Myeloma
Update on Treatment From the American Society
of Hematology (ASH
®
) Annual Meeting
Welcome and Introductions
Myeloma
Update on Treatment From the American Society
of Hematology (ASH
®
) Annual Meeting
William Bensinger, MD
Director of the Autologous Stem Cell Transplant Program
Fred Hutchinson Cancer Research Center
Professor of Medicine
U i
it
f W hi t
University of Washington
Seattle, WA
Disclosures
•
Consulting
Acetylon,
y
,
Bristol
‐
Myers
y
Squibb,
q
,
Celgene,
g
,
Novartis,
,
Onyx,
Pharmacyclics,
Sanofi
•
Research
Funding
Acetylon,
Bristol
‐
Myers
Squibb,
Celgene,
Novartis,
Onyx,
Pharmacyclics,
Sanofi
3
Etiology
of
Multiple
Myeloma
(MM)
•
Exact
cause
unknown
1
•
Multistep process leads
Multistep
process
leads
to
development
of
malignant
clone
1
•
Myeloma
cells
—
Return
to
bone
marrow
2
—
Produce
monoclonal
protein (M protein)
1
protein
(M
protein)
1
—
Alter
cytokine
regulation
in
the
bone
marrow
environment
3
1. McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. 7thed. New York, NY: McGraw-Hill; 2008:2295-2307. 2. Tricot G. Lancet.
Epidemiology
of
MM
•
Prevalence
—
More
than
95,800
people
in
the
US
1
•
Incidence
Ab
t 24 000
l
di
d ith MM
h
i th US
2
—
About
24,000
people
are
diagnosed
with
MM
each
year
in
the
US
2
•
Annual
age
‐
adjusted
incidence
is
5.56
per
100,000
1
•
Mortality
—
Nearly
11,000
US
MM
patients
expected
deaths
in
2014
2
—
The
overall
5
‐
year
relative
survival
rate
for
2004
‐
2010
was
46.7%
1
•
Demographics
—
Median
age
at
diagnosis
is
69
years
1
3 8% f MM
i
h
45
1
•
<3.8%
of
MM
patients
are
younger
than
45
years
1
—
Incidence
is
more
than
twice
as
high
in
blacks
as
in
whites
1
—
More
frequent
in
men
than
women
1
1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD,
http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER Web site, April 2014.
2. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014.
5
Renal Impairment
Spectrum
of
Clinical
Manifestations
of
MM
M protein
Bone Pain
Neuropathy
Hypercalcemia
Immuno-deficiency
Infection
Multiple
Myeloma
Bone-Related
Si
d
Bone Pain
Anemia
Hb
≤
12 g/dL
Lytic Lesions
Marrow
Infiltration
Myeloma
Clinical
Presentation
As many as 20% of patients with MM may be asymptomatic* at
diagnosis
g
1
Signs &
Symptoms
1-4Lab Parameters
1Radiographic
Parameters
1Bone Marrow
1•
Bone pain
•
Fatigue
•
Weight loss
•
Paresthesias
•
Recurrent infection
•
Renal failure
S i
l
d
•
Elevated
paraproteins-M peak
•
Low hemoglobin
•
Hypercalcemia
•
Low albumin
•
Elevated
β
2-microglobulin
El
t d
ti i
•
Lytic lesions
•
Osteoporosis
•
Fractures
•
Increased
plasma cells
1. McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7thed. New York, NY: McGraw-Hill; 2008:2295-2307. 2. Kyle RA, et al. Mayo Clinic Proc. 2003;78:21-33. 3. Bladé J, et al. Hematol Oncol Clin North Am. 2007;21:1231-1246. 4. Nau KC. Am Fam Physician.2008;78:853-859.
5. Landgren OL, et al. JAMA. 2010;304:2397-2404.
*Some patients may be diagnosed due to incidental abnormalities from comprehensive labs and imaging studies.
5•
Spinal cord
compression
•
Back pain
•
Elevated serum creatinine
•
Elevated C-reactive protein
-7
Initial
Diagnostic
Evaluation
•
History
and
Physical
Examination
•
Tests
Serum
Urine
Bone Marrow Aspirate Radiography
•
CBC with differential
•
BUN/creatinine,
electrolytes
•
LDH
•
Calcium, albumin
•
Serum free light
chain assay
Q
tit ti
•
24-hr urine
total protein
•
Urine protein
electrophoresis
(UPEP)
•
Urine
immunofixation
l t
h
i
•
Morphology
•
Histology
•
Cytogenetic analysis
•
Fluorescence in situ
hybridization (FISH)
•
Immunohistochemistry
+/- flow cytometry
•
Skeletal survey
Magnetic Resonance imaging
Positron Emission Tomography
NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma. v.1.2011. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 3, 2011.
