overview of multiple myeloma. the basics of multiple myeloma this program is supported by...
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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
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
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
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
Hoffman R. Hematology: basic principles and practice, 5th edition; 2008. Ropper AH, et al. N Engl J Med. 1998;338:1601-1607.
M-protein
Bone pain
Neuropathy (33%)Hyperviscosity
Amyloidosis
Hypercalcemia (15% to 20%)
Immunedeficiency
Anemia (10% to 35%)
Lytic lesions (70%)
Infection (15%)
Marrow infiltration
Multiple myeloma
cells Destruction of bone
Renal compromise (30%)
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Kumar SK, et al. Mayo Clinic Proc. 2009;84:1095-1110. Schmidt-Hieber M, et al. Haematologica. 2013;98:279-287.
Classification of Myeloma
Heavy chain: IgG, IgA, IgD, IgM, IgE 77% of myeloma cases IgG and IgA most common
Nonsecretory: No detectable
immunoglobulin 1% to 2% of myeloma cases
Light chain (Bence-Jones protein):Kappa (κ) or lambda (λ)
20% of myeloma cases
Serum free light chain
Heavy chain
Light chain
Variable region
Consta
nt region
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Disease Trajectory
< 3 g M-protein
< 10% clonal BMPC
No MM-related end-organ damage
1%/yr risk of progression to MM
Multiple Myeloma
Plasma cell
leukemia
MGUS Smoldering Myeloma
≥ 30 g/L M-protein
≥ 10% clonal BMPC
No MM-related end-organ damage
10%/yr risk of progression to MM in the first 5 yrs
Nonmalignant Accumulation Malignant Transformation Aggressive and
Stromal Independent
Stromaangiogenesis
and IL-6dependent
≥ 10% clonal BMPC
M-protein in serum and/or urine
≥ 1 CRAB features of disease related to organ damage
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)
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.
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Myeloma cells
Bone marrow stromal cells
PBMC
IL-6TNFIL-1
IL-2IFN
CD8+ T cellsNK cells
Bone marrow vessels
ICAM-1
VEGF
bFGF
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.
Role of Bone Marrow Microenvironment in Myeloma
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Diagnostic Evaluation
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Kurtin S. JAdPrO. 2010;1:19-29.
History and physical
CBC, differential and platelet count
Additional laboratory tests
Serum immunoglobulins
− Quantitative (IgG, IgM, IgA, IgD)
− SPEP
− Serum free light chain assay (kappa, lambda)
− BUN, creatinine, electrolytes
− Serum calcium (corrected)
− Serum albumin
− β2-microglobulin
− LDH
− Additional testing based on preliminary analysis
24-hr urine
Bone marrow biopsy and aspiration
Hematopathology
− Presence of plasma cells, %
− Cellularity
− Ploidy
Cytogenetics
FISH
Gene expression profiling
Radiology
Skeletal survey
MRI if vertebral compression fractures suspected
PET/CT
Establish diagnosis of MMMGUSSmolderingActive
Determine subtypeHeavy chain/light chainNonsecretorySolitary plasmacytoma
Determine stage International Staging SystemDurie-Salmon staging system
Estimate prognosisCytogeneticsAlbumin
β2-microglobulinPloidy
Identify need for immediate intervention
Severe hypercalcemiaAcute renal failureCord compressionSevere pain or impending fracture
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Monoclonal Protein—M Spike
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.
Normal SPEP Abnormal SPEP
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International Staging System
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.
Stage Criteria Median OS, Mos
ISerum β2m < 3.5 mg/L
Serum albumin ≥ 3.5 g/dL62
II Serum β2m < 3.5 mg/LSerum albumin < 3.5 g/dL
OR
Serum β2m 3.5 through < 5.5 mg/L
44
III Serum β2m ≥ 5.5 mg/L 29
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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 samplesDoes not detect some aberrationsCannot describe possible heterogeneity within a population of clonal cells
FISH Can be performed in non dividing cellsCan detect translocationsValidation with positive and negative controls is standard
Variable scoring criteriaSome aberrations technically difficult to detect
GEP May be helpful with prognosisMay lead to development of more targeted therapies
Not performed locallyExpensiveUnclear what should be done with the information
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Cytogenetic Classification
mSMART 2.0: classification of active myeloma
High Risk 20% Intermediate Risk 20% Standard Risk 60%
FISH− Del(17p)− t(14;16)− t(14;20)
GEP− High-risk signature
FISH− t(4;14)− 1q gain
Complex karyotype Metaphase deletion
13 or hypodiploidy High PCLI
All others including: Trisomies t(11;14) t(6;14)
OS 3 Yrs OS 4-5 Yrs OS 8-10 Yrs
Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376.
