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Raymond L. Comenzo, MD

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You will notice that in SMM the two higher risk groups have the highest risk in the first 5-10 years, whereas following that they appear to platuea, ... – PowerPoint PPT presentation

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Title: Raymond L. Comenzo, MD


1
Smoldering Myeloma Who and When to Treat
Should Smoldering High Risk Myeloma be
Immediately Treated?
  • Raymond L. Comenzo, MD
  • Professor of Medicine and Pathology
  • Tufts University School of Medicine
  • Boston, Massachusetts

2
Case 1
  • 52 year-old woman, asymptomatic
  • Elevated total protein
  • IgG? M-protein 3.6g/dL
  • FLC ? 123mg/L, Ratio 0.08
  • 190mg BJP
  • 30 PCs, standard risk cyto/FISH
  • Hemoglobin 11.8 g/dL
  • SS and spinal MRI negative
  • GFR and creatinine normal
  • NTXCreat 102 units

3
Case 2
  • 69 year-old man, asymptomatic
  • Elevated total protein
  • IgG? M-protein 3.6g/dL
  • FLC ? 123mg/L, Ratio 0.08
  • 190mg BJP
  • 30 PCs, del13q (6) by CD138-FISH
  • Hemoglobin 11.0 g/dL
  • SS Negative, spinal MRI 2 lesions
  • CKD3
  • NTXCreat Ratio 82 units

4
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5
Smoldering Myeloma
  • Kyle NEJM 1980 (6 cases) We believe that a
    patient whose illness fulfills the criteria for
    the diagnosis of multiple myeloma should be
    observed off therapy if there is no anemia, bone
    lesions, hypercalcemia, or renal insufficiency .
    . . Therapy may lead to leukopenia . . . And
    unnecessary chemotherapy causes unnecessary
    expense, and it is a source of concern to the
    patient.

NEJM 19803021347
6
Monthly Wholesale Acquisition Cost
Drug Cost ()
Carfilzomib (BSA 1.8) 5,936 (cycle 1) 8,013 (cycle 2)
Pomalidomide 10,437
Bortezomib (BSA 1.8) 4,106
Lenalidomide 8,673
Thalidomide 8,092
7
Asymptomatic Myeloma
  • Alexanian Blood 1980 (20 cases) Since
    asymptomatic patients with higher tumor mass
    grades . . . are even less common . . .
    chemotherapy should not be withheld in those rare
    asymptomatic patients with intermediate or high
    tumor mass. Also, the presence of an IgA myeloma
    protein or the excretion of more than 200 mg/day
    of Bence Jones protein favored the need for early
    chemotherapy. . . Serial assessments of myeloma
    protein level provided a useful index of changing
    tumor load and the need for chemotherapy.

Blood 198056521
8
Progression of Asymptomatic Myeloma
Blood 2000962037
9
Two Patterns of Changes in M-Ig Level During
Progression to MM
Blood 20091135418
10
Traditional Elements
  • Traditional variables
  • Monoclonal protein status
  • Bone marrow plasmacytosis
  • Symptoms
  • Time
  • Traditional clinical philosophies
  • Minimalists vs. Intensivists
  • Palliation
  • Prolong survival

11
Modern Elements
  • Translational science
  • Serum free light chains
  • New platforms for clonal genetics
  • New metrics of organ damage
  • Modern clinical philosophy
  • Incurable but treatable
  • Safety of high-dose melphalan
  • Effective less toxic new drugs
  • Patient involvement and advocacy
  • Changing view of risk

