Transcript Plasma Cell Ds and Myeloma 1

Plasma Cell Diseases
MGUS, Smoldering Myeloma, Multiple Myeloma
itage and the dynamics of plasma-cell life in humoral immune responses are shown. B cells that are generated in the bone marrow exit as
sor B cells (pre-B cells), which are immature and express IgM. These cells further mature into naive B cells and then into either marginal-zone B
r follicular B cells. When activated, these marginal-zone and follicular B cells can differentiate into plasmablasts (not shown) and short-lived
a cells, both of which can secrete antibody. Alternatively, with the help of T helper cells, follicular B cells can also differentiate into memory B cells,
are long-lived, and express antibodies of switched class and high affinity for antigen. When reactivated by antigen, memory B cells can
ntiate into plasmablasts, which are competent to become long-lived plasma cells. A small proportion of these plasmablasts stay in the secondary
oid organ (the spleen or the lymph node) where they were generated. Most of the plasmablasts migrate either to inflamed tissue, under the
l of interferon--induced expression of CXC-chemokine receptor 3 (CXCR3; which binds CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11), or
bone marrow, under the control of chemotaxis towards CXCL12 (which binds CXCR4). All three tissues have finite numbers of plasma-cell survival
. Plasmablasts that succeed in the acquisition of such a niche differentiate into plasma cells and become immobile. Resolution of inflamed tissue
a successful immune response terminates the survival niches in the tissue and therefore eliminates the resident plasma cells, and this is the peak
immune response. In the bone marrow, and to a lesser degree in secondary lymphoid organs, long-lived plasma cells survive and provide
ral memory.
Plasma Cells
• The abnormal precursor B-cells originate in
the lymph nodes and migrate to the bone
marrow, which provides a microenvironment
conducive to terminal plasma cell
differentiation
Once in the Bone Marrow
• the malignant plasma cells is “nourished” by
the microenvironment of the bone marrow,
becomes widely disseminated throughout the
axial skeleton
Bone Marrow Specimen from a Patient with MGUS
Blade J. N Engl J Med 2006;355:2765-2770
abnormal SPEP
•
Consequently, clonal
plasma cells expand,
accompanied by
secretion of a
monoclonal
immunoglobulin
Characteristics of Active MM and Its Precursors
Kyle R et al. N Engl J Med 2007;356:2582-2590
•
During the evolution of MM and progression to
advanced stages, additional genetic events (eg,
loss of chromosome 13, secondary MYC
translocation, activation of other oncogenes such
as Ras, p53, and Rb) and dysregulation of the cell
cycle may take place.
•
The result is loss of apoptosis and immortalization
of plasma cells.
Disease Progression, clonal
evolution
MGUS
•
(MGUS) is an asymptomatic genetically malignant
but clinically premalignant clonal plasma cell
proliferative disorder.
•
It occurs in over 3 percent of the general population
over the age of 50.
•
It is typically an incidental finding as part of a w/u for
a wide variety of clinical syndromes (eg, peripheral
neuropathy, vasculitis, hemolytic anemia, skin
rashes, hypercalcemia, elevated sedimentation
rate)
Recommended Testing in Patients with Suspected MGUS
Blade J. N Engl J Med 2006;355:2765-2770
• IgG
• IgA
• IgM
• Free Light Chains
• 24 hr Urine Collection for UPEP
Characteristics of Active MM and Its Precursors
Kyle R et al. N Engl J Med 2007;356:2582-2590
• MGUS Treatment: No Treatment
• Periodic follow-up is recommended, as
MGUS can transform to a more serious
disorder at a rate of approximately 1
percent/year
Current model to stratify MGUS
uses three adverse risk factors:
