should complete remission be the goal for everyone? no! lymphoma myeloma 2014 scottsdale, arizona...
TRANSCRIPT
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Should Complete Remission be the goal for everyone?
NO!Lymphoma Myeloma 2014
Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona
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Background
• Therapy for myeloma has rapidly evolved:• More intense regimens• Prolonged therapies
• This has resulted in deeper and more durable responses
• Translates into doubling (if not tripling) of median overall survival
• BUT, is it really all about depth of response? It is much more than CR deep…
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Patient Mrs. Nora Constance Reynolds • Diagnosed at 62 with IgG kappa MM
• 48% plasma cells, hyperdiploid
• Anemia, lytic disease, compression #
• Treated with CyBorD achieving PR
• ASCT 2009 achieving VGPR (M spike 0.5)
• No Maintenance
• M spike stable until January 2014 – climbing since then to 1.9…
Do you have patients like this?
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My Thesis
• Of course CR is good, and should be the goal for most patients
• However, there remains a subset of patients with more “indolent” myeloma who do not require CR for long term survival
• Identifying those patients is critical:• Modify expectations• Not to over-treat • Estimate prognosis
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Choose the right weapon?
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Recall the Heterogeneity of Myeloma
• Biological and Clinical differences
• Myeloma, based on definition, may indeed be the most common malignancy worldwide!
• We surely cannot treat them all in the same way - individualize
• Emphasizes the importance of risk stratification
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Acute Leukemia
3 decades
Myeloma
M0 M1 M2 M3 M4 M5 M6 M7
SC Pre Pro Early Mid SHM ICS PC
Hyperdiploidy
t(6:14)
t(14;16)
t(4:14)
t(11;14)
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Classification of MM
Ploidy Prognosis H Morph CD20 ras -13Bone
DKK1CCND
t(11;14)(CCND3)
NH Good G LPL +++ ++ -/+ ++ D1D3
t(14;16)(other MAF)
NH Poor A PB - - ++ +/- D2
t(4;14) NH/h Poor A PB - - +++ +/- D2
Other IgH H/NH Poor ? ? - -/+ ? + ?
Hyper H Good G Mature - ++ +/- ++ D1>D2
A
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Mayo Stratification for Myeloma And Risk-adapted Therapy
Newly Diagnosed Myeloma
Website: www.msmart.org
mSMART
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mSMART 2.0: Classification of Active MM
FISH Del 17p t(14;16) t(14;20)
GEP High risk
signature
All others including: Hyperdiploid t(11;14) t(6;14)
FISH t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%
3 years 4-5 years 8-10 years
Mikhael et al Mayo Clinic Proceedings April 2013
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2006-2010 73% 56%
2001-2005 63% 31%
IMPACT OF NOVEL THERAPY 2012/2013
Median 7.3 years
5 YEAR SURVIVAL BY AGE
AGE≤ 65 YRS
AGE> 65 YRS
2012 ASH Abstract #3972 Kumar et al
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Who are these patients that don’t need CR??
Group 1: Patients with MGUS like Myeloma (genotypically)
• Hyperdiploid MM• Possibly some t(11:14)• GEP defined MGUS-like MM
Group 2: Patients with Indolent Clinical Myeloma (phenotypically)
Group 3: Elderly Patients• Achievement of CR may be more toxic
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Group 1 – Genotypically Indolent
Gene-Expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis
Zhan et al Blood 2007
27% of patients identified as MGUS-Like MM
1. Less likely in CR
2. Improved survival over non MGUS-Like MM
3. Majority of long term survivors were MGUS-Like
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Group 1 – Genotypically Indolent
Complete response in myeloma extends survival without, but not with history of prior monoclonal gammopathy of undetermined significance or smouldering disease
Pineda-Roman et BJH 2006
Long-term survival possible in patients post transplant
Patients with “evolved” MM (prior MGUS or SMM) had lower CR in Total Therapy 2 (22% vs 48%)
4 year EFS same 54% vs 56%
Overall survival similar 65% vs 70%
Note that CR was critical in non evolved group
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Group 2 – Phenotypically Indolent
• Long-term prognostic significance of response in multiple myeloma after stem cell transplantation
• Martinez-Lopez et al Blood 2011
Spanish study of 350 pts transplanted 1989-98
• No differences in outcomes in pts in nCR, VGPR and PR
• Plateau at 11 years
• Those alive at 17 years included 35% of CR group and 11% of nCR+VGPR+PR group
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Prognostic effect of CR patients versus those in nCR or VGPR or PR versus patients with SD or PD after HDT/ASCT.
Martinez-Lopez J et al. Blood 2011;118:529-534
©2011 by American Society of Hematology
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Group 3 – Elderly Patients
• The goal of achieving CR can often lead to more intense therapies
• Dose reduction in elderly patients remains critical
• Depth of response may take longer and may not be as deep
• CR does not always predict for PFS or OS
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Efficacy Comparisons
FIRST (Continuous Rd) (Facon)
FIRST (Rd for 72 wks)(Facon)
MM-015 (MPR-R) (Palumbo)
VISTA (VMP arm for 54 wks) (San Miguel)
VMP lite (for 45 wks) (Palumbo)
VMPT-VT (Palumbo)
VMP-VT(Mateos)
CR 15.1% 14.2% 9.9% 30% 24% 38% 46%
PFS 25.5 mo 20.7 mo 31 mo 21.7 mo 24.8 mo 35.3 mo 39 mo
OS 4-yr OS; 59.4%
4-yr OS: 55.7%
3-yr OS: 70%
5-yr OS: 46%
Med OS: 56.4 mo
5-yr OS: 51%
Med OS: 60.6 mo
5-yr OS: 61%
5-yr OS: 69%
Facon et al. ASH 2013 (Abstract 2), plenary presentation Palumbo et al. N Engl J Med 2012;366(19):1759-69 San Miguel et al. N Engl J Med 2008; 359: 906-917
San Miguel et al. J Clin Oncol 2013;31(4):448-55Palumbo et al. ASH 2012 (Abstract 200), oral presentation
Mateos et al. Blood 2012; 120: 2581-2588
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What does this mean for my clinic next week?
• CR is a noble goal and is generally sought after, especially in high risk disease…
• However, it is NOT the goal in all, especially in 3 groups:
1. Genotypically indolent (hyperdiploid, low risk GEP)
2. Phenotypically indolent (prolonged MGUS/SMM)
3. Elderly patients
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So, if your patient meets these criteria
• Be careful not to over-treat (primum non nocere)
• Anticipate prolonged survival in groups 1 and 2
• Remember that CR ≠ CR in standard vs high risk patients
• Response is always depth PLUS duration
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Back to my patient NO CR
• She had 4 years of excellent quality of life on no therapy
• Repeat marrow confirms hyperdiploid and no high risk features
• Has now undergone a second ASCT
• She may never see CR
• But she will likely live a very long time…
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Don’t let the smile fool you….
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Ola is Looking for a CR!