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Transcript of Multiple Myeloma Relapsed/Refractory - NAMCP Myeloma Gasparetto.pdf · 4/28/2014 1 Multiple Myeloma...
4/28/2014
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Multiple MyelomaRelapsed/Refractory
Cristina Gasparetto, MDDuke University Medical Center
April 24, 2014
My Disclosures:
• Advisory Board: Millennium, Celgene, Onyx
• Grant Support: Celgene
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Treatment at relapse: key points
1. Treatment options at relapse
2. Factors to consider when choosing treatment at relapse
3. Re‐treatment approaches
4. Optimal sequencing of novel agents
Multiple Myeloma
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Over the Last Decade: Understanding the Biology of MM
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Thalidomide BortezomibThalidomide+Dexa
MPTEurope
Bortezomib>1 therapy
MPV
Lenalidomide+Dexa
BortezomibDoxil
VDRCyBorD
Maintenance Post‐ASCT
Carfilzomib
Zoledronic AcidTandem Auto
Auto‐Allo
Pomalyst
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Benefits of Induction therapy and Maintenance Therapy
InductionTherapy
Maintenance Phase
Relapse Relapse
A
B
C
Limit of ClinicalDetection
A‐No Maintenance B‐Eradication C‐Sustained disease control
Philippe Moreau Leukemia Research 2012
Definition of Relapsed/Refractory Disease
1. ‘Relapsed’ disease: first progression in the absence of any therapy– Biochemical relapse
– Symptomatic relapse
2. ‘Relapsed and Refractory’: progression on specific therapy or within 60 days of completion of a given therapy– Refractory to bortezomib and/or lenalidomide
3. ‘Primary Refractory’: no response following initial induction therapy
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Factors in selecting treatment for relapsed/refractory myeloma
1. Disease‐related factors– Duration of response to initial therapy– FISH or cytogenetic profile (e.g. t(4;14) or p53 deletion)
2. Regimen‐related– Prior drug exposure (relapsed vs refractory)– Toxicity of regimen (combination vs single agent)– Mode of administration (e.g., oral, sq, IV)– Previous transplant‐durability of response after transplant
3. Patient‐related factors– Pre‐existing toxicities (e.g., cumulative myelosuppression, peripheral
neuropathy)– Co‐morbid conditions (e.g., renal failure, diabetes mellitus)– Age– Performance status– Distance from Center– Insurance
NCCN Guidelines Recommendations: Relapsed/Refractory Multiple Myeloma
NCCN Guidelines
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Patient #1
• 61 year old man diagnosed with MM in 2005 (IgAlambda, BMBX 30%, bone survey negative, normal renal function), T cell rich B cell non‐Hodgkin’s lymphoma.
• 6/2005‐1/2006: R‐CHOP x 6 cycles, PET/CT negative
• 10/2006: relapse MM, lenalidomide/dexa x 4 cycles
• 7/2007 Mel 200 +ASCT (collected x 2 transplants)
• 8/2010: new shoulder pain, NSAID, creatinine 3.2, M‐spike negative
Patient #1 Cont.
• 12/2010: lambda light chain 1320, BMBX 80%, kidney biopsy lambda light chain deposition disease
• 1/2011: Bortezomib/dexa x 2 cycles c/w PN grade 3
• 3/2011: Lenalidomide/dexa
• 8/2011: BMBX 2‐3% residual MM
• 10/2011: Salvage ASCT followed by lenalidomidemaintenance
• 3/14: currently in remission
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Patient #2
• 50 year old Caucasian man
• 12/2010: Diagnosed with MM, ISS III
• anemia, renal insufficiency, hypercalcemia
• IgA kappa 3.8 gm/dl, multiple bone lytic lesions
• BMBX 90% PCs, FISH del13
• 1/2011: CyBorD(Cyclophosphamide/Bortezomib/Dexamethasone) x6 cycles=VGPR
• 7/2011: Cytoxan priming (collection x 2 transplants)
• 8/2011: Melphalan 200 ASCT
• 1/2012: Lenalidomide maintenance
• 6/2012: Complete Remission
Patient #2 Cont.