1. a serum M protein level ≥1.5 gm/dL,
2. non-IgG MGUS, and
3. an abnormal serum FLC ratio
the risk of disease progression over 20 years is as follows :
•3 risk factors (high-risk MGUS) — 58 percent
•2 risk factors (high-intermediate risk MGUS) — 37 percent
•1 risk factor (low-intermediate risk MGUS) — 21 percent
•no risk factors (low-risk MGUS) — 5 percent
Prognosis
• Patients with low-risk MGUS:
• 1. serum M protein ≤1.5 gm/dL,
• 2. IgG subtype, and
• 3. normal serum free light chain (FLC) ratio
• have a risk of progression of only 5 % over 20 years, and
may be followed less frequently
Characteristics of Active MM and Its Precursors
Kyle R et al. N Engl J Med 2007;356:2582-2590
Probability of Progression to Active MM or Primary Amyloidosis in
Patients with Smoldering MM or MGUS
Kyle R et al. N Engl J Med 2007;356:2582-2590
Disorders associated with a MGUS
•Plasma cell disorders
•Monoclonal gammopathy of undetermined significance (MGUS)
•Biclonal gammopathy of undetermined significance
•Idiopathic Bence Jones proteinuria
•POEMS syndrome, Osteosclerotic myeloma
•
B-cell lymphoproliferative disorders
•
Non-Hodgkin's lymphoma
•
CLL
•
Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) IgM
• Post-transplant monoclonal gammopathies
•
Heavy chain diseases
•
Connective tissue disorders
SLE, RA
Miscellaneous disorders
• Acquired von Willebrand disease
• Acquired C1 esterase inhibitor deficiency (angioedema)
• Eosinophilic fasciitis
• Cryoglobulinemia, cryofibrinogenemia
• Myelodysplastic syndrome
• Chronic neutrophilic leukemia
• Sensorimotor neuropathy with MGUS
• Capillary leak syndrome
• T-cell large granular lymphocyte leukemia
• Cold agglutinin disease
A 76-year-old woman was admitted with an exacerbation of chronic obstructive pulmonary disease
Nair S and Pearson S. N Engl J Med 2004;351:1874
Multiple myeloma (MM)
•
accounts for approximately 1 percent of all cancers and
slightly more than 10 percent of hematologic
malignancies in the United States (US)
•
The annual incidence in the US is approximately 4 to 5
per 100,000. About 20,000 new cases a year.
•
MM is a disease of older adults. The median age at
diagnosis is 66 years
Most patients with MM present with signs or symptoms
related to the infiltration of plasma cells into the bone or
other organs (kidney)
• Anemia - 73 percent
•
Bone pain - 58 percent
•
Elevated creatinine - 48 percent
•
Fatigue/generalized weakness - 32 percent
Diagnostic Criteria for MGUS, Multiple Myeloma, and Other Conditions
Blade J. N Engl J Med 2006;355:2765-2770
Panel B: A dense, localized band (red asterisk) representing a monoclonal protein of gamma
mobility is seen on serum protein electrophoresis on agarose gel (anode on left).
Panel A: Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk)
of gamma mobility and a reduction in the normal polyclonal gamma band.
Bone Marrow Specimen from a Patient with MGUS (May-Grunwald-Giemsa Staining)
Blade J. N Engl J Med 2006;355:2765-2770
Multiple Myeloma Marrow
Diagnostic criteria
•
Multiple Myeloma (all 3 criteria must be met)
•
•
•
1.Presence of a serum or urinary monoclonal protein
2.Presence of clonal plasma cells in the bone marrow or a plasmacytoma
3.Presence
of end organ damage felt related to the plasma cell dyscrasia,
such
as:
• •Increased calcium concentration
• •Lytic bone lesions
• •Anemia, or
• •Renal failure
•
Asymptomatic (smoldering) multiple myeloma (SMM, both criteria must be
met)
• percent
1. Serum monoclonal protein >3 g/dL and/or bone marrow plasma cells >10
• 2. No end organ damage related to plasma cell dyscrasia (see list above)
•
MGUS
•
1. Serum monoclonal protein <3 g/dL
Adapted from Br J Haematol 2003;121:749 and Rajkumar,
SV et al. Leukemia 2001;15:1274.