LDH, lactate dehydrogenase.
•
Quantitative
immunoglobulins
•
β
2-microglobulin
•
Serum protein
electrophoresis (SPEP)
•
Serum immunofixation
electrophoresis (SIFE)
electrophoresis
(UIFE)
8
Hallmark
of
MM
Serum Protein Electrophoresis (SPEP)
Multiple myeloma
M protein
Serum Protein Electrophoresis (SPEP)
Normal
Reprinted with permission from the American Academy of Family Physicians. © 1999. George ED, et al. Am Fam Physician. 1999;59:1885-1894.
Albumin
α
1α
2β
ϒ
9
Diagnostic
Criteria
for
Symptomatic
MM
•
Presence
of
M
protein
in
serum
or
urine
•
Identification
of
>10%
monoclonal
plasma
cells
in
bone marrow
bone
marrow
•
Evidence
of
end
‐
organ
damage:
CRABi
CRABi: Symptomatic MM Quintad
C
alcium Elevation
Serum calcium
≥
11 mg/dL
R
enal Failure
Serum creatinine
≥
2 mg/dL
i
nfections
R
enal Failure
Serum creatinine
≥
2 mg/dL
A
nemia
Hemoglobin <12 g/dL
B
one
Lytic lesions, pathologic fractures, or severe osteopenia
International
Staging
System
for
MM
1 2
Stage
International Staging System
1Median Survival
2I
Serum β
2-microglobulin <3.5 mg/L
Serum albumin ≥3.5 g/dL
62 months
II
Neither stage I nor stage III
44 months
1. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma. v.1.2011. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 3, 2011. 2. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
III
Serum β
2-microglobulin ≥5.5 mg/L
29 months
11
Impact
of
Genetic
Abnormalities
on
Prognosis
in
MM
Prognosis may vary according to type of chromosomal abnormality
1-7*
Chromosomal abnormality
(FISH based)
Incidence (%)
Prognosis
Hyperdiploidy 39%-45% Favorable
Isolated del 13 48% No significance
t(11;14) 7.8%-21% No significance
t(14;16) 1.9%-5% Poor
t(4;14) 6.5%-15% Poor
1. Dewald GW, et al. Blood. 2005;106:3553-3558. 2. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. 3. Avet-Loiseau H, et al. Blood. 2007;109:3489-3495. 4. Fonseca R, et al. Leukemia. 2009;23:2210-2221. 5. Rajkumar SV, et al. Mayo Clin Proc. 2006;81:693-703.
6. Munshi M. Hematology 2008. American Society of Hematology. 2008;298-305. 7. Walker BA, et al. Blood. 2010;116:e56-65.
*Chromosomal abnormalities may be found in MGUS patients as well.
5del 17p 11% Poor del 13 with • del 17p • t(4;14) 8.6% 11.9% Poor
12
Myeloma
Treatment:
A
Historical
Perspective
Present
Introduction of novel agents
Autologous stem cell transplant
Combination of carmustine + cyclophosphamide +
melphalan + vincristine + prednisone
Melphalan + prednisone (MP) established
1974
1969
1983
1990
1987
High-dose melphalan and stem cell rescue as standard therapy
Rhubarb pill and orange peel infusion
Phlebotomy and application of leeches as “maintenance”
Urethane established as standard of care
Melphalan
Corticosteroids
Melphalan prednisone (MP) established
1844
1947
1958
1962
1969
Kyle RA, et al. Blood. 2008;111:2962-2972.
13
Managing
Myeloma:
The
Components
Autologous
l
Initial
Therapy
Tx
Ineligible
Transplant
(consolidation)
±
Addl.
