Overview of Multiple Myeloma
The Basics of Multiple Myeloma
This program is supported by educational grants from Celgene
Corporation, Millennium: , and Onyx Pharmaceuticals.
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What Is Multiple Myeloma?
 Cancer of the plasma cells
in bone marrow
 Growth of myeloma cells:
– Disrupts normal bone
marrow function
– Reduces normal immune
function
– Results in abnormal
production and release of
monoclonal protein into
blood and/or urine
– Destroys and invades
surrounding bone
Barlogie B, et al. In: Williams Hematology; 2006. Durie BG. IMF 2007.
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Multiple Myeloma Epidemiology
New Cases, n
(US, 2014)
Deaths, n
(US, 2014)
Mean Age at
Diagnosis, Yrs
5-Yr Relative Survival
Rates 2004-2010, %
24,050
11,090
62
44.9
 Death rates
– Decreased during 1991-2005
– 11.3% decrease for women,
7.25% decrease for men
 Risk factors
– Unknown in the majority of
cases
– Increased with age, male sex,
obesity, and black race
 Variable response to treatment
and variation in survival
– From a few mos to > 10 yrs
– High-risk attributes are thought
to play a primary role
– 20% of patients survive
> 10 yrs, regardless of therapy
– Novel agents may neutralize
the effects of some high-risk
features
Badros AZ. J Natl Compr Canc Netw. 2010;8:S28-S34. Kurtin S. Oncology Nurse Ed. 2011;25. Siegel R, et al.
CA Cancer J Clin. 2014;64:9-29. SEER Stat Fact Sheets: Myeloma.
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Myeloma Can Result in a Broad Spectrum
of Clinical Manifestations
Renal compromise
(30%)
Neuropathy (33%)
Hyperviscosity
Amyloidosis
M-protein
Immune
deficiency
Infection (15%)
Hypercalcemia
(15% to 20%)
Multiple
myeloma
cells
Destruction
of bone
Bone pain
Lytic lesions (70%)
Hoffman R. Hematology: basic
principles and practice, 5th edition;
2008. Ropper AH, et al. N Engl J
Med. 1998;338:1601-1607.
Marrow
infiltration
Anemia (10% to
35%)
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Classification of Myeloma
Heavy chain:
 IgG, IgA, IgD, IgM, IgE
Light chain (Bence-Jones
protein):
 77% of myeloma cases
Kappa (κ) or lambda (λ)
 IgG and IgA most common
20% of myeloma cases
Variable
region
Light chain
 No detectable
immunoglobulin
Constant
region
Nonsecretory:
Heavy chain
 1% to 2% of myeloma cases
Kumar SK, et al. Mayo Clinic Proc. 2009;84:1095-1110.
Schmidt-Hieber M, et al. Haematologica. 2013;98:279-287.
Serum free light chain
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Disease Trajectory
Nonmalignant
Accumulation
Aggressive and
Stromal Independent
Malignant Transformation
Stroma
angiogenesis
MGUS
Plasma
cell
leukemia
and IL-6
dependent
Smoldering Myeloma
Multiple Myeloma

< 3 g M-protein

≥ 30 g/L M-protein

≥ 10% clonal BMPC

< 10% clonal BMPC

≥ 10% clonal BMPC

M-protein in serum and/or urine

No MM-related
end-organ damage

No MM-related
end-organ damage

≥ 1 CRAB features of disease related
to organ damage

1%/yr risk of
progression to MM

10%/yr risk of
progression to MM in
the first 5 yrs
C: Calcium elevation > 11.5 mg/L or ULN
R: Renal dysfunction (serum creatinine
> 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g < normal)
Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca
A, et al. Leukemia. 2006;20:193-199. Agarwal A, et al. Clin
Cancer Res. 2013;19:985-994. Durie BG, et al. Hematol J.
2003;4:379-398. Kurtin SE. JAdPrO, 2010;1:19-29.
B: Bone disease (lytic lesions or
osteoporosis)
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Role of Bone Marrow Microenvironment in
Myeloma Myeloma cells
IL-6
TNF
IL-1
Bone marrow
stromal cells
ICAM-1
Bone marrow
vessels
VEGF
bFGF
PBMC
IL-2
IFN 
CD8+ T cells
NK cells
Hideshima T, et al. Blood. 2000;96:2943-2950.
Davies FE, et al. Blood. 2001;98:210-216.
Gupta D, et al. Leukemia. 2001;15:1950-1961.
Mitsiades N, et al. Blood. 2002;99:4525-4530.
Lentzsch S, et al. Cancer Res. 2002;62:2300-2305.
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Diagnostic Evaluation
History and physical
CBC, differential and platelet count
Additional laboratory tests
Bone marrow biopsy and aspiration
Serum immunoglobulins
Hematopathology
− Quantitative (IgG, IgM,
IgA, IgD)
− SPEP
− Presence of plasma cells, %
− Cellularity
− Ploidy
− Serum free light chain assay
(kappa, lambda)
Cytogenetics
− BUN, creatinine, electrolytes
FISH
− Serum calcium (corrected)
− Serum albumin
Gene expression profiling
− β2-microglobulin
− LDH
− Additional testing based on
preliminary analysis
24-hr urine
Radiology
Skeletal survey
MRI if vertebral compression fractures suspected
PET/CT
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.
Kurtin S. JAdPrO. 2010;1:19-29.
Establish diagnosis of MM
MGUS
Smoldering
Active
Determine subtype
Heavy chain/light chain
Nonsecretory
Solitary plasmacytoma
Determine stage
International Staging System
Durie-Salmon staging system
Estimate prognosis
Cytogenetics
Albumin
β2-microglobulin
Ploidy
Identify need for immediate
intervention
Severe hypercalcemia
Acute renal failure
Cord compression
Severe pain or
impending fracture
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Monoclonal Protein—M Spike
Normal SPEP
Abnormal SPEP
 Amount/type of M-protein varies among patients (IgG, IgA 80% of
cases)
 Abnormal M-protein (immunoglobulin) loses immune function and
adheres and binds to tissues
Barlogie B, et al. In: Williams Hematology; 2006. p. 1501.
Durie. IMF 2007. MMRF. Intro to Myeloma. 2005.
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International Staging System
Stage
I
II
III
Criteria
Serum β2m < 3.5 mg/L
Serum albumin ≥ 3.5 g/dL
Serum β2m < 3.5 mg/L
Serum albumin < 3.5 g/dL
OR
Serum β2m 3.5 through < 5.5 mg/L
Serum β2m ≥ 5.5 mg/L
Median OS, Mos
62
44
29
 Serum β2m reflects tumor load and is elevated in renal
failure
Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
Dimopoulos M, et al. Leukemia. 2009;23:1545-1556.
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Cytogenetic Testing Methodologies
Methodology
Advantages
Disadvantages
Karyotype
analysis
Highly sensitive for the detection of
chromosomal abnormalities in
dividing cells
Low yield of karyotype abnormalities
from MM bone marrow samples
Does not detect some aberrations
Cannot describe possible
heterogeneity within a population of
clonal cells
FISH
Can be performed in non dividing
cells
Can detect translocations
Validation with positive and negative
controls is standard
Variable scoring criteria
Some aberrations technically difficult
to detect
GEP
May be helpful with prognosis
May lead to development of more
targeted therapies
Not performed locally
Expensive
Unclear what should be done with
the information
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Cytogenetic Classification
 mSMART 2.0: classification of active myeloma
High Risk 20%
 FISH
− Del(17p)
− t(14;16)
− t(14;20)
 GEP
− High-risk signature
OS 3 Yrs
Intermediate Risk 20%
 FISH
− t(4;14)
− 1q gain
 Complex karyotype
 Metaphase deletion
13 or hypodiploidy
 High PCLI
OS 4-5 Yrs
Standard Risk 60%
All others including:
 Trisomies
 t(11;14)
 t(6;14)
OS 8-10 Yrs
Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:10951110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376.
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Normal Karyotypes
Female
Strupp C, et al. Leukemia. 2003;17:1200-1202.
Male
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Hyperdiploidy
Belurkar S, et al. Ind J Med Sci. 2013;67:188-192.
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Fluorescence in Situ Hybridization
Analysis
 t(14;20)
 Chromosome
14 stained green
 Chromosome
20 stained red
Stralen E, et al. Leukemia. 2009;23:801-803.
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Gene Expression Profiling in Myeloma
Decaux O, et al. J Clin Oncol. 2008;26:4798-4805.
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Natural History of Myeloma
Asymptomatic
Symptomatic
M-Protein (g/L)
100
2. RELAPSE
ACTIVE
MYELOMA
1. RELAPSE
50
20
REFRACTORY
RELAPSE
MGUS or
smoldering
myeloma
Plateau
remission
First-line therapy
Second-line
therapy
Third-line
therapy
Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Siegel
DS, et al. Community Oncol. 2009;6:12:22-29. Durie BG, et al. Hematol J. 2003;4:379-398; adapted with
permission from Durie B.
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Survival in Myeloma Is Improving With
Novel Agents
Proportion Surviving
5-Yr Survival by Age
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median 7.3 yrs
≤ 65 Yrs
> 65 Yrs
2006-2010
73%
56%
2001-2005
63%
31%
2006-2010
2001-2005
0
1
2
3
4
5
6
7
8
9
Follow-up From Diagnosis (Yrs)
Kumar SK, et al. ASH 2012. Abstract 3972.
10
The use of novel
agent inductions with
melphalan and ASCT
have doubled
median survival for
nearly all patients
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Treatment of Multiple Myeloma
Confirmed Diagnosis of Multiple Myeloma: CRAB Criteria
Determination of transplant
Immediate interventions for
eligibility
serious adverse events
Individualized Treatment Selection for Induction Therapy
Transplant Eligible
Transplant Ineligible
Works rapidly (CR, nCR, VGPR)
Achieving a CR or nCR
Well tolerated
Level of evidence: 1 or 2A
Spares stem cells
Tolerability and QoL
Level of evidence: 1 or 2A
PS and comorbidities
Continued Treatment
Salvage therapy
Maintenance therapy
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.
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Clinical Considerations in Deciding
Induction Therapy
 High tumor burden
– Pulse dexamethasone
– Combination therapies with
alkylators and IMiDS and
bortezomib
 Renal failure
– Pulse dexamethasone
– Combination therapies with
alkylators and thalidomide and
bortezomib (role of
lenalidomide uncertain)
 Hypercalcemia
– Pulse dexamethasone
– Bisphosphonates
 Frail
– Avoid high-dose
dexamethasone
 Clotting or bleeding history
– Assess risk of use of
lenalidomide/ thalidomide and
anticoagulation
 Preexisting neuropathy
– Assess use of bortezomib/
thalidomide
 Cytogenetic abnormalities
– Indication for bortezomib/
lenalidomide
Niesvizky R, et al. Oncology (Williston Park). 2010;24:14-21. NCCN. Clinical practice guidelines in
oncology: multiple myeloma. v.2.2014. Stadtmauer EA. Oncology (Williston Park). 2010;24:7-13.
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NCCN Recommendations for Adjunctive
Treatment