12
Would you consider treatment for High Risk
Smoldering multiple myeloma? PostPosted Thu Feb
28, 2013 423 pm by DanaH I would welcome the
community's thoughts on early treatment of High
Risk Smoldering multiple myeloma (high risk for
progression to active disease) in the clinical
trial setting. I am aware of early clinical trial
intervention studies with Revlimid w/ Dex
(Spanish study group as well as some centers in
the US, I believe Dr. Lonial _at_ Emory ) and
carfilzomib, Revlimid w/ Dex (NIH w/ Dr.
Landgren). Have any smolderers considered this
and actually participate(d) in these trials? Or
would anyone currently under treatment for active
multiple myeloma have or had considered this
option prior to commencing treatment once their
multiple myeloma became active, had you known you
were at high risk for progression ? All opinions
will be very much appreciated.
13
Re Would you consider treatment for High Risk
Smoldering mu PostPosted Thu Feb 28, 2013 519
pm by mrsv118 Dana H, I am in the NIH trial. I
went to the NIH and had all the testing done
planning to enter the natural history study. My
testing showed that i was a high risk smolderer
according to the both the Italian and Spanish
study protocol. Dr Landgren felt that I had a 75
chance of converting to active myeloma in the
next two years. They had introduced the CRD for
smolderers at a previous visit so I was already
considering it and those odds were not for me. I
didn't want to wait to be symptomatic before
starting to fight it. They are having great
results thus far! You need to meet them and have
an evaluation before you think too much about
this. Nothing wrong with standard therapy. Lots
involved in making a decision like this besides
the labs. Can you get there easily, (its an
eight month treatment, almost weekly). You may or
may not be able to work depending on your
response to the meds and what kind of job you
have. Expenses are not totally covered. Your
comfort level with the docs. Good luck with your
eval and your decision.
14
Symptomatic
Nature of the Clone
Organs at risk
15
Conditional Models Time to Event Risk of
Event Predictive Tests
16
Mayo Clinic Risk Factors for Progression
BM PC gt10 M-protein gt 3 g/dL Skewed sFLC
ratio lt0.125 or gt8.0
Leukemia 2010241121 Seminars Hematol 2011484
17
PETHEMA Risk Factors for Progression
aBMPC gt 95 Immunoparesis
Blood 20071102586 Seminars Hematol 2011484
18
Criteria for Diagnosis
  • Symptomatic MM
  • M-protein
  • ?10 PC
  • Smoldering MM
  • ?3 g M-protein
  • or ?10 PC
  • MGUS
  • lt3 g M-protein
  • lt10 PC

No related organ or tissue impairment (no
end-organ damage including bone lesions) or no
symptoms
Related organ or tissue impairment (end-organ
damage, including bone lesions) CRAB
BJH 2003121749 Leukemia 2010241121
19
Waiting For The
20
Clinical Trials in SMM
Adapted from Clin Cancer Res 201319985
21
QuiReDex
Induction phase 28d cycles x 9 cycles
Maintenance
Lenalidomide 25 mg/d D1-21 Dexamethasone 20 mg/d
D1-4, 12-15
Lenalidomide 10 mg/d D1-21 every 2 mos
High risk SMM
Observation
High risk SMM Both BMPC10 AND M-protein 3
gm/dL OR one of the above plus aPC gt95 and
immunoparesis
Mateos ASH 2011
22
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23
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24
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25
QuiReDex
  • SMM within the past 5 years
  • Stratified
  • Combined Mayo/PETHEMA high risk
  • But no serum FLC
  • Asymptomatic
  • Skeletal survey at screening
  • Repeated only with symptoms
  • No MRI

26
QuiReDex
  • Absolute risk reductions at 3 years
  • Progression 82
  • Death 69
  • Overall survival at 3 years
  • 94 with LenDex
  • 80 with observation
  • Number needed to treat
  • Two to prevent 1 progression
  • Seven to prevent 1 death

NEJM 20133695 BMJ 19993071492
27
IMWG Guidelines for SMM
Preventive clinical trials need to be considered
for patients with high risk smoldering
myeloma. Patients with smoldering myeloma with
FLC ratio lt0.125 or gt 8 plus gt 10 plasma cells
in the marrow are at high risk of progression in
the first 2 years following recognition. These
patients should be considered candidates for
chemoprevention trials. However, off-study,
observation is still the standard even in this
group.
Leukemia 2010241121
28
Numerous SMM Trials
29
Monthly Wholesale Acquisition Cost
Drug Cost ()
Carfilzomib (BSA 1.8) 5,936 (cycle 1) 8,013 (cycle 2)
Pomalidomide 10,437
Bortezomib (BSA 1.8) 4,106
Lenalidomide 8,673
Thalidomide 8,092
30
Case 1
  • 52 year old-woman, asymptomatic
  • Elevated total protein
  • IgG? M-protein 3.6g/dL
  • FLC ? 123mg/L, Ratio 0.08
  • 190mg BJP
  • 30 PCs, standard risk cyto/FISH
  • Hemoglobin 11.8g/dL
  • SS and spinal MRI negative
  • GFR and creatinine normal
  • NTXCreat 102 units