•
Stage I (Low cell mass - <0.6 x 10(12) cells/m2)
•
•
•
•
•
•
•
All of the following present:
Hgb >10 g/dL
Serum IgG <5 g/dL
Serum IgA <3 g/dL
Normal serum calcium
Urine monoclonal protein excretion <4 g/day
No generalized lytic bone lesions
•
•
Stage II
Intermediate cell mass - neither stage I nor stage III
•
Stage III
•
•
•
•
•
•
•
One or more of the following:
Hgb < 8.5 g/dL
Serum IgG >7 g/dL
Serum IgA > 5 g/dL
Serum calcium >12 mg/dL (3 mmol/L)
Urine monoclonal protein excretion >12 g/day
Advanced lytic bone lesions
Durie-Salmon staging system
(High cell mass - >1.2 x 10(12) cells/m2)
A: Serum creatinine <2 mg/dL
B: Serum creatinine >2 mg/dL
The International staging system
(ISS)
• An International Staging System (ISS), based on 10,750
previously untreated patients with myeloma from over 17
institutions worldwide has been developed. It is based on the
levels of serum beta-2 microglobulin (B2M) and serum albumin
alone
•
Stage I — B2M <3.5 mg/L and serum albumin less 3.5 g/dL
•
Stage II — neither stage I nor stage III
•
Stage III — B2M 5.5 mg/L
Prognosis by ISS
• Stage Criteria
Median Overall Survival
•
I Serum Beta 2-microglobulin < 3.5 mg/L
•
AND Serum albumin > 3.5 g/dL
•
II Neither stage I or stage III
44 months
•
III Serum Beta2-microglobulin > 5.5 mg/L
29 months
• Median Overall Survival
• Stage Age < 65 years
62 months
Median Overall Survival
Age > 65 years
•
I
69 months
47 months
•
II
50 months
37 months
Prognosis by
• Poor
•
t(4;14)
•
t(14;16)
•
–17p13
Risk Group
Cytogenetics
Median Overall Survival
24.7 months
• Intermediate
•
–13q14
42.3 months
• Good
•
All others and
50.5 months
Treatment Plan
• Induction of Remission
• Maintenance Therapy
• Infectious Disease Prophylaxis
• Bone Disease: Fractures and Osteoporosis
Changing Treatment Paradigm
• OLD DRUGS
NEW DRUGS
• Melphalan Prednisone
Thalidomide
• Vincristine Doxoribicine
Bortezomib
Dexamethasone (VAD)
• Dexamethasone
Lenalidomide
iv Melphalan
An Approach to the Treatment of Newly Diagnosed Multiple Myeloma
Bortezomib or Velcade™
• Proteasome inhibitors target the ubiquitin-proteasome system,
which is the primary intracellular degradation pathway for protein.
• Within cells, this system plays a key role in regulating the
transcriptional activity of nuclear factor-kappa B (NF-kB).
Bortezomib, a boronic acid dipeptide, is a reversible inhibitor of the
26S proteasome complex.
• Through proteasome inhibition, bortezomib causes the
downregulation of NF-kB activity, thereby reducing NF-kB–
mediated tumor growth, angiogenesis, and cell survival.
•
Mechanism of Action of Bortezomib
Proteins are targeted to the 26S
proteasome for degradation by a
process of polyubiquitination.
Bortezomib inhibits the catalytic
activity of the proteasome, thus
preventing proteolysis. Ub
denotes ubiquitin.
26S Proteosome is a garbage
disposal of proteins
Mitchell B. N Engl J Med 2003;348:2597-2598
This inhibition disrupts signaling within cancer cells, fostering
antiproliferative, proapoptotic, antiangiogenic, and antitumor
activity.
Thalidomide and Lenalidomide (Revlimid™)
•immunomodulary agents with antiangiogenic
properties.
•Thalidomide is approved for first-line
treatment of multiple myeloma in combination
with dexamethasone.
•Lenalidomide is an analogue of thalidomide
The mechanisms of action
• both lenalidomide and thalidomide are similar
and incompletely characterized
• inhibiting the actions of TNF-α and IL-6
• both agents may exhibit antiangiogenic
• Both are oral agents
Lenalidomide
• Lenalidomide is a thalidomide derivative that
down-regulates IL-6 and NF -B and activates
caspase 8 in vitro.
• The drug is up to 50,000 times as potent as
its parent molecule in inhibiting TNF
Actions of Immunomodulatory Drugs
List A. N Engl J Med 2007;357:2183-2186
Figure 1. Actions of Immunomodulatory Drugs in Multiple My
Immunomodulatory drugs arrest growth and induce apoptosis in
in inhibit
Multiple
Myeloma
adhesion
to bone marrow stroma. Stromal elaboration of
response to vascular endothelial growth factor (VEGF) and basi
factor are reduced by immunomodulatory drugs, a process that
angiogenesis. Generation of the paracrine myeloma growth fact
tumor necrosis factor (TNF-) by stromal cells is reduced, which
myeloma-cell growth. The immunomodulatory drugs costimula
promote secretion of interleukin-2 and interferon- (INF-), which
activate natural killer cells and myeloma-specific immune respo
adapted from Teo.6 VCAM denotes vascular-cell adhesion mole
helper T.
Myeloma cells and the Microenviroment
Practical Applications and Clinical Advances in Multiple Myeloma
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Summary of Novel Agent Induction Trials
(Randomized Studies)
≥ VGPR Rates Postinduction and Posttransplantation
Postinduction
Posttransplantation
57%
76%
59%
49%
44% to 50%
*
*
15%
to
16%
VincAD[1]
39%
BortD[1]
42%
24%
33%
42%
RD[2,3]
Rd[2,3]
TAD[4]
PAD[5,6]
62%
BortThalD[7,8]
*Posttransplantation data not available.
