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

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…

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?

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

Choose the right weapon?

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

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)

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

Mayo Stratification for Myeloma And Risk-adapted Therapy

Newly Diagnosed Myeloma

Website: www.msmart.org

mSMART

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

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

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

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

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

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

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

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

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

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

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

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…

Don’t let the smile fool you….

Ola is Looking for a CR!