diagnosis and current standard treatments for multiple myeloma
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Diagnosis and Current Standard Treatments for
Multiple Myeloma
Natalie S. Callander, M.D
Professor of Medicine
Goals • Introduce and/or compliment understanding of
plasma cell disorders-MGUS, SMM and
symptomatic MM
• Explain common blood and urine tests- more
with Dr. Wassenaar
• Explain importance of cytogenetics and FISH
testing-prognosis
• Current FDA approved treatments for newly
diagnosed disease
• Autologous stem cell transplantation- more with
Dr. Dhakal
How long has myeloma been around?
Seer Data; Blood 125:410, 2015
Risk Factors
• Associated with Agent Orange exposure, benzene, radiation exposure (Hiroshima experience), 9/11 FR
• Higher incidence in farmers, wood and leather manufacturers
• Small Inherited Risk
• Landgren et al First degree relatives of 4488 Swedish MGUS pts had 3 X increased relative risk of Myeloma, WM, CLL, MGUS
– (Int J Cancer. 2006;118:3095–3098)
• Familial cases exist, 1q and 4q loci regions of interest for germinal genetic mutations; paratarg 7 (Grass et al Blood 2011:118:635)
• Not clear that there are specific polymorphisms, mutations that put pts at risk for development of myeloma
Normal B cell Development
Normally, plasma cells are not found in large numbers inside bone marrow
Normal vs Myeloma
20th Annual Update in
Primary Care
Lots of different types of
whole antibodies
Whole Ab and excess light
chains – and too many of both!
Normal
Myeloma
IgG κ
IgG L
IgA κ
IgA L
IgD κ
IgD L
IgE κ
IgE L
IgM κ
IgM L
IgG κ
IgG κ
IgG L
IgA κ
IgA L
IgD κ
IgD L
IgE κ
IgE L
IgM κ
IgM L
IgG κ
Symptoms:
lytic lesions like these can
fracture….
“LYTIC” BONE LESIONS
Myeloma deposits can exist outside of bone marrow as well
(just like lymphoma): require biopsy to prove plasma cell
origin
Extramedullary deposits
MRI offers ability to see inside of bones, standard of care to
evaluate for spinal cord compression
PET-newer imaging tool for myeloma
• typically using fluorinated glucose to
measure metabolic activity
• About 90% of myeloma pts show uptake-
i.e. some will not have informative PET
• Helpful for pts whose myeloma does not
make protein
• May help predict response
• Likely will become part of initial
evaluation
Laboratory testing:
Interpretation of SPEP (serum protein electrophoresis)
Immunoglobulin molecule
• Immunofixation of
serum or urine (abs
IFE)
• Identifies type of
heavy chain (G, A,
rarely D) and light
chain (kappa or
lambda)of the
monoclonal protein
• ex
Excess protein in urine
Makes “suds”
UPEP- sensitivity to pick up abnormal proteins varies
from lab to lab
NORMAL
Free Light Chain Assay: measures levels of kappa , lambda NOT bound to heavy chains
• Free light assay- designed to detect portions of unbound light chains in serum
• Automated
• Results reported out in mg/L of mg/dl and in κ/λ ratio
• At low concentrations, lower specificity and sensitivity, or if pt has kidney failure
• “significant values > 100mg/L or 10 mg/dL or abnormal ratio (<.015 or >8)
• Levels>100mg/dl now definition of myeloma
• Also ay be used for following amyloidosis pts or confirming CR, or possibly non secretory MM
• REMEMBER: “ normal” value of M protein is 0; but it is normal to have light chains at low levels
In order to definitively diagnose myeloma, a
biopsy must show increase in plasma cells > 10%
Pathologist must prove clonality by IHC staining
Plasma cells can be identified as well by CD 138 expression on flow cytometry
Cytogenetic and Fluorescence In Situ Hybridization
(FISH) are important prognostic tools
27
• Finding small amounts of myeloma cells in bone marrow after treatment may have some importance
What happens to people with MGUS
• Among adults age 50 3% have MGUS, 10% of
80 year old
• The prevalence of MGUS therefore makes
SPEP/UPEP/light chains poor screening tests
• 75% of pts with MGUS will never develop
myeloma
• Times to consider adding these tests to an
evaluation-unexplained renal failure, proteinuria,
osteoporosis in a young person, anemia
SMOLDERING MYELOMA
DEFINITIONS DIFFER
INTERNATIONAL CONCENSUS CRITERIA:
M protein > 3 g/dl
>10% but <60% plasma cells in marrow
no end organ damage
Some use a flow cytometry definition
no renal insufficiency, bone damage (including osteopenia or any lesion found by MRI) , anemia, hypercalcemia, recurrent bacterial infections
• these patients progress much more often to myeloma-
RISK OF PROGRESSION 10%/year
• risk factors for progression include: IgA vs IgG, low
uninvolved immunoglobulins, sheets of plasma cells on
bone marrow biopsy, presence of urinary light chains
• after five years, risk reverts to MGUS risk
• Clinical trials underway to see if early intervention will
prevent most patients from progressing to myeloma
Plasmacytoma-isolated collection of myeloma cells
Isolated plasmacytomas- about 5%
Soft tissue based-sometimes isolated; often cured
with radiation therapy
Bone based-typically progress to myeloma in
several years
Solitary Plasmacytoma
Solitary plasmacytoma (cont)
Long term prognosis
When should you start treatment for
myeloma?