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Normal Karyotypes
Female Male
Strupp C, et al. Leukemia. 2003;17:1200-1202.
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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.
clinicaloptions.com/oncologyNursing Considerations for Patients With Multiple Myeloma
Natural History of Myeloma
MGUS or smoldering myeloma
Asymptomatic Symptomatic
ACTIVE MYELOMA
M-P
rote
in (
g/L
)
20
50
100
1. RELAPSE
2. RELAPSE
REFRACTORY RELAPSE
First-line therapy
Plateau remission
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
5-Yr Survival by Age
≤ 65 Yrs > 65 Yrs
2006-2010 73% 56%
2001-2005 63% 31%
Kumar SK, et al. ASH 2012. Abstract 3972.
Median 7.3 yrs1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
po
rtio
n S
urv
ivin
g
0 1 2 3 4 5 6 7 8 9 10Follow-up From Diagnosis (Yrs)
2006-2010
2001-2005
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
Continued TreatmentSalvage therapy Maintenance therapy
Confirmed Diagnosis of Multiple Myeloma: CRAB Criteria
Determination of transplant eligibility
Immediate interventions for serious adverse events
Individualized Treatment Selection for Induction Therapy
Transplant EligibleWorks rapidly (CR, nCR, VGPR)
Well toleratedSpares stem cells
Level of evidence: 1 or 2A
Transplant IneligibleAchieving a CR or nCR
Level of evidence: 1 or 2ATolerability and QoLPS and comorbidities
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.
clinicaloptions.com/oncologyNursing Considerations for Patients With Multiple Myeloma
NCCN Recommendations for Adjunctive Treatment Bone disease
– Bisphosphonates (category 1)
– Radiation therapy
– Orthopedic consultation
– Vertebroplasty or kyphoplasty
Hypercalcemia– Hydration, steroids, furosemide
– Zoledronic acid preferred
Hyperviscosity– Plasmapheresis
Anemia– Consider erythropoietin
Infection– IVIG for recurrent infections
– Pneumovax and influenza vaccine
– PCP, herpes and antifungal prophylaxis for high-dose orlong-term steroids
– Herpes zoster prophylaxis with bortezomib
Renal dysfunction– Avoid aggravating factors: contrast,
NSAIDs, dehydration
– Not a contraindication to HCT
– Monitor bisphosphonates closely
Coagulation/thrombosis– Prophylactic anticoagulation with
IMiDsNCCN. 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.
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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
MGUS or smoldering myeloma
Asymptomatic Symptomatic
ACTIVE MYELOMA
M-P
rote
in (
g/L
)
20
50
100
1. RELAPSE
2. RELAPSE
REFRACTORY RELAPSE
First-line therapy
Plateau remission
Second-line therapy
Third-line therapy
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Clinical Manifestations of Symptomatic Multiple Myeloma Renal
compromise (30%)M-protein
Bone pain (75% to 80%)
Neuropathy (33%)
Hypercalcemia (15% to 20%)
Immunedeficiency
Anemia (70%)
Lytic lesions (70%)
Infection (15%)
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).
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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 MGUS[1,2] Smoldering Myeloma[1]
Symptomatic Myeloma[1]
M-protein < 3 g/dL spike ≥ 3 g/dL spike and/or
In serum and/or urine[2]
Monoclonal plasma cells in bone marrow, %
< 10 ≥ 10 ≥ 10[2]
End-organ damage
None None ≥ 1 CRAB* feature[3]
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.
*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)
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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
Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
100
80
60
40
20
00 5 10 15 20 25
Yrs Since Diagnosis
Pro
bab
ility
of
Pro
gre
ssio
n (
%)
51
6673 78
410
1621
MGUS
Smoldering Multiple Myeloma
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Initial Diagnostic Evaluation
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.
Evaluation
History and physical
Blood workup CBC with differential and platelet countsBUN, creatinineElectrolytes, calcium, albumin, LDHSerum quantitative immunoglobulinsSerum protein electrophoresis and immunofixationβ2-MSerum free light chain assay
Urine 24-hr protein Protein electrophoresis (quantitative Bence-Jones protein)Immunofixation electrophoresis
Other Skeletal surveyUnilateral bone marrow aspirate and biopsy evaluation with immunohistochemistry or flow cytometry, cytogenetics, and FISHMRI and PET/CT as clinically indicated
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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 ISS Criteria for
Symptomatic Myeloma
Stage I ß2-M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL
Stage II Not stage I or III
Stage 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
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.
