses (n=62) 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 Most heme toxicity Gr 1-2 2 atrial fibrillation 2 VTE 1 death fungal pneumonia
Median TTP and PFS 12 months
CR/nCR PR Total
All 21% 47% 68%
Prior btz
17% 40% 57%
PriorIMiD
15% 40% 57%
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)
Kumar et al. ASH 2007 (Abstract 3594)Time (months)
Su
rviv
al
00.0
20 40 60 80 100
0.2
0.4
0.6
0.8
1.0
P<0.001
Relapsed before 1998Relapsed 1998–1999Relapsed 2000–2001Relapsed 2002–2003Relapsed 2004–2005
Introduction of novel agents for relapsed myeloma have greatly improved survival
Important QuestionsManagement 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 relapseShould 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
Len + Dex Bortezomib-based therapy
? Comparative Overall Survival ?
Bortezomib +/- steroids Len + Dex
ASCT in t(4;14) Myeloma
Study N # ASCT Median PFS (mos)
Chang/2004 16 1 9.9
Gertz/2005 26 1 8.2
Moreau/2007 100 2 21
• Translocation between heavy Ig gene locus and MMSET + FGFR3• Found in 15% of patients• Associated with IgA myeloma
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
Regimen N Response rate
Median 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
1Jaksic 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 14
Dysregulated expression of FGFR3 and MMSET
Oncogenic transformation
DNA break in IgH4 14
DNA break in proximity of FGFR3 and MMSET
FGFR3 and MMSET under the control of the IgH enhancer
IgH
MMSET FGFR3
Chr. 14
Chr. 4
IgH
MMSET
FGFR3
IgH
der(14)
der(4)
Adapted from Grassot et al. Nucleic Acids Res. 2003 Jan 1; 31(1): 353-8.
CHIR258 IC50 in uMRTKFLT3 <0.001c-KIT 0.002CSFR1/c-fms 0.036FGFR1 0.008FGFR3 0.009VEGFR1/Flt1 0.01VEGFR2/Flk1 0.013VEGFR3/Flt4 0.008PDGFR 0.027PDGFR 0.21INSR 2EGFR1 2c-MET >3EphA2 4TIE2 4IGFR1 >10HER2 >20
CHIR258 is a Potent Inhibitor of Class III, IV & V Receptor Tyrosine Kinases
I II III IV V
IGFR1
CHIR258 IC50 < 210 nMCHIR258 IC50 >2 M
N
NN
N O
F N N
CHIR258 Inhibits Tumor Growth in a Xenograft Model of FGFR3 Myeloma
Placebo 60mg/kg 30mg/kg
Trudel S, 2004
R3Mab Antibody against FGFR3
Unique anti-FGFR3 monoclonal antibody (Genentech)
Advantage of selectivityAnti-tumor activity
mediated in part via ADCCPMH 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
Author/Year N # ASCT
Median PFS
(mos)
Chang/2005 10 1 7.9
Gertz/2005 18 1 8.7
• Loss of p53 gene
• Found in 10% of patients at diagnosis and up to 30% at relapse
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 survivalDrugs 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)
MPN=(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)
San Miguel JF, et al. Blood 2008;112: abstract 650.
*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
Trial Candidate
After ASCT No prior ASCT
SecondASCT
Lenalidomide + dex +/-CYBortezomib +/- steroids +/- CY
Thalidomide +/- steroidsCyclophosphamide + prednisone
Bortezomib + dex + panobinostatBortezomib + 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])
no yes
Repeat M+P
≥ 2 year benefit≥ 1 year benefit
Treatment of Relpased/Refractory Multiple Myeloma-(1)
Many options/combinationsMay repeat initial therapy in selected patientsCombinations with novel agents produce high overall
and complete response rates—effect on PFS awaitedBortezomib 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 factorsTherapy 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
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