Bone disease

– Bisphosphonates (category 1)
– IVIG for recurrent infections
– Radiation therapy
– Pneumovax and influenza vaccine
– Orthopedic consultation
– PCP, herpes and antifungal
prophylaxis for high-dose or
long-term steroids
– Vertebroplasty or kyphoplasty

Hypercalcemia
– Herpes zoster prophylaxis with
bortezomib
– Hydration, steroids, furosemide
– Zoledronic acid preferred


– Not a contraindication to HCT
Anemia
– Consider erythropoietin
Renal dysfunction
– Avoid aggravating factors: contrast,
NSAIDs, dehydration
Hyperviscosity
– Plasmapheresis

Infection
– Monitor bisphosphonates closely

NCCN. Clinical practice guidelines in oncology: multiple
myeloma. v.2.2014. Miceli T, et al. Clin J Oncol Nurs. 2011;15(suppl):
9-23. Faiman B, et al. Clin J Oncol Nurs. 2011;15(suppl):66-76.
Coagulation/thrombosis
– Prophylactic anticoagulation with
IMiDs
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Epidemiology of Multiple Myeloma
 23,500 new cases and 10,710 deaths from myeloma were
expected in the United States in 2012
 More common in men than in women
 Higher incidence in blacks vs whites (2:1)
 Median age at diagnosis: 70 yrs
Cancer facts and figures 2012. American Cancer Society; 2012. Altekruse SF, et al, eds. SEER cancer
statistics review, 1975-2007. National Cancer Institute. NCCN. Clinical practice guidelines in oncology:
multiple myeloma. v.1.2013.
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Multistep Pathogenesis of Multiple Myeloma
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Natural History of Noncurable
Malignancies
Symptomatic
Asymptomatic
M-Protein (g/L)
100
2. RELAPSE
ACTIVE
MYELOMA
1. RELAPSE
50
20
REFRACTORY
RELAPSE
MGUS or
smoldering
myeloma
Plateau
remission
First-line therapy
Second-line
therapy
Third-line
therapy
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Clinical Manifestations of Symptomatic
Multiple Myeloma
Renal
compromise (30%)
M-protein
Neuropathy (33%)
Immune
deficiency
Infection (15%)
Hypercalcemia
(15% to 20%)
Marrow
infiltration
Destruction
of bone
Adapted from: Hoffman R. Hematology: Basic Principles and Practice,
5th edition; 2008. Ropper AH. N Engl J Med. 1998;338:1601-1607.
Rajkumar SV. Curr Probl Cancer. 2009;33:7-64. IMF update 2003
(http://myeloma.org/ArticlePage.action?articleId=1044).
Bone pain
(75% to 80%)
Lytic lesions (70%)
Anemia (70%)
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Challenges in Treatment
 “High-risk” disease, expected OS: 2-3 yrs
– t(4;14), t(14;16), del(17p), 1q21 amplification by FISH
– del(13q) by cytogenetics, hypodiploid cytogenetics
– High β2-M (≥ 5.5 mg/L)
– IgA, high plasma cell labeling index
 Clinical treatment challenges
– Renal failure
– Older population, median age at diagnosis: 70 yrs
– Significant comorbidities: heart, lung disease
– Extramedullary disease
– Managing light-chain disease
Patient Assessment
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Diagnostic Criteria for Myeloma
Patient Criteria
M-protein
Monoclonal
plasma cells in
bone marrow, %
End-organ
damage
MGUS[1,2]
Smoldering
Myeloma[1]
Symptomatic
Myeloma[1]
< 3 g/dL spike
≥ 3 g/dL spike
and/or
In serum and/or
urine[2]
< 10
≥ 10
≥ 10[2]
None
None
≥ 1 CRAB*
feature[3]
*C: Calcium elevation (> 10.5 mg/L or ULN)
R: Renal dysfunction (serum creatinine > 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g < normal)
B: Bone disease (lytic lesions or osteoporosis)
1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.
3. Durie BG, et al. Hematol J. 2003;4:379-398.
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Progression to Symptomatic Myeloma
MGUS: up to 3% of persons 50 yrs of age or older and ~ 6% of those older
than 70 yrs

For asymptomatic myeloma, maximum risk in the first 5 yrs
Probability of Progression (%)