Risk Factors Standard Risk(Expected OS: 6-7 Yrs)
High Risk(Expected OS: 2-3 Yrs)
FISH t(11;14)t(6;14)
Del(17p)Del(1p)
Gain(1q)t(4;14)*t(14;16)
Cytogenetics Hyperdiploidy Hypodiploidy
β2-microglobulin* Low (< 3.5 mg/L) High (≥ 5.5 mg/L)
Isotype -- IgA
Gene expression profile Good risk High risk
*Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease.
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Effect of t(4;14), FISH Status, ISS Staging and Age on OS in Multiple Myeloma
Avet-Loiseau H, et al. Leukemia. 2013;27:711-717.
Pat
ient
s re
mai
ning
aliv
e, %
A vs B: P < .0001C vs D: P < .03E vs F: P < .05
Pat
ien
ts R
em
ain
ing
Ali
ve
(%)
A vs B: P < .0001C vs D: P < .03E vs F: P < .05
Yrs From Start of Treatment
100
80
60
40
20
05 10 150
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)
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Initial Approach to Treatment of Myeloma
Nontransplantation candidate (based on age, performance score,
and comorbidities)
Induction treatment
Transplantationcandidate
Induction treatment (nonalkylator-based
induction x 4-6 cycles)
Stem cell harvest
Stem cell transplantation
Maintenance
Maintenance
Consolidation therapy ?
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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)
NCCN Category 2B
– Thalidomide/dexamethasone (TD)
– Dexamethasone
– Liposomal doxorubicin/vincristine/dexamethasone (DVD)
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.
New (3/8/2013): Carfilzomib in combination with lenalidomide and dexamethasone
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Trial Regimens n ≥ VGPR, %
After Induction
After First ASCT
After Maintenance
Cavo[1] VTD x 3TD
241239
6228
7958
IFM 2005-01[2] VD x 4VAD
223218
37.715.1
54.337.2
HOVON-65/GMMG-HD4[3]
PAD x 3VAD
371373
4214
6236
PETHEMA/GEM[4]
TVT
a2-IFN
74
CR rate improved by 23% (TV), 11% (T), 19%
(a2-IFN)
PETHEMA/GEM[5] VTDTD
VMBCP/VBAD/B
130127129
602936
E4A03[6] RDRd
445422
5040
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.
Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients
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Lenalidomide/Dexamethasone Induction Followed by SCT: OS
Siegel D, et al. ASH 2010. Abstract 38. Reprinted with permission.
94%
78%
E4A03 trial RD vs Rd
Landmark analysis: 4 mos
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
Pro
bab
ilit
y
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 4812 24 36
Mo
Early SCT: no 141Early SCT: yes 68
13268
12264
5334
00
Log-rank test: Chi sq = 6.971 (P = .008)
Early SCT: no (n = 141)Early SCT: yes (n = 68)
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1. Cavo M, et al. Blood. 2012;120:9-19. 2. Cavo M, et al. Lancet. 2010;376:2075-2085.
VTD vs TD for SCT Induction in Newly Diagnosed Myeloma
Median follow-up: 36 mos
Estimated 3-yr OS: 86% for VTD vs 84% for TD (P = .30)[2]
Progression-free survival[1]
PFS[1]
100
75
50
25
00
PF
S (
%)
6 12 18 24 30 35
Mos From Start of Consolidation Therapy
VTDTD 60%
48%
P = .042
HR: 0.69 (95% CI: 0.48-0.99; P = .043)
EventsTDVTD
N7151
%4432
Patients at Risk, nTDVTD
161160
153154
136142
114125
8486
4353
2126
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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 Long-term 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)
Gay F, et al. Blood. 2011;117:3025-3031.
PFS OS
P < .001 P < .001Pro
bab
ility
of
PF
S
1.0
0.8
0.6
0.4
0.2
00 24 48 72
Mos
Pro
bab
ility
of
OS
1.0
0.8
0.6
0.4
0.2
00 24 48 72
MosCR VGPR PR
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Trial Regimens n Median Follow-up,Mos
Median OS Median PFS, Mos
IFM 99-06[1]
MPMPT
MEL100
196125126
51.533.2 mos51.6 mos 38.3 mos
17.827.519.4
IFM 01/01[2] MPTMP
223218
47.544.0 mos29.1 mos
24.118.5
Rajkumar SV et al[3] RDRd
371373
1-yr interim96%*87%*
19.125.3
MM-015[4]
MPR-RMPRMP
152153154
3045.2 mos
NRNR
311413
VISTA[5] VMPMP
344338
6056.4 mos43.1 mos
NANA
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;366:1759-1769. 5. San Miguel JF, et al. J Clin Oncol. 2013;31:448-455.