• 12/2012: Rapid Relapse ~16 months post HDT
• Started salvage induction therapy at home with VDR (bortezomib/dexamethasone/lenalidomide)
• 2/2013: Admission to DUMC with severe anemia (Hgb 5.6), hypercalcemia, Herpes Zoster infection, IgA 3.7 gm/dl, BMBX >95%, bone survey/CT scan multiple plasmacytomas (sternum, left femur, right hip)
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Kaplan‐Meier curves for EFS and OS for all patients (n=286) with relapsed/refractory MM
SK Kumar et al. Leukemia 2012, 26, 149‐157
Best Response to Regimen, by Regimen Number
0
5
10
15
20
25
30
35
40
45
50
1st 2nd 3rd 4th 5th
CR%
VGPR%
PR%
N=213 N=90 N=49 N=27 N=18
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Treatment Options
1. Novel agents – Thalidomide– Lenalidomide– Pomalidomide– Bortezomib– Carfilzomib
2. Old chemotherapy3. Novel agents + old chemotherapy combinations4. Salvage autologous stem cell transplant5. Allogeneic transplant 6. Clinical trial‐Testing new drugs and or new
combinations
Next Gen Proteasome Inhibitors
Drug Bortezomib Ixazomib Delanzomib Carfilzomib Oprozomib Marizomib
Structure Boronate(PS‐341)
Boronate(MLN9708/MLN2238)
Boronate(CEP‐18770)
Epoxyketone(PR‐1710
Epoxyketone(ONX‐0912/PR‐0477)
‐lactone(NPI‐0052)
Stage FDA‐approved Phase III Phase I/II FDA‐approved Phase I/II Phase Ib
Type of inhibition
Reversible(slowly)
Reversible Reversible Irreversible Reversible Irreversible
Half‐lifeminutes
110 18 N/A <30 N/A <10‐15
Route IV/SC IV/PO IV/PO IV IV/PO IV/PO
Activity CT‐L (C‐L) CT‐L CT‐L CT‐L CT‐L CT‐L,T‐L,(C‐L)
C‐L Caspase activityT‐L Trypsin‐like‐activityCT‐L Chymotrypsin‐like activity
Lawasut et al. Curr Hematol Malign 2012
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CarfilzomibPhase II Trial (PX‐171‐003‐A1)
• 266 patients with RRMM, who have received a median of 5 prior lines of therapy, including bortezomib and lenalidomide
• Treatment regimen– Carfilzomib 20 mg/m2 IV on day 1, 2, 8, 9, 15, and 16 (cycle 1) then 27 mg/2 IV on day 1,2,8,9,15,and 16 every 28 days for up to 12 cycles total.
– Dexamethasone 4 mg IV prior to each Carfilzomibdose in cycle 1 and as needed thereafter.
• Primary endpoint– Overall response rate
Siegel DS et al. Blood 2012.120:2817‐2825
Efficacy: Phase II Trial (PX‐171‐003‐A1)
Response N=257
ORR 23.7%
CR 0.4%
VGPR 5.1%
PFS 3.7 months
OS 15.6 months
All patient except one had received prior Bortezomib
Siegel DS et al. Blood 2012.120:2817‐2825
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Toxicity: Phase II Trial (PX‐171‐003‐A1)
Grade ¾ toxicity N=526
Thrombocytopenia 23%
Anemia 22%
Lymphopenia 18%
Pneumonia 11%
Neutropenia 10%
Fatigue 8%
Leukopenia 5%
Dyspnea 5%
Increased serum creatinine 3%
Upper respiratory infection 3%
Siegel DS et al. Haematologica , 2013, 98:1753‐1761
Pomalidomide: MM‐003 Phase III Trial
Miguel J et al. Lancet Oncology 2013:14;1055‐1066
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Efficacy: MM‐003 Phase III Trial
Response Pom+Dex(n=302)
Dex(n=153)
PFS 4.0 months 1.9 months
OS 12.7 months 8.1 months
TTP 4.7 months 2.1 months
ORR 31% 10%
CR/VGPR 6% <1%
Miguel J et al. Lancet Oncology 2013:14;1055‐1066
Pomalidomide: MM‐003 Phase III Trial
Miguel J et al. Lancet Oncology 2013:14;1055‐1066
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Study Schema
1 2 8 9 15 16
1 8 15 22
1 21
Carfilzomib
Pomalidomide
Dexamethasone
Patients treated until Progressive Disease/Adverse event
•Cycle 1‐6: 28 day cycle
• Cycle 7 + : Maintenance Cycles
Carfilzomib dosed on days 1, 2, 15, 16; Pomalidomide/dex unchanged
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Patient demographics
Prior stem cell transplant 21 (65.6%)
Prior bortezomib 31 (97%)All but 2 refractory*
Prior lenalidomide 32 (100%)All refractory
* Includes multiple bortezomib combos
Phase I/II Car‐Pom‐D: AmyC Study
Best Overall Response N=79
VGPR 21 (27%)
PR 34 (43%)
MR 10 (13%)
SD 13 (16%)
PD 1 (1%)
ORR=70%
CBR=83%
Shah et al. Abstract 690, ASH 2013
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Patient #3• 66 year old man
• 12/08 diagnosed with MM, free kappa light chain of 6147 mg/L. Bone marrow biopsy showing 40% plasma cells in the marrow.
