Transcript Mentorship: A critical component of medical education

Should Complete Remission be the goal for
everyone?
NO!
Lymphoma Myeloma 2014
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACP
Staff 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
t(11;14)
M0
M1
M2
M3
M4
M5
M6
M7
t(4:14)
t(14;16)
SC
Pre
Pro
Early
Mid
SHM
Myeloma
ICS
PC
t(6:14)
Hyperdiploidy
3 decades
Classification of MM
Ploidy
Prognosis
H
NH
Good
G
NH
Poor
t(4;14)
NH/h
Other IgH
t(11;14)
(CCND3)
t(14;16)
(other MAF)
Hyper
Bone
Morph
CD20
ras
-13
k
LPL
+++
++
-/+
++
D1
A
l
PB
-
-
++
+/-
D2
Poor
A
l
PB
-
-
+++
+/-
D2
H/NH
Poor
?
?
?
-
-/+
?
+
?
H
Good
G
k
Mature
-
++
+/-
++
D1>D2
A
DKK1
CCND
D3
mSMART
Mayo Stratification for Myeloma And Risk-adapted Therapy
Newly Diagnosed Myeloma
Website: www.msmart.org
mSMART 2.0: Classification of Active MM
High-Risk 20%
 FISH
 Del 17p
 t(14;16)
 t(14;20)
 GEP
High risk
signature
Intermediate-Risk 20%
 FISH
 t(4;14)*
 Cytogenetic
Deletion 13 or
hypodiploidy
Standard-Risk 60%
All others including:
 Hyperdiploid
 t(11;14)
 t(6;14)
 PCLI >3%
3 years
Mikhael et al Mayo Clinic Proceedings April 2013
4-5 years
8-10 years
IMPACT OF NOVEL THERAPY 2012/2013
Median 7.3 years
5 YEAR SURVIVAL BY AGE
AGE
AGE
≤ 65 YRS > 65 YRS
2012 ASH Abstract #3972 Kumar et al
2006-2010
73%
56%
2001-2005
63%
31%
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
FIRST (Rd
MM-015
VISTA
VMP lite
VMPT-VT
VMP-VT
(Continuous
Rd)
(Facon)
for 72 wks)
(Facon)
(MPR-R)
(Palumbo)
(VMP arm
for 54 wks)
(San Miguel)
(for 45 wks)
(Palumbo)
(Palumbo)
(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):448-55
Palumbo 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!