100
Smoldering Multiple Myeloma
80
66
60
73
78
51
40
MGUS
20
4
10
0
0
5
21
16
15
10
Yrs Since Diagnosis
20
25
Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
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Initial Diagnostic Evaluation
Evaluation
History and physical
Blood workup
CBC with differential and platelet counts
BUN, creatinine
Electrolytes, calcium, albumin, LDH
Serum quantitative immunoglobulins
Serum protein electrophoresis and immunofixation
β2-M
Serum free light chain assay
Urine
24-hr protein
Protein electrophoresis (quantitative Bence-Jones protein)
Immunofixation electrophoresis
Other
Skeletal survey
Unilateral bone marrow aspirate and biopsy evaluation with
immunohistochemistry or flow cytometry, cytogenetics, and FISH
MRI and PET/CT as clinically indicated
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.
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Symptomatic Myeloma Staging
Risk factors: higher M spike, higher plasma cell burden,
type of M-protein, abnormal free light-chain ratio, circulating
plasma cells
Stage
Stage I
Stage II
Stage III
ISS Criteria for
Symptomatic Myeloma
ß2-M < 3.5 mg/L and
serum albumin ≥ 3.5 g/dL
Not stage I or III
ß2-M ≥ 5.5 mg/L
Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
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Multiple Myeloma: Risk Categories
Risk Factors
FISH
Cytogenetics
β2-microglobulin*
Isotype
Gene expression profile
Standard Risk
(Expected OS: 6-7 Yrs)
High Risk
(Expected OS: 2-3 Yrs)
t(11;14)
t(6;14)
Del(17p)
Del(1p)
Gain(1q)
t(4;14)*
t(14;16)
Hyperdiploidy
Hypodiploidy
Low (< 3.5 mg/L)
High (≥ 5.5 mg/L)
--
IgA
Good risk
High risk
*Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have
intermediate-risk disease.
Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Fonseca R, et al. Leukemia. 2009;23:2210-21.
Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-288. Munshi N, et al. Blood. 2011;117:4696-4700.
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Patients remaining alive, %
Patients Remaining Alive (%)
Effect of t(4;14), FISH Status, ISS Staging
and Age on OS in Multiple Myeloma
100
80
60
A vs B: P < .0001
A vs B: P < .0001
C vs D: P < .03
C vs D: P < .03
E vs F: P < .05
E vs F: P < .05
40
20
0
0
5
10
Yrs From Start of Treatment
15
Events, n/N
Estimated 4-Yr OS, % (Range)
a. ISS I/II & -FISH & aged < 65 yrs
270/935
75 (72-78)
b. ISS I/II & -FISH & aged ≥ 65 yrs
159/409
62 (56-67)
c. ISS/II/III & -FISH or ISS I & + FISH & aged < 65 yrs
278/526
48 (44-53)
d. ISS II/III & -FISH or ISS I +FISH & aged ≥ 65 yrs
136/230
38 (31-45)
e. ISS II/III & +FISH & aged < 65 yrs
241/378
37 (32-43)
f. ISS II/III & +FISH & aged ≥ 65 yrs
113/160
24 (16-32)
Avet-Loiseau H, et al. Leukemia. 2013;27:711-717.
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Initial Approach to Treatment of Myeloma
Nontransplantation candidate
(based on age, performance
score, and comorbidities)
Transplantation
candidate
Induction treatment
Induction treatment
(nonalkylator-based
induction x 4-6 cycles)
Maintenance
Stem cell harvest
Stem cell transplantation
Consolidation therapy ?
Maintenance
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Case: 43-Yr-Old Male Presents With Acute
Severe Lower Back Pain From Lifting Groceries
Patient assessment:
 X-ray of lumbar spine: L4 compression fracture, lytic
disease in L2 and L5
 Blood work: Hb 9.5 mg/L, plt 178/mm3, creatinine
1.5 mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca
9.8 mg/dL, LDH 190 U/L
 SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL,
IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains
 Bone marrow: 40% plasma cells, cytogenetics normal;
FISH: no t(4;14), t(14;16), or del(17p)
 Skeletal survey: multiple lytic lesions
Overview of Induction Regimens
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Induction Therapies: Transplantation
Eligible

NCCN Category 1
– Bortezomib/dexamethasone (VD)
– Bortezomib/thalidomide/dexamethasone (VTD)
– Bortezomib/doxorubicin/dexamethasone (PAD)
– Lenalidomide/dexamethasone (RD)

NCCN Category 2A
– Bortezomib/cyclophosphamide/dex (CyBorD)
– Bortezomib/lenalidomide/dexamethasone (VRD)

New (3/8/2013):
Carfilzomib in
combination with
lenalidomide and
dexamethasone
NCCN Category 2B
– Thalidomide/dexamethasone (TD)
– Dexamethasone
– Liposomal doxorubicin/vincristine/dexamethasone (DVD)
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.
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Phase III Trials: Novel Agent Induction for
Transplantation-Eligible Patients
Trial
Cavo[1]
IFM 2005-01[2]
HOVON-65/GMMGHD4[3]
Regimens
≥ VGPR, %
n
After
Induction
After First
ASCT
VTD x 3
TD
241
239
62
28
79
58
VD x 4
VAD
223
218
37.7
15.1
54.3
37.2
PAD x 3
VAD
371
373
42
14
62
36
PETHEMA/GEM[4]
TV
T
a2-IFN
PETHEMA/GEM[5]
E4A03[6]
74
VTD
TD
VMBCP/VBAD/B
130
127
129
60
29
36
RD
Rd
445
422
50
40
After
Maintenance
CR rate improved
by 23% (TV),
11% (T), 19%
(a2-IFN)
1. Cavo M, et al. Lancet. 2011;376:2075-2085. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629.
3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. ASH 2011. Abstract 3962. 5.
Rosiñol L, et al. Blood. 2012;120:1589-1596. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
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Lenalidomide/Dexamethasone Induction
Followed by SCT: OS
 E4A03 trial RD vs Rd
94%
 Early SCT after 4 cycles
vs continued therapy
with lenalidomide
 94% OS at 3 yrs for
those undergoing SCT
vs 78% for those
continuing protocol
therapy
Probability
 Landmark analysis:
4 mos
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
78%
Log-rank test: Chi sq = 6.971 (P = .008)
0
Early SCT: no 141
Early SCT: yes 68
Siegel D, et al. ASH 2010. Abstract 38. Reprinted with permission.
Early SCT: no (n = 141)
Early SCT: yes (n = 68)
12
132
68
24
122
64
Mo
36
53
34
48
0
0
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VTD vs TD for SCT Induction in Newly
Diagnosed Myeloma
 Median follow-up:
36 mos
[1]
Progression-free
survival
[1]
PFS
100
VTD
TD
PFS (%)
75
50
60%
48%
Events N %
71 44
TD
51 32
VTD
25
P = .042
 Estimated 3-yr OS:
86% for VTD vs
84% for TD
(P = .30)[2]
HR: 0.69 (95% CI: 0.48-0.99; P = .043)
0
0
6
12
18
24
30
Mos From Start of Consolidation Therapy
Patients at Risk, n
TD
161
153
VTD 160
154
136
142
114
125
84
86
43
53
35
21
26
1. Cavo M, et al. Blood. 2012;120:9-19. 2. Cavo M, et al. Lancet. 2010;376:2075-2085.
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Case
 Your 43-yr-old patient receives bortezomib/lenalidomide/
dexamethasone (VRD) for 3 cycles
 Re-evaluation
– M-protein not detectable in blood or urine, IFE positive
– Serum free light chain: kappa 0.8 mg/dL, lambda
4.3 mg/dL
– Bone marrow: 2% PC, 0.8% clonal PC by flow cytometry
– Skeletal survey unchanged
– CBC, creatinine, calcium within normal limits
How would you treat this patient now?
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CR to Novel Agents Correlates With Longterm PFS and OS in Elderly Patients

Retrospective analysis of frontline treatment in 3 randomized European trials
(GISMM-2001, GIMEMA MM0305, and HOVON groups; N = 1175)

Regimens: MP (n = 332), MPT (n = 332), VMP (n = 257), VMPT-VT (n = 254)
PFS
OS
1.0
Probability of OS
Probability of PFS
1.0
0.8
0.6
0.4
0.2
P < .001
0.6
0.4
0.2
P < .001
0
0
0
0.8
24
48
Mos
Gay F, et al. Blood. 2011;117:3025-3031.
0
72
CR
VGPR
24
PR
48
Mos
72
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Phase III Trials: Novel Agent Induction for
Transplantation-Ineligible Patients
Trial
IFM
99-06[1]
IFM 01/01[2]
Rajkumar SV et al[3]
MM-015[4]
VISTA[5]
Regimens
n
MP
MPT
MEL100
196
125
126
MPT
MP
Median Follow-up,
Mos
Median OS
Median PFS,
Mos
51.5
33.2 mos
51.6 mos
38.3 mos
17.8
27.5
19.4
223
218
47.5
44.0 mos
29.1 mos
24.1
18.5
RD
Rd
371
373
1-yr interim
96%*
87%*
19.1
25.3
MPR-R
MPR
MP
152
153
154
30
45.2 mos
NR
NR
31
14
13
VMP
MP
344
338
60
56.4 mos
43.1 mos
NA
NA
*Median OS not yet reached; % alive at time of follow-up is reported.
1. Facon T, et al. Lancet. 2007;370:1209-1218. 2. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670.
3. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 4. Palumbo A, et al. N Engl J Med. 2012;366:17591769. 5. San Miguel JF, et al. J Clin Oncol. 2013;31:448-455.
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MM-015: MPR Induction Plus Lenalidomide
in Newly Diagnosed Elderly MM Patients
Stratified by age
and disease stage
Newly
diagnosed
transplantationineligible
MM patients
65 yrs
of age or older
(N = 459)
Primary endpoint:
PFS
Cycles 1-9 (28-day cycles)
Cycles 10+
MPR-R
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg/day on Days 1-21
Continued
lenalidomide
MPR
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg/day on Days 1-21
Discontinued
lenalidomide,
placebo added
MP
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Placebo on Days 1-21
Continued
placebo
Double-blind treatment phase
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.
Lenalidomide 25 mg/day
± Dexamethasone
Updated analysis of randomized, multicenter, placebo-controlled phase III trial
Disease progression