*Median OS not yet reached; % alive at time of follow-up is reported.
Phase III Trials: Novel Agent Induction for Transplantation-Ineligible Patients
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MM-015: MPR Induction Plus Lenalidomide in Newly Diagnosed Elderly MM Patients Updated analysis of randomized, multicenter, placebo-controlled phase III trial
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.
Newlydiagnosed
transplantation-ineligible
MM patients65 yrs
of age or older(N = 459)
MPR-RMelphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg/day on Days 1-21
MPMelphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 +
Placebo on Days 1-21
MPRMelphalan 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
Discontinued lenalidomide,
placebo added
Continued placebo
Dis
eas
e p
rog
ress
ion
Len
alid
om
ide
25 m
g/d
ay
± D
exam
eth
aso
ne
Cycles 1-9 (28-day cycles) Cycles 10+
Double-blind treatment phase Open-label extension/ follow-up phase
Stratified by age and disease stage
Primary endpoint: PFS
clinicaloptions.com/oncologyMultiple Myeloma: Case-Based Workshops With the Experts
Mos
MPR-R vs MPR: HR: 0.49 (P < .001)
Median PFS, Mos
MPR-R 31
MPR 14
MP 13
Data cutoff : May 11, 2010
All Patients66% Reduced Risk of Progression
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission.
MM-015: Progression-Free Survival
0 5 10 15 20 25 30 35 40
Pat
ien
ts (
%)
0
25
50
75
100
MPR-R vs MP: HR: 0.40 (P < .001)
Mos
HR: 0.301(P < .001)
Median PFS, Mos
MPR-R 31
MPR 15
MP 12
65-75 Yrs of Age70% Reduced Risk of Progression
0 10 20 30 40
Pat
ien
ts (
%)
0
25
50
75
100
HR: 0.618(P = .006)
clinicaloptions.com/oncologyMultiple Myeloma: Case-Based Workshops With the Experts
Data cutoff : February 28, 2011
0
All Patients 65-75 Yrs of AgeMPR-R MPR MP
MM-015: Overall Survival
Mos0 10 20 30 40 50
0
25
50
75
100
Mos
Pat
ien
ts (
%)
0 10 20 30 40 500
25
50
75
100
Pat
ien
ts (
%)
MPR-R MPR MP
Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission.
clinicaloptions.com/oncologyMultiple Myeloma: Case-Based Workshops With the Experts
Delforge M, et al. Eur J Haematol. 2012;89:16-27.
Median OS benefit: 13.3 mos5-yr OS rates: 46.0% vs 34.4%
100
90
80
70
60
50
40
30
20
10
0
Pat
ien
ts A
live
(%
)
0 6 12 18 24 30 36 42 48 54 60 66 72 78Mos
Pts at Risk, n338 301 262 240 216 196 168 153 133 112 61 24 3344 300 288 270 246 232 216 199 176 158 78 34 1
Group n Events Median HR (95% CI) P Value
MP 338 211 43.1
VMP 344 176 56.4 0.695 (0.567-0.852) .0004
VISTA: VMP vs MP in Patients With Multiple Myeloma > 65 Yrs of Age
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PFS
VMPT + VT Maintenance vs VMP as Frontline Therapy
VMPT VMP P
5 yr PFS 29% 13% <.00015 yr TTNT 41% 19% <.00015 yr OS 61% 51% .01
Palumbo A, et al. ASH 2012. Abstract 200. Reprinted with permission.
1.00
0.75
0.50
0.25
0.00
Pat
ien
ts (
%)
700 10 30 40 50 6020
Median 35.3 months
Median 24.8 months
HR 0.58 (95% CI, 0.47-0.71, P < 0.0001)
clinicaloptions.com/oncologyMultiple Myeloma: Case-Based Workshops With the Experts
Novel Agents for Frontline Treatment of MyelomaStudy 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
Berdeja et al[3] 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
Lonial et al[4] Elotuzumab/Rd
73 ORR: 82%≥ VGPR: 48%
Grade 3/4 cytopenias: 16%, grade 1/2 diarrhea: 56%
Kaufman et al[5] 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
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
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
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.
Placebo(n = 307)
Patients younger than 65 yrs of age with
nonprogressive disease, ≤ 6 mos
after first-line ASCT
(N = 614)
Lenalidomide 10-15 mg/day
(n = 307)
Consolidation: Lenalidomide 25 mg/day on Days 1-21 of
every 28 days for 2 mos
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Attal M, et al. N Engl J Med. 2012;366:1782-1791.