• Unlike lymphomas, stage of myeloma doesn’t tell you what treatment is appropriate or when it should start
• MGUS should not be treated outside of clinical trial
• Symptomatic from myeloma
• Asymptomatic but with CRAB/IWMG criteria
• Smoldering or otherwise asymptomatic can wait with reasonably close follow up
• Patients with renal failure due to myeloma should be treated promptly
What are the clinical trial “phases”?
Phase I Phase II Phase III
Tests Safety Tests how well
treatment works Compares new
treatment to
standard treatment
Limited treatment for myeloma
In the first half of 20th century-
radiation, pain medication
Traditional cancer drugs only work for the short time a cell
actively replicating DNA in order to divide
Myeloma cells grow slowly and don’t spend much time doing this
Modern Age of Myeloma Therapy:
discovery of thalidomide for myeloma
Sold between 1957-1961 to treat morning
sickness
Banned in 1962 in US due to phocomelia
Interest revived in drug after it was reported to be helpful in leprosy in 1965
Suggested as useful in myeloma due to antiangiogenic properties
Kaplan–Meier Estimates of Overall Survival and Event-free Survival.
Singhal S et al. N Engl J Med 1999;341:1565-1571.
Thalidomide/Dexamethasone vs Dexamethasone in
Newly Diagnosed MM
Phase III ECOG E1A00 Study Design
Thalidomide, 200 mg/d orally
Dexamethasone, 40 mg/d*
Days 1–4, 9–12, and 17–20
(n=103)
Stop therapy at Month 4
for stem cell
transplantation or
continue at physician’s
discretion
Stop therapy
Dexamethasone alone, 40 mg/d*
Days 1–4, 9–12, and 17–20
(n=104)
Newly diagnosed,
untreated
symptomatic MM
(n=207)
CR/PR/
stable
Any
progression
4 cycles
*Administered as a monthly cycle
All patients received monthly pamidronate or zoledronic acid
Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205]
NF-kB inhibition by Velcade (Bortezomib)
Multivariate analysis showed that receiving VRD, age <65 associated with
Better disease control and survival
“VRD is the current Standard of Care
How else do you decide appropriate initial
treatment?
1. Availability of clinical trials
2. Host characteristics (age, Performance
Status, comorbidities)
3. Disease aggressiveness-high risk versus
standard risk cytogenetic
4. Intent to transplant
• High Risk Disease
• (75% of pts have what is termed “standard risk” myeloma
(hyperdiploidy, t(11;14), t(6:14) MS->8 yrs
• 15% have high risk (17p, t(14;16), t(14;20) high risk GEP MS-2-3
yrs; high LDH, “plasma cell leukemia”
• triplet therapy (VRD, carfilzomib RD, VDT, CVRD, possibly VRD
plus additional agent
• Extended or indefinite maintenance
• Or Auto stem cell transplant or allogeneic stem cell transplant
followed by maintenance
CLINICAL TRIAL RESULTS PENDING: SWOG S1211: VRD versus
VRD plus elotuzumab
Other combinations under study for newly diagnosed pts
• S0777 has confirmed value of “triplet” therapy
• Not yet considered STANDARD outside of trial
– Carfilzomib, lenalidomide, dex
– Daratumumab, lenalidomide, dex
– Daratumumab, bortezomib, dex
– Daratumumab, lenalidomide, bortezomib, dex
– Elotuzumab, lenalidomide, dexamethasone
– Carfilzomib, daratumumab, lenalidomide, dex
• Special considerations:
• Some patients may be too frail for
intensive therapy, frequent clinic or
hospital visits.