Open-label extension/
follow-up phase
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MM-015: Progression-Free Survival
65-75 Yrs of Age
70% Reduced Risk of Progression
All Patients
66% Reduced Risk of Progression
Median PFS, Mos
100
MPR-R
31
14
MPR
15
13
MP
12
MPR-R
31
MPR
MP
75
75
MPR-R vs MPR:
HR: 0.49 (P < .001)
Patients (%)
Patients (%)
Median PFS, Mos
100
50
MPR-R vs MP:
HR: 0.40 (P < .001)
25
HR: 0.301
(P < .001)
HR: 0.618
(P = .006)
50
25
0
0
0
5
10
15
20 25
Mos
30
35
40
Data cutoff : May 11, 2010
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.
0
10
20
30
40
Mos
Palumbo A, et al. ASH 2011. Abstract 475.
Reprinted with permission.
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MM-015: Overall Survival
All Patients
65-75 Yrs of Age
MPR-R
MPR
MP
100
75
75
Patients (%)
Patients (%)
MPR-R
MPR
MP
100
50
25
50
25
0
0
0
0
10
20
30
Mos
40
50
Data cutoff : February 28, 2011
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.
0
10
20
30
40
Mos
Palumbo A, et al. ASH 2011. Abstract 475.
Reprinted with permission.
50
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VISTA: VMP vs MP in Patients With
Multiple Myeloma > 65 Yrs of Age
Median OS benefit: 13.3 mos
5-yr OS rates: 46.0% vs 34.4%
100
Patients Alive (%)
90
80
70
60
50
40
30
Group n
20
10
Events Median
MP
338
211
VMP
344
176
43.1
56.4
0
0
6
Pts at Risk, n
338 301
344 300
HR (95% CI)
P Value
0.695 (0.567-0.852)
.0004
12
18
24
30
36
262
288
240
270
216
246
196
232
168
216
Delforge M, et al. Eur J Haematol. 2012;89:16-27.
42
Mos
153
199
48
54
60
66
72
133
176
112
158
61
78
24
34
3
1
78
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VMPT + VT Maintenance vs VMP as
Frontline Therapy
PFS
1.00
VMPT VMP
Patients (%)
0.75
Median 35.3 months
5 yr PFS
5 yr TTNT
5 yr OS
0.50
0.25
Median 24.8 months
HR 0.58 (95% CI, 0.47-0.71, P < 0.0001)
0.00
0
10
20
30
40
50
60
70
Palumbo A, et al. ASH 2012. Abstract 200. Reprinted with permission.
29%
41%
61%
P
13% <.0001
19% <.0001
51%
.01
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Novel Agents for Frontline Treatment of
Myeloma
Study
Treatment
n
Outcomes
Safety
Richardson et al[1]
RVD
66
≥ VGPR: 67%; 18-mo PFS:
75%; 24-mo OS: 97%
Sensory neuropathy: 80%
(mostly grade 1);
fatigue: 64% (mostly grade 1)
Jakubowiak et al[2]
Carfilzomib/
Rd
53
≥ nCR: 62%
ORR: 98%
Only grade 1/2 PN
Ixazomib/
Rd
15
No DLT up to 2.23 mg/m2
ixazomib;
MTD: 2.97 mg/m2/wk
Only grade 1 PN in 3 pts;
6 pts required dose reductions
due to AEs
Elotuzumab/
Rd
73
ORR: 82%
≥ VGPR: 48%
Grade 3/4 cytopenias: 16%,
grade 1/2 diarrhea: 56%
Vorinostat/
RVD
11
1 pt completed 8 cycles,
1 completed 4 cycles and
transplantation
DLTs (1 each): syncope, grade 3
ALT elevation; PN: 6 pts
Berdeja et al[3]
Lonial et al[4]
Kaufman et al[5]
1. Richardson PG, et al. Blood. 2010;116:679-686. 2. Jakubowiak, et al. Blood. 2012;120:1801-1809.
3. Berdeja JG, et al. ASH 2011. Abstract 479. 4. Lonial S, et al. ASH 2011. Abstract 303.
5. Kaufman JL, et al. ASH 2010. Abstract 3034.
Maintenance Therapy
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Case: 43-Yr-Old Male With Stage I
Myeloma
 He received VRD induction x 3 cycles and achieved CR.
He then received melphalan 200 mg/m2 and ASCT, and by
Day 60, he was fully recovered
 Patient assessment
– SPEP, UPEP no monoclonal protein
– IFE negative, normal serum free light chains ratio
– Bone marrow normal, no clonal plasma cells by flow
cytometry
– Findings consistent with stringent CR
How would you treat this patient now?
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Phase III Maintenance Studies
Trial
Planned
Accrual,
N
Regimen
Outcomes
Nordic MSG 15[1]
400
Bortezomib x 21 wks vs no maintenance
CR/nCR:
54% vs 35%
IFM 2005-02[2]
614
Lenalidomide vs placebo as maintenance
following first or second ASCT
4-yr PFS:
60% vs 33%
CALGB 100104[3]
460
Lenalidomide vs placebo as maintenance
therapy after ASCT
Median TTP:
46 vs 27 mos
UPFRONT[4]
423
Bortezomib/dexamethasone
vs bortezomib/thalidomide/dexamethasone
vs bortezomib/melphalan/prednisone
CR/nCR:
30% vs 40%
vs 33%
1. Mellqvist UH, et al. ASH 2009. Abstract 530. 2. Attal M, et al. N Engl J Med. 2012;366:1782-1791. 3.
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. 4. Niesvizky R, et al. ASH 2011. Abstract 478.
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IFM 2005-02: Lenalidomide vs Placebo
Maintenance After ASCT for Myeloma
Patients younger
than 65 yrs
of age with
nonprogressive
disease, ≤ 6 mos
after first-line
ASCT
(N = 614)
Consolidation:
Lenalidomide
25 mg/day on
Days 1-21 of
every 28 days for
2 mos
Placebo
(n = 307)
Lenalidomide
10-15 mg/day
(n = 307)