• 12/08: Started Revlimid/Dexamethasone
• 8/09: Cytoxan priming
• 9/09: Melphalan 200 mg/m2
• 3/10 – progression. Started on velcade/dexa with improvement.
• 12/10 progressive disease on VD, bone survey with new lesions
• 12/10 Revlimid added
• 4/11 Progression on Rev/Dex/Velcade
• 5/11: Started Velcade/Doxil/Dexamethasone x 4 cycles c/w syncopalepisode
• 10/11: Carfilzomi/pomalidomide/dexa
• 5/12: Rapid disease progression
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Promising Novel Agents
[TITLE]
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[TITLE]
[TITLE]
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Oprozomib (ONX‐0912)Structural Analog of Carfilzomib
• Oral proteasome inhibitor that binds selectively and irreversibly to its target
• 2 formulations: PIC‐powder‐in‐capsule and MR‐modified release
• PIC active in solid tumor and hematologic malignancies 1
• PIC vs. MR: Phase Ib/II dose escalation in heavily pretreated MM 2
– MR‐ORR 21.7%– GI toxicity lower for MR vs PIC
1. Papadopoulos et a. JCO 2011, 2. Siegel IMWG 2013
PanobinostatPotent, oral pan‐deacetylase inhibitor (pan‐DACi)
• Panobinostat has low nanomolar activity against all class I, II, and IV histone deacetylase (HDAC) enzymes1
• Panobinostat increases acetylation of proteins involved in multiple oncogenic pathways1
1. Atadja P. Cancer Lett. 2009;280:233‐241. 2. Heise C, et al. 4th Annual HDAC Inhibitors Meeting, 2010.
IC50 of Enzyme Inhibition [nM]
Class I Class II Class IV
Drug HDAC1 HDAC2 HDAC3 HDAC8 HDAC4 HDAC5 HDAC6 HDAC7 HDAC9 HDAC10 HDAC11
Panobinostat1 2.5 13.2 2.1 277 203 7.8 10.5 531 5.7 2.3 2.7
Vorinostat1 75.5 362 57.4 1069 15056 163 27.1 12522 78.1 88.4 109
Romidepsin2 7 28 103 34 96 80 33 279 2729 368 64
Implicated as potential tumor targets in MM
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• Inhibition of the aggresome and proteasome pathways causes a buildup of intracellular misfolded cytotoxic proteins, leading to MM cell apoptosis1‐4
Panobinostat + BortezomibSynergistic anti‐myeloma activity
Unfolded/misfolded proteins Bortezomib
Panobinostat
Ubiquitinatedprotein aggregates
Dynein
Microtubule
Aggresomeformation
Lysosomal degradation
Proteindegradation
Proteindegradation
Ubiquitinatedprotein
Proteasomal degradation
1. Hideshima T, et al. Proc Natl Acad Sci USA. 2005;102:8567‐8572. 2. Ocio EM, et al. Haematologica. 2010;95:794‐803. 3. Catley L, et al. Blood. 2006;108:3441‐3449. 4. Hideshima T, et al. Mol Cancer Ther. 2011;10:2034‐2042.
HDAC6
Melissa Alsina, Robert Schlossman , Donna M. Weber, Steven E. Coutre, Sagar Lonial, Cristina Gasparetto,
GhulamWarsi, Michael Ondovik, Sutapa Mukhopadhyay, Carole Paley, and Paul G. Richardson
PANORAMA 2: A phase II study of panobinostat in combination with bortezomiband dexamethasone in patients with relapsed and bortezomib‐refractory multiple myeloma
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PANORAMA 2 Study DesignPhase II, Simon 2‐stage study in BTZ‐refractory MM
a Response measured according to modified European Group for Blood and Marrow Transplantation 1998 criteria.CR, complete response; nCR, near CR; PD, disease progression; PR, partial response.1. Anderson KC, et al. Leukemia. 2008;22:231‐239.