31
Wb-MRI in SMM
End organ damage currently is the most important
factor for the classification and the decision
to treat systemically in monoclonal plasma cell
disease. Therefore, serum calcium, renal damage,
anemia, and bone destruction (ie, osteoporosis or
focal lytic bone lesions) are the most important
parameters (ie, CRAB criteria).
JCO 2010281606
32
NTXCreatinine Ratio
Leukemia 2010241700
33
Case 2
  • 69 year-old man, asymptomatic
  • Elevated total protein
  • IgG? M-protein 3.6g/dL
  • FLC ? 123mg/L, Ratio 0.08
  • 190mg BJP
  • 30 PCs, del13q (6) by CD138-FISH
  • Hemoglobin 11.0g/dL
  • SS Negative, spinal MRI 2 lesions
  • CKD3
  • NTXCreat Ratio 82 units

34
QuiReDex
  • CD138-FISH abnormal in 91/123 (74)
  • 41 gain 1q
  • 42 del 13q
  • 9 del 17p
  • 17 t(1114)
  • 12 t(414), 6 t(1416)
  • 8 14q32 with unknown partner
  • No group or grouping predicted POD
  • 11 before and at progression
  • Suggestive GEP

haematologica 2012971439
35
E3A06
  • Groups 1 and 2 if the FLC ratio is lt0.125 or gt8.0
  • Within 12 months of diagnosis
  • SS negative
  • Serum FLC monthly
  • GEP
  • MRI spine and pelvis

NEJM 200735625 Blood 2008 111785
36
CRd at NIH for High-risk SMM
  • Pilot study
  • 8 cycles of CRd then 12 cycles lenalidomide
    extended dosing
  • Stem cell harvest after gt 4 cycles
  • Primary objective is response rate
  • Correlative studies GEP, proteasome activity,
    MRD by flow, FDG PET-CT

http//static9.light-kr.com/documents/IMW2013/Land
gren20-20CRd20Smoldering20Myeloma.pdf
37
CRd at NIH for High-risk SMM
  • During screening for the trial many SMM patients
    had bone lesions detectable by CT or PET-CT
    these patients were ineligible for the trial (due
    to multiple myeloma)
  • Among SMM without bone lesions, about 30 had
    increased PET uptake in the bone marrow
  • Depending on the extent of imaging, SMM for E3A06
    but MM for CRd?

38
Cases
  • Case 1
  • Vaccinate
  • Observe at 3 month intervals
  • Bisphosphonate
  • Offer E3A06
  • Case 2
  • Manage co-morbid conditions
  • Offer CRd or E3A06
  • Observe expectantly

39
Who and When to Treat
  • Not newly diagnosed patients with no evidence of
    evolving organ damage
  • Vaccinate
  • Observe at 3 month intervals
  • Offer E3A06
  • Observation
  • Follow clonal proliferation based on increasing
    M-protein or FLC
  • Follow for trends in organ damage
  • Biomarkers, including NT-proBNP

40
Should all high risk SMM patients be treated
immediately?
  • Not as standard of care
  • Determine what the patient wants
  • Offer E3A06 or NIH CRd trial
  • Use best metrics for clone and organ damage
  • Follow trends
  • Image appropriately
  • MRI, PET/CT

41
Changing Landscape
  • Up-dated IMWG guidelines will be forthcoming
  • How rational are our definitions?
  • How radically should they be changed?
  • Should we
  • re-define myeloma needing treatment?
  • re-group plasma cell diseases?
  • risk from clone and from organ damage
  • We must improve criteria for SMM trials
  • We must keep foremost in mind the urgency of
    relapsed refractory disease as the major driver
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