Stratified based on diagnostic β2-M, del(13q), VGPR after ASCT

Primary endpoint: PFS

Secondary endpoints: CR, TTP, OS, feasibility of long-term lenalidomide
Attal M, et al. N Engl J Med. 2012;366:1782-1791.
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IFM 2005-02: PFS and OS
PFS
OS
100
75
75
Lenalidomide
23%
50
41%
25
OS (%)
PFS (%)
Placebo
100
Lenalidomide
50
25
Placebo
HR: 0.50; P < .001
0
P = .29
0
0
6
12 18 24 30 36
Mos of Follow-up
Pts at Risk, n
Lenalidomide 307 267 236 216 172
Placebo
307 255 211 169 102
103
57
49
22
42 48
10
6
1
1
Attal M, et al. N Engl J Med. 2012;366:1782-1791.
0
6
12 18 24 30 36
Mos of Follow-up
Pts at Risk, n
Lenalidomide 307 298 292 282 240
Placebo
307 297 282 279 247
162
167
92
87
42 48
38
31
5
6
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IFM 2005-02: Second Malignancies at 3 Yrs
Type of Lesion, n
Placebo
(n = 302)
Lenalidomide
(n = 306)
Total
(N = 608)
5
13
18
 AML/MDS
4
5
9
 ALL
0
3
3
 Hodgkin’s lymphoma
0
4
4
 Non-Hodgkin’s lymphoma
1
1
2
4
10
14
 Esophageal/hypopharynx
0
1
2
 Colon
0
3
3
 Prostate
1
2
3
 Breast
0
2
2
 Renal
1
1
2
 Melanoma
1
0
1
Basal cell carcinoma
3
5
8
Total
6
25
31
Hematologic
Nonhematologic
Risk factors for second malignancies (P = .01): treatment (placebo vs lenalidomide), age (≤ 55 vs
> 55 yrs), sex (male vs female), ISS stage (I + II vs III), induction with DCEP (yes vs no; P = .02)
Attal M, et al. N Engl J Med. 2012;366:1782-1791.
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CALGB 100104: Lenalidomide vs Placebo
as Maintenance Therapy After ASCT
1.0
1.0
Lenalidomide
0.8
0.6
Lenalidomide
0.4
0.2
Probability of OS
Probability of PFS
2-sided P < .001
0.8
0.6
Placebo
0.4
2-sided P = .03
0.2
Placebo
0
0
0
10 20 30 40 50 60
Mos Since Autologous HSCT
Outcome
70
0
10
20
30
40
50
60
70
Mos Since Autologous HSCT
Lenalidomide
(n = 231)
Placebo
(n = 229)
P Value
HR
(95% CI)
Median PFS, mos
46
27
.001
NR
3 yr OS, %
88
80
NR
0.62
(0.40-0.95)
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
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CALGB 100104: Subgroup Analysis
TTP Subgroup
Lenalidomide induction
Yes
No
Thalidomide induction
Yes
No
Elevated β2-M level
Yes
No
CR at randomization
Yes
No
HR (95% CI)
P Value for Interaction
.06
1.10 (0.58-1.7)
0.57 (0.25-0.89)
.36
0.57 (0.17-0.98)
0.86 (0.49-1.2)
.76
0.67 (0.17-1.2)
0.77 (0.44-1.1)
.38
0.53 (-0.001 to 1.1)
0.86 (0.53-1.2)
-2
-1
0
1
2
OS Subgroup
Lenalidomide induction
Yes
No
Thalidomide induction
Yes
No
Elevated β2-M level
Yes
No
CR at randomization
Yes
No
HR (95% CI)
P Value for Interaction
.03
1.40 (0.43-2.4)
0.18 (-0.32 to 0.67)
.05
0.01 (-0.62 to 0.64)
0.89 (0.29-1.5)
.56
0.37 (-0.39 to 1.1)
0.58 (0.06-1.1)
.64
0.25 (-0.67 to 1.2)
0.53 (0.05-1.0)
-2
-1
0
1
2
Placebo Better Lenalidomide Better
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
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HOVON-65 Phase III Trial: Bortezomib in
Induction and Maintenance
Newly
diagnosed MM
patients with
stage II/III
disease aged
18-65 yrs
(N = 744)
PAD x 3 cycles
Bortezomib 1.3 mg/m2 on
Days 1, 4, 8, 11 +
Doxorubicin 9 mg/m2 on
Days 1-4 +
Dexamethasone 40 mg on
Days 1-4, 9-12, 17-20
(n = 371)
Stem cell
collection and
transplantation
Bortezomib
1.3 mg/m2
every 2 wks
2 yrs
VAD x 3 cycles
Vincristine 0.4 mg on Days 1-4 +
Doxorubicin 9 mg/m2
on Days 1-4 +
Dexamethasone 40 mg
on Days 1-4, 9-12, 17-20
(n = 373)
Stem cell
collection and
transplantation
Thalidomide
50 mg/day
Stem cell collection: cyclophosphamide/doxorubicin/dexamethasone + granulocyte colonystimulating factor
Transplantation: ASCT + melphalan 200 mg/m2. Allogeneic stem cell transplantation with no
maintenance offered when possible. German patients enrolled through GMMG underwent 2 ASCTs.
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
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HOVON-65 Phase III Trial of Bortezomib in
Induction and Maintenance: PFS and OS
PFS
OS
100
100
VAD
PAD
80
OS (%)
PFS (%)
75
50
n
25
F
VAD 414 273
PAD 413 242
P = .008
0
0
12
VAD
PAD
60
40
n
20
VAD 414 130
PAD 413 109
P = .07
0
36
24
48
60
0
12
D
Mos
Pts at Risk, n
Arm A:VAD 414
Arm B: PAD 413
325
356
227
261
120
140
36
48
60
200
224
86
104
16
18
24
Mos
44
51
8
9
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
Pts at Risk, n
Arm A:VAD 414
Arm B: PAD 413
361
374
327
338
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Maintenance: Why Not?
 No survival advantage in IFM or MM-015 trials
– Longer follow-up needed in all trials
 Cost ~ $8000/mo
 Toxicities
– Myelosuppression
– Second primary malignancies
– Quality of life
 Unknown response to higher doses of lenalidomide at
relapse
– Potential development of resistant clones
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Case: What Would You Do if the Initial
Patient Were 78 Yrs of Age Instead of 43?
Patient assessment:
 X-ray of lumbar spine: L4 compression fracture, lytic disease in
L2,5
 Blood work: Hb 9.5 mg/L, plt 178k/mm3, creatinine 1.5 mg/dL,
albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca 9.8 mg/dL, LDH 190 U/L
 SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL,
IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains
 Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no
t(4;14), t(14;16) or del(17p)
 Skeletal survey: multiple lytic lesions
In addition to zoledronic acid, what would
you choose for induction therapy?
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Case: 78-Yr-Old Male With Stage I
Myeloma
 He received VD induction x 8 cycles and achieved very
good PR
How would you treat this patient now?
Management of Adverse Events
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Risk Assessment for VTEs in Patients
Receiving Thalidomide or Lenalidomide
 VTE prophylaxis for individual risk factors or myelomarelated risk factors (eg, hyperviscosity)
– If ≤ 1 risk factor present, aspirin 81-325 mg/day
– If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin
40 mg/day) or full-dose warfarin (target INR: 2-3)
 VTE prophylaxis for myeloma therapy–related risk factors
(eg, high-dose dexamethasone, doxorubicin, multiagent
chemotherapy)
– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose
warfarin (target INR: 2-3)
Palumbo A, et al. Leukemia. 2008;22:414-423.
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Current Treatment of MM Bone Disease
 Bisphosphonates
– Pamidronate
– Zoledronic acid
 Denosumab (investigational)
 Surgical procedures
– Vertebroplasty
– Balloon kyphoplasty
 Radiotherapy
 Treatment of myeloma
Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.
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Bisphosphonates and Osteonecrosis
 Uncommon complication
causing avascular necrosis of
maxilla or mandible
 Suspect with tooth or jaw pain
or exposed bone
 May be related to duration of
therapy
 Incidence unknown but 2004
IMF Web-based survey
revealed
– 5% incidence with
zoledronic acid
– 4% incidence with pamidronate
Durie BG, et al. N Engl J Med. 2005;353:99-102.
Peripheral Neuropathy
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Thalidomide- and Bortezomib-Emergent
Peripheral Neuropathy: Symptoms
Peripheral Neural Tract
Sensory
Motor
Autonomic
Symptom(s)
Thalidomide
Bortezomib
Hypo-esthesia
paresthesia: numbness,
tingling, pin-prick sensation
hyperesthesia
Common
Common
Ataxia, gait disturbance
Rare
Rare
Neuropathic pain
Rare
Common
Weakness
Rare
Rare
Tremor
Common
Rare
Gastrointestinal
Constipation
Constipation
Others
Impotence
Bradycardia
Orthostatic
Hypotension
1. Chaudhry V, et al. Neurology 2002;59:1872-1875. 2. Mileshkin L, et al. Leuk Lymphoma. 2006;47:22762279. 3. Argyriou AA, et al. Blood 2008;112:1593-1599. 4. Cata JP, et al. J Pain 2007;8:296-306.
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Proposed Guidelines for Bortezomib Dose
Modification for Management of PN
Severity of PN Signs/Symptoms
Modification of Dose and Regimen
Grade 1 (paresthesia, weakness,
and/or loss of reflexes without pain or
loss of function)
Reduce current bortezomib dose by 1 level (1.3 to 1.0 to 0.7
mg/m2). For patients receiving a twice-weekly schedule, change
to a once-per-wk schedule using the same dose. For patients
with previous PN, consider starting with 1.3 mg/m2 once per wk
Grade 1 with pain or grade 2 (no pain
but interfering with basic activities of
daily living)
For patients receiving twice per wk bortezomib, reduce current
dose by 1 level or change to a once-per-wk schedule using the
same dose
For patients receiving bortezomib on a once-per-wk schedule:
reduce current dose by 1 level or consider temporary
discontinuation; upon resolution (grade ≤ 1), restart once-per-wk
dosing at lower dose level in cases of favorable benefit-to-risk
ratio
Grade 2 with pain, grade 3
(limiting self-care and activities
of daily living), or grade 4
Discontinue bortezomib
 Subcutaneous bortezomib substantially decreases PN
Richardson PG, et al. Leukemia. 2012;26:595-608.
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Drugs, Dietary Modifications, and
Supplements Used for Neuropathy
 Vitamins/supplements
– Multi-B complex vitamins with
B1, B6, B12
– Folic acid
– Vitamin E
 FDA-approved drugs for
diabetic neuropathy
– Duloxetine
– Pregabalin
 Amino acid supplements
– Magnesium for muscle cramps
– Acetyl-carnitine
– Potassium (ie, apple cider
vinegar, bananas, oranges) for
muscle cramps
– α-lipoic acid
 Miscellaneous
– Topical creams, eg, cocoa
butter (rich in vitamin E)
– Tonic water (quinine) for leg
cramps
Colson K, et al. Clin J Oncol Nurs. 2004;8:473-480. Maestri A, et al. Tumori. 2005;91:135-138.
Pisano C, et al. Clin Cancer Res. 2003;9:5756-5767.
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Conclusions
 All combination therapies provide high response rates during
induction: the optimal choice depends on patient characteristics,
patient and physician preference and toxicity profiles
 Doublets or triplets are appropriate induction for transplant
ineligible patients
 Cytogenetics have the strongest prognostic significance
 Maintenance therapy is now an accepted standard for most
myeloma patients, although gains need to balanced with cost
and QOL
 Best treatment of neuropathy is prevention
Optimal Treatment of Relapsed/
Refractory Multiple Myeloma
This program is supported by educational grants from
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Symptoms and End-Organ Damage