1. Harousseau et al. ASH/ASCO symposium during ASH 2008. 2. Rajkumar SV, et al. ASCO 2008. Abstract 8504. 3.
Rajkumar SV. ASH/ASCO symposium during ASH 2008. 4. Lokhorst HM, et al. Haematologica. 2008;93:124-127. 5.
Sonneveld P, et al. ASH 2008. Abstract 653. 6. Sonneveld P, et al. IMW 2009. Abstract 152. 7. Cavo M, et al. ASH 2008.
Abstract 158. 8. Cavo M, et al. IMW 2009. Abstract 451.
Practical Applications and Clinical Advances in Multiple Myeloma
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Effect of Novel Agents on Outcome
in Newly Diagnosed Myeloma
100
OS From Diagnosis
Alive (%)
80
1971-1976
1977-1982
1983-1988
1989-1994
1994-2000
2001-2006
60
40
20
0
0
20
40
60
80
100 120 140
Kumar SK,
et al. Blood. 2008;111:2516-2520. This research was originally
Mos
published in Blood. © American Society of Hematology.
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Improvements in Survival by Age
10-Yr Relative Survival (%)
Period Estimates of 10-Yr Survival by Major Age Groups
in Defined Calendar Periods
50
45
40
35
30
25
20
15
10
5
0
Age, yrs
< 50
50-59
60-69
70-79
80+
19871984-1986 1989
19901993199619991992
1995
1998
2001 2002-2004
Calendar Period
Improvements in survival for elderly patients expected with
longer follow-up of ongoing trials
Brenner H, et al. Blood. 2008;111:2521-2526.
This research was originally published in Blood. © American Society of Hematology.
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Influence of Response After Induction: Superior
Outcome When CR Is Achieved Before ASCT
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
OS (Probability)
EFS (Probability)
CR vs nCR: P = .1
CR vs PR: P = .05
nCR vs PR: P = .9
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
12 24 36 48 60 72 84 96
Mos
CR (n = 101)
nCR (n = 96)
CR vs nCR: P = .1
CR vs PR: P = .07
CR vs SD: P = .02
nCR vs PR vs SD: P = .9
PR (n = 346)
0
12 24 36 48 60 72 84 96
Mos
SD (n = 63)
Lahuerta JJ, et al. J Clin Oncol. 2008;26:5775-5782. Reprinted with permission. © 2008
American Society of Clinical Oncology. All rights reserved.
PD (n = 26)
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Impact of Result of 1st ASCT on the
2nd ASCT
VGPR or CR After First ASCT
(P = .70)
< VGPR After First ASCT
(P < .001)
100
100
Double
transplantation
(n = 46)
75
OS
OS
75
50
Single
transplantation
(n = 81)
25
Double
transplantation
(n = 128)
50
Single
transplantation
(n = 84)
25
0
0
0
23
46
69
92
0
Mos After First Transplantation
Attal M, et al. N Engl J Med. 2003;349:2495-2502.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
24
48
72
Mos After First Transplantation
96
Summary
Bortezomib-based combinations appear to be
superior to thalidomide-based combinations
The addition of a third agent to TD or VD
appears to improve the pre- and post-ASCT
VGPR rate and may translate into a longer
PFS
Conclusion
 The use of novel agents has changed the
treatment paradigm for younger patients without
severe comorbidities
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Need for New First-line Regimens for
Patients Ineligible for Transplantation
 MP combination has been considered standard treatment; however,
results are disappointing
– Response rate: 40% to 60%
– Median RFS: 18 mos
– CRs rare
– Median OS: 3 yrs
 Age a significant risk factor with conventional chemotherapy
 Other complications may contribute to poor outcomes
– Eg, renal impairment
Urgent need for more active therapies for elderly patients and
patients not eligible for transplantation
Brenner H, et al. Blood. 2008;111:2521-2626.
Ludwig H, et al. Blood. 2008;111:4039-4047.
Reece DE. Hematology Am Soc Hematol Educ Program. 2005:353-359.
National Comprehensive Cancer Network. http://www.nccn.org.