• First trial: continuous lenalidomide and
dex based on results of FIRST trial; low
dose VRD or CyBorD possible as well
Lenalidomide and Dex may be very appropriate for some
patients
High Dose Therapy for Myeloma
Lancet 322: 822, 1983
Autologous transplant improves disease control and survival
Attal M et al. NEJM N Engl J Med 1996; 335:91-97
Maintenance Therapy
CALGB 100104:
Post transplant,
Randomization to
Lenalidomide or
Placebo
Treatment given
indefinitely
Holstein S et al In press
3 of 17 identified studies fulfilled criteria[1]
Lenalidomide maintenance intended to be given until progression
– IFM elected to discontinue lenalidomide in 2010 due to second primary malignancy signal, whereas the NCI and GIMEMA chose to continue until progression
Lenalidomide Maintenance After ASCT in
MM: Meta-analysis Studies
Study Treatment Arms Pts, n
CALGB 100104[2] Lenalidomide maintenance
Placebo
231
229
IFM 2005-02[3] Lenalidomide maintenance
Placebo
307
307
GIMEMA[4]
(RV-MM-PI-209)
Lenalidomide maintenance
No maintenance
67
68
1. Attal M, et al. ASCO 2016. Abstract 8001. 2. McCarthy PL, et al. N Engl J
Med. 2012;366:1770-1781. 3. Attal M, et al. N Engl J Med. 2012;366:1782-
1791. 4. Palumbo A , et al. N Engl J Med. 2014;371:895-905. Slide credit: clinicaloptions.com
Lenalidomide Maintenance After ASCT in
MM: Pooled Patient Characteristics
Characteristic Lenalidomide
(n = 605)
Control
(n = 604)
Median age, yrs 58 58
60 yrs of age or older, % 39 38
ISS stage at diagnosis, %
I
II
III
37
31
19
45
28
15
CR/VGPR after ASCT, % 53 56
Prior lenalidomide induction, % 24 24
Adverse risk cytogenetics,* % 15 10
Attal M, et al. ASCO 2016. Abstract 8001.
*t(4;14) or del(17p); from IFM and GIMEMA studies only.
Slide credit: clinicaloptions.com
Lenalidomide Maintenance After ASCT in
MM: Overall Survival
Lenalidomide maintenance significantly improved survival after ASCT from pooled data analysis
– 7-yr OS: 62% vs 50% in the control arm
– Median OS: not estimable* vs 86.0 mos in control arm (median follow-up: 80 mos)
– Overall HR: 0.74 (95% CI: 0.62-0.89; P = .001)
All studies showed lenalidomide benefit, but results were heterogeneous (P = .047)
– CALGB HR: 0.56 (95% CI: 0.42-0.76)
– IFM HR: 0.91 (95% CI: 0.72-1.15)
– GIMEMA HR: 0.66 (95% CI: 0.34-1.26)
Attal M, et al. ASCO 2016. Abstract 8001. Slide credit: clinicaloptions.com
*Median OS for lenalidomide arm extrapolated to be 116 mos based on median of control arm and HR of 0.74.
Summary of frontline therapy.
Philippe Moreau et al. Blood 2015;125:3076-3084
©2015 by American Society of Hematology
Dr. Hari will discuss
Treatments for relapsed disease
SURVIVAL HAS NEVERY BEEN LONGER
Kenneth C. Anderson Clin Cancer Res 2016;22:5419-5427
©2016 by American Association for Cancer Research
Bisphosphonates
Developed in mid 1990s for bone strengthening properties and treatment of hypercalcemia
1996- (Berenson, NEJM) randomized trial of pamidronate vs. placebo in patients with MM for 2 yrs.->40% reduction in skeletal events, pain
Zoledronate, pamidronate used more than alendronate
Higher bioavailability
Less GI toxicity
Same pt after rx, transplant,
Bisphosphonates, 18 mo later
KEY TO BONE HEALTH:
CONTROL MYELOMA!
Study Design
Presented By Noopur Raje at 2017 ASCO Annual Meeting
Results: Exploratory Endpoint
Presented By Noopur Raje at 2017 ASCO Annual Meeting
Only small phase 2 studies of denosumab in relapsed myeloma; no effect on disease progression
(Vij et al Am J Hematol 2009 84:650)
Exercise
• May reduce “inflammation”
• Helps pain, depression
CLINICAL TRIALS UNDERWAY NOW:
THESE ARE THE KEY TO IMPROVING SURVIVAL
• S1211- “high risk” MM
pts will do better with
four drugs (including
an antibody drug)
rather than the three
best drugs
• E1A11-is carfilzomib
better than
bortezomib? Length
of maintenance
• CTN1401- making a
“personalized”
vaccine to give to a
MM pt after a
transplant will help
them repel myeloma,
much like a vaccine
does for shingles, etc.
Conclusions
• Myeloma is a devastating disease
• However, MM patients living longer than ever before; this
is due largely to clinical trials and new drugs that have
incrementally improved survival
• Increasing number of choices for initial treatment
• COST WILL BE HUGE ISSUE NOW AND IN THE
FUTURE—CLINICAL TRIALS CAN SHOW US THE WAY!!!!
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