Bones
– Pain
– Lytic lesions, fractures
– High calcium

Kidneys
– Elevated creatinine
– Reversible renal failure

Hematopoietic organ
– Anemia
– Reversible cytopenias

Peripheral nerves

Humoral immune system
– Low Ig levels
– Hyperviscosity
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Multiple Myeloma: Risk Categories
Risk Factors
Standard Risk
(Expected OS: 6-7 Yrs)
High Risk
(Expected OS: 2-3 Yrs)
t(11;14)
t(6;14)
del(17p)
t(4;14)*
t(14;16)
Hyperdiploidy
Hypodiploidy
del(13q)
β2-M*
Low (< 3.5 mg/L)
High (≥ 5.5 mg/L)
PCLI
< 3%
High (≥ 3%)
--
IgA
Good risk
High risk
FISH
Cytogenetics
Isotype
Gene expression profile
*Patients with t(4;14), β2-M < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease.
Kumar SK, et al. Mayo Clin Proc. 2009 Dec;84(12):1095-1110. Fonseca R, et al. Leukemia. 2009;23:221021. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-88. Munshi N, et al. Blood. 2011;117:4696-4700.
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Considerations in Patients With
Relapsed/Refractory Myeloma
 Types of previous therapy
 Response to previous therapy
 Patient characteristics and other prognostic factors
– Older than 65 yrs
– Increased β2-M, decreased serum albumin, low platelet count
– Cytogenetic abnormalities: t(4;14)
– Renal dysfunction
– Up to 50% of patients with MM have renal dysfunction
– Between 20% and 30% of patients have concomitant renal failure
– Extensive bone disease; extramedullary MM
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Facon
T, et al. Blood. 2001;97:1566-1571. Barlogie B, et al. Blood. 2004;103:20-32. Fonseca R, et al. Cancer Res.
2004;64:1546-1558. Kyle RA. Stem Cells. 1995;13(suppl 2):56-63. Bladé J, et al. Arch Intern Med.
1998;158:1889-1893.
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Case 1
 A 65-yr-old male with ISS stage 1 MM received lenalidomide
plus low-dose dexamethasone induction therapy for 4 cycles
followed by HDT consolidation treatment. He declined
lenalidomide maintenance treatment and was in CR for 2 yrs
 He now presents with M protein of 0.6 g/dL and no anemia or
other abnormalities on skeletal survey
 Hb is 14 g/dL, UPEP is negative, serum free light chain ratio is
2:1, and creatinine and calcium levels are normal
 3 mos later, repeat testing shows M protein of 0.8 g/dL
 6 mos later, M protein is 0.9 g/dL with no changes in the other
laboratory values
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When to Consider Retreatment
 Differences between biochemical relapse and symptomatic
relapse need to be considered
 Patients with asymptomatic rise in M protein can be observed to
determine the rate of rise and nature of the relapse
Caveat: patients with known aggressive or high-risk disease should
be considered for salvage even in the setting of biochemical relapse
 CRAB criteria are still listed as the indication to treat in the
relapse setting
C: Calcium elevation (> 11.5 mg/L or ULN)
R: Renal dysfunction (serum creatinine > 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g < normal)
B: Bone disease (lytic lesions or osteoporosis)
Optimal Salvage Treatment
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Case 2
 A 65-yr-old female presents with ISS stage 2 MM. She is
treated with RVD followed by ASCT. Posttransplantation,
she achieves a VGPR and is started on lenalidomide
maintenance therapy
 After 2 yrs, she progresses on lenalidomide maintenance
therapy. She has no neuropathy
 M protein is 1.2 g/dL, Hb is 9.3 g/dL, calcium is normal,
serum free light chain ratio is 6:1, and IgG is 2900 mg/dL
 Skeletal survey shows new lytic disease. UPEP is
negative, bone marrow shows 10% to 20% plasma cells
with normal cytogenetics
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Overview of Phase III Trials With Len and
Bortezomib in Relapsed/Refractory MM
ORR, CR or ≥ VGPR,
%
nCR, %
%
Regimen
Trial
Len + dex
MM-009[1]
61
24
Len + dex
MM-010[2]
60
APEX[3]
MMY-3001[4]
Bortezomib
Vdox
DOR,
Mos
TTP or
PFS,
Mos
Median
OS,
Mos
NE
16
11
25
NE
17
11
43
16
NE
8
6
30
44
13
27
10
9
NE
35[5]
1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med.
2007;357:2123-2132. 3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin
Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412.
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Case 3
 A 63-yr-old male with a history of relapsed MM after
induction with RVD and transplantation presents now with
relapse on maintenance therapy with lenalidomide. He is
started on salvage therapy with RVD
 After 2 cycles, he has rapid and significant progression
with progressive anemia and creatinine increasing to
1.5 mg/dL
 M protein increases to 2.5 g/dL, Hb is 9 g/dL, creatinine is
1.5 mg/dL, LDH is 250 mg/dL, marrow is packed, genetics
shows del(17p)
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Carfilzomib
Approved for patients who progress within 60 days of last therapy and have received ≥ 2
therapies including bortezomib and an IMiD.
Trial
N*
Population
Previous
Lines, n
ORR,
%
MR/SD,
%
Median TTP,
Mos
003-A0[1]
39
Relapsed/
refractory
>2
18
8/41
6.2
003-A1[2]
257
Relapsed/
refractory
≥2
24
12/--
--
004 (Bz exposed)[3]
35
Relapsed/
refractory
1-3
17
12/35
4.6
004 (Bz naive)[4] 20 mg/m2
20/27 mg/m2
59
67
Relapsed/
refractory
1-3
42
52
17/22
12/15
8.3
NR
006 (combo with len/dex)[5]
50
Relapsed/
refractory
1-3
78
2/8
--
*Evaluable for response.
Neuropathy from phase II experience: 9.6% grades 1/2 and 1.4% grade 3
1. Jagannath S, et al. ASCO 2009. Abstract 8504. 2. Siegel DSD, et al. ASCO 2011. Abstract 8027. 3. Vij R,
et al. Br J Haematol. 2012;158:739-748. 4. Vij R, et al. Blood. 2012;119:5661-570. 5. Wang M, et al. ASCO
2011. Abstract 8025.
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PX-171-003A1: Phase II Trial of Carfilzomib
in Relapsed/Refractory MM
Study population (N = 266)
 Progression during treatment or within
60 days of completion of the
treatment, or stable disease (SD) as a
best response = refractory to last