Practical Applications and Clinical Advances in Multiple Myeloma
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Exploring Alternatives to
Melphalan/Prednisone in Elderly Myeloma
Patients
 Novel Combinations as Induction Therapy for Patients Who
Are Not Eligible for Transplantation:
– Thalidomide-Based
– Lenalidomide-Based
– Bortezomib-Based
 Special Considerations: Treatment Choices in Patients With
Comorbidities, the Role of Cytogenetic Abnormalities, and
Considerations in Very Elderly Patients
Practical Applications and Clinical Advances in Multiple Myeloma
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Novel Agents as Induction Therapy for
Patients NOT Eligible for Transplantation
MP
Thalidomide
MP vs MPT
Thal/Dex
CTD
Bortezomib
Lenalidomide
MP vs VMP
VMP vs VTP
VMP vs VMPT
MPR
RD vs Rd
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Phase III ECOG E4A03 Trial: Lenalidomide +
High-Dose Dex (RD) vs Low-Dose Dex (Rd)
RD (n = 223)
Lenalidomide
25 mg/day, Days 1-21
Dexamethasone (high dose)
40 mg/day, Days 1-4, 9-12, 17-20
Newly
diagnosed MM
patients
(transplant
eligible)
Four 28-day cycles
CR/PR/SD
Rd (n = 222)
Lenalidomide
(N = 445)
CR/PR
Proceed to SCT, or
continue RD/Rd, or
no further treatment
25 mg/day, Days 1-21
< PR
Thalidomide +
Dexamethasone
for 4 cycles
Dexamethasone (low dose)
40 mg/day, Days 1,8,15, 22
Four 28-day cycles
Rajkumar SV, et al. ASCO 2008. Abstract 8504.
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Phase III ECOG Trial: RD vs Rd
 After 4 induction cycles:
– ≥ VGPR 51% with RD vs 40% with Rd
– ≥ PR 81% with RD vs 70% with Rd
 OS: 75% at 3 years
– Although initial findings suggested better OS with Rd;
– OS at 3 years identical for both treatment arms
– (P = .46 log-rank; P = .01 Pepe-Fleming)
Rajkumar SV, et al. 2008 ASH/ASCO. Abstract.
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Phase III VISTA Study: VMP vs MP in
Untreated MM Pts Ineligible for HDT-ASCT
 Pts (N = 682): symptomatic MM/end organ damage with measurable disease
– ≥ 65 yrs or < 65 yrs
– Not transplantation eligible
– KPS ≥ 60%
–
R
A
N
D
O
M
I
Z
E

VMP
Cycles 1-4
Bortezomib 1.3 mg/m2 IV, Days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV, Days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV, Days 1,8,22,29
Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, Days 1-4
9 x 6-week cycles (54 weeks) in both arms
Primary endpoint: TTP
Secondary endpoints:
CR rate, ORR, time to
response, DOR, time to
next therapy, OS, PFS, QoL
(PRO)
MP
Cycles 1-9
Stratification:
β2-microglobulin,
albumin,
region
2 IV, Days 1-4
Melphalan
9 mg/m2 IV and prednisone
60 mg/m
San Miguel JF, et al. N Engl J Med. 2008;359:906-917.
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VMP vs MP in Untreated Myeloma: Efficacy
Data
ORR: VMP 71%, MP 35%
CR: VMP 30%, MP 4%
TTP
OS



100
VMP
MP
80
60
40
VMP: 24.0 mos
20 MP: 16.6 mos
P < .000001
0
0
3
6
9 12
15
Mos
18
21
24
~ 36% reduced risk of death on VMP
Patients Without Event (%)
Patients Without Event (%)
~ 52% reduced risk of progression on VMP
100
80
60
Median follow-up: 25.9 mos
3-year OS:
VMP: 72%
MP: 59%
P = .0032
40
20
0
27
43% of MP patients received bortezomib upon progression
OS with > 4 cycles bortezomib: 98.5% at 1 yr, 89% at 2 yrs
Treatment-related death: 2% in both arms
San Miguel JF, et al. N Engl J Med. 2008;359:906-917.
VMP
MP
0
4
8
12
16
20 24
Mos
28
32
36
40
San Miguel JF, et al. ASH 2008. Abstract 650.
Copyright © 2008
Massachusetts
Society.
All rights
reserved.
SanMedical
Miguel JF,
et al. ASH
2008. Abstract
650.
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Preferences for 1 MP Combination?
1.Consolidate data.............................
2.Antecedent or risk of DVT...............
3.Antecedent of PN............................
4.Renal insufficiency..........................
5.Distance from hospital....................
6.Poor patient accomplishment.........
7.Costs...............................................
TMP, VMP
VMP
LMP/Rd
Bort-based combination
LMP or MPT
VMP
MPT
Conclusions
• New Agents are transforming the life
expectancy in the young with MM but also in
the elderly.
• Better and more effective pain control, better
and longer quality of life
• New drugs and combination may bring “cure”
to MM in my life time.