consolid
Maintenance
Treatment
of
Relapsed
disease
Consolidation/
Maintenance/
Continued therapy
Tx
Eligible
Supportive
Care
Ineligible
Continued
therapy
Goals
of
Therapy
•
Control
the
myeloma
disease
activity
I
di
t
•
Improve
disease
symptoms
–
Bone
damage
(pain
and
fractures)
–
High
calcium,
kidney
problems
(weakness)
–
Anemia
(fatigue,
shortness
of
breath)
–
Kidney
problems
(fatigue)
Reduce frequent infections
–
Reduce
frequent
infections
•
Achieving
a
“remission”
•
Minimize
treatment
‐
related
symptoms
15
Current
Status
of
Treatment
for
MM
•
Therapy
has
become
better
thanks
to
new
drugs
and
the use of autologous stem cell transplantation
the
use
of
autologous
stem
cell
transplantation
•
Survival
for
many
patients
now
approaches
ten
years
(120
months)
•
Cure
is
still
elusive,
thus
the
interest
in
consolidation/maintenance
M
d
d
d
l
d
•
Many
new
drugs
and
new
drug
classes
are
under
development
Drugs
for
MM
Class
Drugs
Steroids
dexamethasone prednisone
Steroids
dexamethasone, prednisone
Alkylators
cyclophosphamide, melphalan,
bendamustine
Vinca alkyloids
vincristine
Anthracyclines
doxorubicin, PEG-DOX
IMiDs
thalidomide, lenalidomide
pomalidomide
Proteasome inhibitors
bortezomib, carfilzomib
17
Initial
Treatment
•
Transplant
Candidates
–
Bortezomib
dexamethasone,
thalidomide*
or
lenalidomide
–
Bortezomib
dexamethasone*
L
lid
id d
h
*
–
Lenalidomide
dexamethasone*
–
Bortezomib,
doxil
+/
‐
dexamethasone
–
Cyclophosphamide,
bortezomib,
dex
–
Thalidomide dexamethasone*
–
VAD, DVD, Dexamethasone
•
Non
‐
transplant
candidates
/
–
Melphalan prednisone + thalidomide or lenalidomide (MPT/R)*
–
MP + bortezomib (MPV)*
–
Lenalidomide
+
dexamethasone
Measuring
Treatment
Response
•
Remission
No sign of disease. Sometimes the terms
complete remission
(response) or
partial remission
(response) are used
(response) or
partial remission
(response) are used.
•
Complete Response (CR)
No sign of M protein in blood and urine. Normal percent of plasma
cells or no sign of myeloma cells in marrow (5% plasma cells in
bone marrow), stable bones on skeletal survey
•
Very Good Partial Response (VGPR)
19
90% reduction in blood and (<100 mg) urine proteins
•
Partial Response
More than a 50% decrease in M protein in the blood and reduction in
24-h urinary M-protein by 90%.
You
Need
Good
Combinations
Autologous
Stem
Cell
Transplantation
•
Considered
important
therapy
for
eligible
multiple
myeloma patients
myeloma
patients
•
High
rates
of
CR
to
VGPR,
CR
correlates
with
survival
•
Disease
control
better
in
all
trials,
but
there
is
not
always
a
survival
benefit
•
Low
mortality
(<2%)
•
No
donor
limitation
•
Less
effective
for
high
‐
risk
groups
•
Still
not
curative
for
most
patients
(<15%)
ASCT
Improves
Major
Responses
After
Traditional
or
Novel
Induction
Trial
Regimens
No
≥
nCR%
Induction
ASCT
Induction
ASCT
GIMEMA
VcTD x3
TD x3
241
239
31*
11
52*
31
IFM
VcD x4
VAD x4
223
218
15*
6
35*
18
Hovon
VcAD x3
VAD 3
371
373
11*
5
30*
15
VAD x3
373
5
15
Ludwig
VcTD x4
CVcTD x4
49
48
51
44
85
77
Reeder
CyBorD x4
28
46
72
IFM
VcRD x3
31
23
42
23
Updates
from
ASH
2014
#4739 – Carfilzomib, Cyclophosphamide & Dexamethasone is an Active Regimen for
Induction Therapy Prior to ASCT in the Management of Newly Diagnosed Patients with
Multiple Myeloma
28 patients age 44–74, median 64
Carfilzomib 2x weekly ¾ weeks, Cy, dex weekly x6 cycles
Maximum Carfilzomib dose 56 mg/m
2O
ll
t 91% 2 CR 10 VGPR
Overall response rate 91%, 2 CR, 10 VGPR
1 patient discontinued for progressive disease
#175 – Weekly Carfilzomib, Cyclophosphamide, Dexamethasone in Newly Diagnosed
Multiple Myeloma
30 patients age >65 or transplant-ineligible, median age 74
Up to 9 cycles + maintenance
Overall response rate 86%,
complete response 25%
Maximum tolerated dose 70 mg/m
213% of patients discontinued
#79 – ASPIRE Study: Lenalidomide + Dexamethasone with or without Carfilzomib in
Relapsed Multiple Myeloma
Relapsed Multiple Myeloma
792 patients, median of 2 prior therapies, median age 64 years
Overall response rate 87% with CRd v. 67% with Rd
Complete response rate 32% CRd, 9% RDd
Duration of response 29 months CRd, 21 months Rd
Median duration of treatment 22 months CRd, 14 months Rd
Progression-free survival median 26 months CRd, 18 months Rd
24
1. Bensinger WI, et al. 2014 American Society of Hematology. Abstract 4739. 2.Palumbo A, et al. 2014 American Society of Hematology. Abstract 175. 3. Stewart AK, et al. 2014 American Society of Hematology. Abstract 79.