regimen
 Cycle 1: 20 mg/m2 IV
 Cycles 2-12: 27
mg/m2 IV
 Neuropathy: Grade 1 or 2 without pain
 Primary endpoint: ORR (CR + VGPR + PR [IMWG criteria])
 Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS,
TTP, OS, safety
Siegel DS, et al. Blood. 2012;120:2817-2825.
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003A1: Overall Response Rate
All Patients
(n = 257)
Patients With Unfavorable
Cytogenetics/FISH Markers
(n = 71)
61 (23.0)
21 (3.0)
CR
1 (0.4)
0 (0)
VGPR
13 (5.1)
3 (4.2)
PR
47 (18.3)
18 (25.4)
MR
34 (13.2)
3 (4.2)
SD
81 (31.5)
28 (39.4)
PD
69 (26.8)
15 (21.1)
Not evaluable
12 (4.7)
4 (5.6)
Response Category, n (%)
ORR
Median DOR: 7.8 months (95% CI: 5.6-9.2)
Siegel DS, et al. Blood. 2012;120:2817-2825.
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003A1: Progression-Free Survival
Proportion of Patients Alive
and Without Progression (%)
100
75
Median PFS: 3.7 mos (95% CI: 2.8-4.6)
50
25
Censored observations
Confidence band
0
0.0
2.5
10.0
5.0
12.5
7.5
Mos From Start of Treatment
Siegel DS, et al. Blood. 2012;120:2817-2825.
15.0
17.5
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003A1: Overall Survival (N = 266)
Proportion of Patients Alive (%)
100
Median OS: 15.6 mos (95% CI: 13.0-19.2)
75
50
25
Censored observations
Confidence band
0
0
3
6
9
12
15
18
21
Mos From Start of Treatment
Siegel DS, et al. Blood. 2012;120:2817-2825.
24
27
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003A1: Common Hematologic AEs
AEs Regardless of Relationship, %
All Grades
Grade 3
Grade 4
Anemia
46
22
2
Thrombocytopenia
39
17
12
Lymphopenia
23
18
2
Siegel DS, et al. Blood. 2012;120:2817-2825.
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003A1: Common Nonhematologic AEs
Nonhematologic AE, n (%)
Fatigue
Nausea
Dyspnea
Diarrhea
Pyrexia
Headache
Upper respiratory tract infection
Increased serum creatinine
Vomiting
Peripheral neuropathy
Hypophosphatemia
Pneumonia
Hyponatremia
Renal failure (acute)
Febrile neutropenia
Tumor lysis syndrome
Siegel DS, et al. Blood. 2012;120:2817-2825.
All Grades
130 (49.0)
119 (45.0)
90 (34.0)
86 (32.0)
83 (31.0)
74 (28.0)
71 (27.0)
67 (25.0)
59 (22.2)
33 (12.4)
32 (12.0)
32 (12.0)
31 (11.7)
13 (4.9)
2 (0.8)
1 (0.4)
Grade 3/4
20 (7.5)
5 (1.9)
9 (3.4)
2 (0.8)
4 (1.5)
5 (1.9)
12 (4.5)
7 (2.6)
2 (0.8)
3 (1.1)
16 (6.0)
25 (9.4)
22 (8.3)
9 (3.4)
2 (0.8)
0 (0)
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Results: Cardiac Analysis
003-A0
(n = 46)
003-A1
(n = 266)
004
(n = 164)
005
(n = 50)
All Patients
(N = 526)
Cardiac arrhythmia
5 (10.9)
38 (14.3)
20 (12.2)
7 (14.0)
70 (13.3)
Grade 3/4/5
0
8 (3.0)
3 (1.8)
1 (2.0)
12 (2.3)
Cardiac failure
6 (13.0)
16 (6.0)
9 (5.5)
7 (14.0)
38 (7.2)
Grade 3/4/5
4 (8.8)
13 (4.9)
9 (5.5)
4 (8.0)
30 (5.7)
Cardiomyopathy
2 (4.3)
4 (1.5)
2 (1.2)
1 (2.0)
9 (1.7)
Grade 3/4
1 (2.2)
2 (0.8)
0
0
3 (0.6)
3 (6.5)
11 (4.1)
4 (2.4)
0
18 (3.4)
1 (2.2)
6 (2.3)
0
0
7 (1.4)
Dose reduction
0
5 (1.9)
1 (0.6)
0
6 (1.1)
Discontinuation
6 (13.0)
16 (6.0)
8 (4.9)
2 (4.0)
28 (5.3)
Cardiac deaths*
0
4 (1.5)
1 (0.6)
0
5 (1.0)
Cardiac component to other deaths†
0
3 (1.1)
0
0
3 (1.1)
SMQ grouping, n (%)
Ischemic heart disease
Grade 3
Patient disposition in response to cardiac AEs
*003-A1, 3 cardiac arrest, 1 dyspnea; 004, 1 cardiac disorder. †Three deaths reported as disease
progression by the investigator.
Lonial S, et al. ASH 2012. Abstract 4037. Reprinted with permission.
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Survival Distribution Function
PX-171-004: PFS With Carfilzomib in
Bortezomib-Naive Patients
n Median 95% CI
59
8.2
6.0-12.3
Cohort 1: 20 mg/m2
1.00
Cohort 2: 20/27 mg/m2 67
NR
11.3-NE
0.75
0.50
0.25
0
0
5
Pts at Risk
59
10
15
20
25
Mos From the Start of Treatment
33
19
7
4
(n)
67
38
Vij R, et al. Blood. 2012;119:5661-570.
33
1
0
30
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CCd: Time to Onset for Best Response in
Newly Diagnosed MM Patients
• CCd: Carfilzomib (20/36 mg/m2), cyclophosphamide, dexamethasone
• AEs: Grade 4: neutropenia (5%); Grade 3/4: infection (10%), cardiac
(5%), renal failure (5%); discontinued due to AEs: 0%
1.00
PR
% of Patients
0.75
VGPR
0.50
sCR/CR/nCR
0.25
Median treatment duration, cycles (range): 5 (1-9)
0.0
0.0
2.5
5.0
7.5
Months
Palumbo A, et al. Blood 2012;120:730
10.0
12.5
Management of Adverse Events
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Case 4
 A 63-yr-old male with a history of relapsed MM after
induction with RVD and transplantation now presents with
relapse on maintenance therapy with lenalidomide. He is
started on salvage therapy with VCD
 After 2 cycles of VCD, he develops PN with pain in the
lower extremities. He is currently on twice-weekly dosing
of IV bortezomib
 Laboratory tests show a PR and normal renal function,
and Hb is 10.5 g/dL (improved). Examination shows
painful grade 2 PN in the lower extremities
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Proposed Guidelines for Bortezomib Dose
Modification for Management of PN
Severity of PN Signs/Symptoms
Modification of Dose and Regimen
Grade 1 (paresthesia, weakness,
and/or loss of reflexes without pain or
loss of function)
Reduce current bortezomib dose by 1 level (1.3 - 1.0 - 0.7
mg/m2). For patients receiving a twice-weekly schedule, change
to a once-per-wk schedule using the same dose. For patients
with prior PN, consider starting with 1.3 mg/m2 once per wk
Grade 1 with pain or grade 2 (no pain
but interfering with basic activities of
daily living)
For patients receiving twice-weekly bortezomib, reduce current
dose by 1 level or change to a once-per-wk schedule using the
same dose
For patients receiving bortezomib on a once-per-wk schedule,
reduce current dose by 1 level, OR consider temporary
discontinuation; upon resolution (grade ≤ 1), restart once-per-wk
dosing at lower dose level in cases of favorable benefit-to-risk
ratio
Grade 2 with pain, grade 3
(limiting self-care and activities
of daily living), or grade 4
Discontinue bortezomib