• Adult pts
• Relapsed and BTZ‐refractory MM
• ≥ 2 prior lines of therapy
• Exposed to IMiDs
Panobinostat
BTZ
Dexamethasone
Panobinostat
BTZ
Dexamethasone
ScreeningTreatment Phase 1Eight 3‐wk cycles
Treatment Phase 26‐wk cycles until PD
After 8 cycles, continuation into Treatment Phase 2 in pts with clinical benefit
Primary endpoint: overall response rate (CR + nCR + PR)a
BTZ‐refractory disease defined as relapse on or within 60 days of last BTZ‐containing line of therapy1
Preliminary Response DataActivity in BTZ‐refractory MM patients
Best confirmed response (confirmed at 6 wks) N = 55
Overall response (CR + nCR + PR) 17 (31%)
Complete response –
Near complete response 1 (2%)
Partial response 16 (29%)
Clinical benefit (CR + nCR + PR + MR)1-3 28 (51%)
Minimal response 11 (20%)
VGPR 3 (6%)
• Responses were typically observed after 1 to 2 cycles
• Stable disease observed in 2 pts; progressive disease in 10 pts
1. Anderson KC, et al. Leukemia. 2008;22:231‐239. 2. Richardson PG, et al. Br J Haematol. 2009;144:895‐903. 3. Niesvizky R, et al. Br J Haematol. 2009;143:46‐53. Data cutoff 20 February 2012.
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Safety
• Thrombocytopenia, the most common grade 3/4 AE (62%), managed with dose reduction/interruption
– No bleeding AEs in pts with thrombocytopenia
– No pts discontinued due to thrombocytopenia
• Treatment‐emergent peripheral neuropathy (31% overall), generally mild, with only one grade 3/4 event (2%)
• Fatigue and asthenia (73% and 20% overall), predominantly mild and managed with hydration, dose reduction, and supportive care
• No reports of QTc prolongation
Multiple MyelomaMonoclonal Antibody Therapy
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Investigational Monoclonal Abs
Daratumumab
• A human CD38 mAb with Broad‐Spectrum Killing Activity
• Phase I/II Study of monotherapy in Relapsed or Relapsed/Refractory Multiple Myeloma
• Trial Design: Open label, weekly IV infusion, 8 weeks, dose‐escalation 3+3 scheme (0.005‐24 mg/kg)
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[TITLE]
[CAPTION]
[TITLE]
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[TITLE]
[TITLE]
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• Elotuzumab (HuLuc63) is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein
• CS1 is highly and uniformly expressed on MM cells
– Restricted expression on NK cells
– Little to no expression on normal tissues
Elotuzumab: Background
1. Hsi ED et al. Clin Cancer Res. 2008;14:2775‐2784. 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. Blood. 2009;114:432.
Elotuzumab
• Monoclonal antibody targeting cell surface protein CS1
• Demonstrated activity in relapsed/refractory myeloma when given in combination Bortezomib and Lenalidomide
• Preliminary results from the Lenalidomide‐dex study showed an overall response rate of 82%
• The most common side effects seen with elotuzumab are infusion reactions.
• Being evaluated in combination with Revlimid‐low‐dose‐dexin two Phase III trials. One study is in relapsed or refractory myeloma, the other is in newly diagnosed disease. ELOQUENT‐1 and ELOQUENT‐2
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Years
0 2 61 3 4 5
Prob
abili
ty o
f Sur
viva
l, %
Probability of survival after transplant for multiple myeloma, by donor type 1998‐2008
HLA-matched sibling, Allo (N=878)
autologous transplant (N=22,254)
Unrelated, Allo (N=143)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
P < 0.0001
CIBMTR data from 22,254 patients who received autologous transplant and 1021 patients who received allogeneic transplant
Allogeneic transplant CTN 1302: Disease Specific Eligibility
Prior Relapse or Progression
Myeloma Disease response
None High risk: del13 by conv. karyotyping only; hypodiploidy, 1q amplification or 1p deletion, t(4;14), t(14;16), t(14;20) or deletion of 17p by FISH or conv. karyotyping; high risk criteria based on GEP; or Beta-2M ≥ 5.5 mg/L.
≥ PR
None Plasma Cell Leukemia ≥ VGPR
≤ 1 - Progression within 18 mo after an AutoHCT, or- High risk as above within 18 mo from initiation of therapy (no prior AutoHCT)
≥ VGPR
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Conclusion
1. Many treatment options available at time of relapse2. When selecting salvage therapy take in consideration:
Disease‐related factorsRegimen‐related
– Prior drug exposure (relapsed vs refractory)– Toxicity of regimen– Mode of administration– Previous transplant
Patient‐related factors– Pre‐existing toxicities– Co‐morbid conditions– Age– Performance status– Distance from Center– Insurance
The ‘Multiple Challenges of Multiple Myeloma’