Subcutaneous bortezomib causes less peripheral neuropathy
Richardson PG, et al. Leukemia. 2011;26:595-608.
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Risk Assessment for VTEs in Patients
With MM Receiving Thal or Len
 VTE prophylaxis for individual risk factors or myelomarelated risk factors (eg, hyperviscosity)
– If ≤ 1 risk factor present, aspirin 81-325 mg/day
– If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin
40 mg/day) or full-dose warfarin (target INR: 2-3)
 VTE prophylaxis for myeloma therapy–related risk factors
(eg, high-dose dexamethasone, doxorubicin, multiagent
chemotherapy)
– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose
warfarin (target INR: 2-3)
Palumbo A, et al. Leukemia. 2008;22:414-423.
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Len/Dex: Cytopenia Management
 Monitoring CBCs
– At least biweekly
monitoring
– Standard dose reductions
 Neutropenia
– For grade ≥ 3, monitor
WBCs and consider
G-CSF prophylaxis or
lenalidomide dose
reduction
Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.
 Thrombocytopenia
– For grade ≥ 3, monitor
platelet count and
consider interrupting
treatment or dose
reductions
 Anemia
– Consider ESAs for Hb
< 10 g/dL
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Herpes Zoster Prophylaxis With
Bortezomib Treatment
 Immunocompromised patients at risk of developing VZV
infection
 Bortezomib is associated with increased risk of VZV
infection[1]
 Acyclovir and other antiviral prophylaxis appear effective
at preventing VZV infection in patients treated with
bortezomib for MM (with or without corticosteroids)[2]
 Vaccine not recommended
1. Chanan-Khan AA, et al. J Clin Oncol. 2008;26:4784-4790.
2. Vickrey E, et al. Cancer. 2009;115:229-232.
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Renal Dysfunction
 To avoid renal failure
– Maintain hydration
– Avoid use of NSAIDs
– Avoid IV contrast
– Plasmapheresis (NCCN category 2B)
 Renal dysfunction is not a contraindication to
transplantation
 With chronic use of bisphosphonates, it is crucial to
monitor for renal dysfunction
NCCN Clinical Practice Guidelines: Multiple Myeloma (V.1.2013).
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Lenalidomide Starting Dose
Adjustment for Renal Impairment
Category
Moderate renal impairment
Severe renal impairment
End-stage renal disease
Lenalidomide [package insert].
Renal Function
(Cockcroft-Gault)
CLcr, mL/min
Dose
30-60
10 mg
Every 24 hr
< 30
(not requiring dialysis)
15 mg
Every 48 hr
< 30
(requiring dialysis)
5 mg
Once daily
(on dialysis days,
administer following
dialysis)
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Current Treatment of MM Bone Disease
 Bisphosphonates
– Pamidronate
– Zoledronic acid
 Denosumab (investigational)
 Surgical procedures
– Vertebroplasty
– Balloon kyphoplasty
 Radiotherapy
 Treatment of myeloma
Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.
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Bisphosphonates and Osteonecrosis

Uncommon complication causing
avascular necrosis of maxilla or
mandible

Suspect with tooth or jaw pain or
exposed bone

May be related to duration of therapy

Incidence unknown but 2004 IMF
web-based survey revealed:
– 5% incidence with
zoledronic acid
– 4% incidence with pamidronate
Durie BG, et al. N Engl J Med. 2005;353(1):99-102.
Novel Strategies
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Case 5
 A 63-yr-old man, with a history of relapsed MM after
induction with RVD and transplantation, relapsed on
maintenance therapy with lenalidomide and progressed
after 2 cycles of RVD
 M protein increased to 2.5 g/dL, Hb was 9 g/dL, creatinine
1.5 mg/dL, LDH 250 mg/dL, marrow was packed, and
cytogenetics showed del(17p)
 Carfilzomib was begun and the dose increased to 36
mg/m2 with stable disease
 After 7 cycles of carfilzomib, he has progressive anemia
and M-protein increase of 0.9 g/dL
What would you recommend now?
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PX-171-006: Phase II Trial of Carfilzomib
Plus Len/Dex in Relapsed/Refractory MM
Carfilzomib
20/27 mg/m2 IV
20 mg/m2 cycle 1 Days 1 and 2 only,
27 mg/m2 all days, all cycles thereafter
D15/D16
D8/D9
D1/D2
Week 1
D1
Dexamethasone
40 mg/day PO
Week 2
D8
Week 3
D15
Response (N = 51)
CR/nCR
VGPR
PR
MR
SD
ORR
Niezvizky R, et al. Clin Cancer Res. 2013;19:2248-2256.
Week 4: rest
Lenalidomide D1-D21
25 mg/day PO
D22
n (%)
12 (24)
9 (18)
19 (37)
1 (2)
3 (6)
40 (78)
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MM-002: Study Design
 Open-label, randomized phase I/II trial[1]
– Phase I portion previously presented[2]
Patients with
relapsed/
refractory MM
Pomalidomide 4 mg on Days 1-21 +
Low-Dose Dexamethasone 40 mg/wk
28-day cycle
(n = 113)
PD
(N = 221)
Pomalidomide* 4 mg on Days 1-21
28-day cycle
(n = 108)
Primary endpoint: PFS
Secondary endpoints: ORR, duration
of response, OS, safety
*Option to add low-dose dexamethasone
40 mg/wk in cases of PD or no response after
4 treatment cycles (n = 61).
Anticoagulants and granulocyte colony-stimulating factor added after cycle 1
Erythroid growth factors, bisphosphonates, platelet, and/or RBC transfusions added as clinically indicated
1. Richardson PG, et al. ASH 2011. Abstract 634. 2. Richardson PG, et al. ASH 2010. Abstract 864.
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clinicaloptions.com/oncology
MM-002: Response and Survival
Outcomes
Outcome
Pomalidomide +
Low-Dose Dexamethasone
Pomalidomide
(n = 113)
(n = 108)
 ORR, %
34
13
 Median time to response, mos
1.9
2.9
 Median duration of response, mos
7.9
8.5
 Median PFS, mos
4.7
2.7
 Median OS, mos
16.9
14
Overall population
• For patients with PD as best response
Double-refractory population
5.4
(n = 69)
(n = 64)
 ORR, %
30
16
 Median time to response, mos
1.8
2.0
 Median duration of response, mos
6.5
8.3
 Median PFS, mos
3.9
2.0
 Median OS, mos
13.7
12.7
• For patients with PD as best response
Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.
4.6
Multiple Myeloma: Case-Based Workshops With the Experts
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MM-002: Adverse Events
Grade 3/4 Adverse Event in ≥ 5%
Patients, %
Pomalidomide +
Low-Dose Dexamethasone
(n = 112)
Pomalidomide
(n = 107)
38
45
4
7
19
21
5
9
21
17
 Pneumonia
19
8
 Fatigue
10
8
Hematologic
 Neutropenia
• Requiring dose reduction
 Thrombocytopenia
• Requiring dose reduction
 Anemia
Nonhematologic
Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.
Multiple Myeloma: Case-Based Workshops With the Experts
clinicaloptions.com/oncology
MM-003: Pomalidomide and Low-Dose Dex
in Relapsed/Refractory Myeloma
 Randomized, phase III trial
Patients with relapsed/
refractory multiple
myeloma with ≥ 2 previous
treatments, incl failure of
lenalidomide and
bortezomib
(N = 455)
Primary endpoint: PFS
Secondary endpoints: ORR (≥ PR),
duration of response, OS, safety
Dimopoulos, et al. ASH 2012. Abstract LBA-6.
Pomalidomide 4 mg on Days 1-21 +
Low-Dose Dex (LoDex)40 mg/day
Days 1, 8, 15, 22; 28-day cycles
(n = 302)
PD or
unacceptable
toxicity
Dex (HiDex) 40 mg/day
Days 1-4, 9-12, 17-20; 28-day cycles
(n = 153)
Multiple Myeloma: Case-Based Workshops With the Experts
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MM-003: PFS (ITT Population)
Proportion of Patients
Without Progression
1.0
Median PFS
POM + LoDEX: 3.6 mo
0.8
HiDEX: 1.8 mo
0.6
HR: 0.45; P < .001
0.4
0.2
0.0
0
4
8
Months
Dimopoulos et al. ASH 2012, Abstract LBA-6. Reprinted with permission.
12
16
Multiple Myeloma: Case-Based Workshops With the Experts
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MM-003: Other Findings
 Median OS (95% CI)
– Pom + LoDex: Not reached (11.1 mos – NE)
– HiDex: 7.8 mos (5.4 – 9.2)
 ORR significantly higher for Pom + LoDex
Response
Pom +
LoDex
HiDex
P value
ORR (≥ PR), %
21
3
< .001
• VGPR
3
1
--
10.1 mo
(6.2 – 12.1)
NE
--
Median DOR
(range)
Dimopoulos et al. ASH 2012. Abstract LBA-6. Reprinted with permission.