IFM 2005-02: PFS and OS
PFS OS
HR: 0.50; P < .001
100
75
50
25
0
PF
S (
%)
0 6 12 18 24 30 36 42 48
Mos of Follow-up
23% 41%
Lenalidomide
Placebo
Pts at Risk, nLenalidomidePlacebo
307307
267255
236211
216169
172102
10357
4922
106
11
P = .29
100
75
50
25
0
OS
(%
)
0 6 12 18 24 30 36 42 48
Mos of Follow-up
Lenalidomide
Placebo
Pts at Risk, n LenalidomidePlacebo
307307
298297
292282
282279
240247
162167
9287
3831
56
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Type of Lesion, n Placebo (n = 302)
Lenalidomide (n = 306)
Total(N = 608)
Hematologic 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
Nonhematologic 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
Attal M, et al. N Engl J Med. 2012;366:1782-1791.
IFM 2005-02: Second Malignancies at 3 Yrs
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)
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CALGB 100104: Lenalidomide vs Placebo as Maintenance Therapy After ASCT
Outcome 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.
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ilit
y o
f P
FS
Mos Since Autologous HSCT
700 10 20 30 40 50 60
2-sided P < .001
Lenalidomide
Placebo
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ilit
y o
f O
SMos Since Autologous HSCT
700 10 20 30 40 50 60
2-sided P = .03
Lenalidomide
Placebo
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CALGB 100104: Subgroup Analysis
Placebo Better Lenalidomide Better
-2 -1 0 1 2
OS Subgroup HR (95% CI) P Value for InteractionLenalidomide induction
YesNo
Thalidomide inductionYesNo
Elevated β2-M levelYesNo
CR at randomizationYesNo
.031.40 (0.43-2.4) 0.18 (-0.32 to 0.67)
.050.01 (-0.62 to 0.64)0.89 (0.29-1.5)
.560.37 (-0.39 to 1.1)0.58 (0.06-1.1)
.640.25 (-0.67 to 1.2)0.53 (0.05-1.0)
-2 -1 0 1 2
TTP Subgroup HR (95% CI) P Value for InteractionLenalidomide induction
YesNo
Thalidomide inductionYesNo
Elevated β2-M levelYesNo
CR at randomizationYesNo
.061.10 (0.58-1.7)0.57 (0.25-0.89)
.360.57 (0.17-0.98)0.86 (0.49-1.2)
.760.67 (0.17-1.2)0.77 (0.44-1.1)
.380.53 (-0.001 to 1.1)0.86 (0.53-1.2)
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
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Newly diagnosed MM patients with
stage II/III disease aged
18-65 yrs (N = 744)
Stem cell collection: cyclophosphamide/doxorubicin/dexamethasone + granulocyte colony-stimulating 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.
PAD x 3 cyclesBortezomib 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)
2 yrsVAD 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)
Bortezomib 1.3 mg/m2
every 2 wks
Thalidomide 50 mg/day
Stem cell collection and transplantation
Stem cell collection and transplantation
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
HOVON-65 Phase III Trial: Bortezomib in Induction and Maintenance
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Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
HOVON-65 Phase III Trial of Bortezomib in Induction and Maintenance: PFS and OS
PFS OS
100
75
50
25
0
PF
S (
%)
0 12 24 36 48 60
Mos
VADPAD
Pts at Risk, nArm A:VADArm B: PAD
414413
325356
227261
120140
4451
89
VADPADP = .008
n
414413
F
273242
100
80
60
20
0
OS
(%
)0 12 24 36 48 60
Mos
VADPAD
Pts at Risk, nArm A:VADArm B: PAD
414413
361374
327338
200224
86104
1618
VADPADP = .07
n
414413
D
130109
40
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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 myeloma-
related 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 myelomaRoodman 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 pamidronateDurie BG, et al. N Engl J Med. 2005;353:99-102.
Peripheral Neuropathy
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Thalidomide- and Bortezomib-Emergent Peripheral Neuropathy: SymptomsPeripheral Neural Tract Symptom(s) Thalidomide Bortezomib
Sensory Hypo-esthesiaparesthesia: numbness,
tingling, pin-prick sensationhyperesthesia
Common Common
Ataxia, gait disturbance Rare Rare
Neuropathic pain Rare Common
Motor Weakness Rare Rare
Tremor Common Rare
Autonomic Gastrointestinal Constipation Constipation
Others Impotence Bradycardia
OrthostaticHypotension
1. Chaudhry V, et al. Neurology 2002;59:1872-1875. 2. Mileshkin L, et al. Leuk Lymphoma. 2006;47:2276-2279. 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
Subcutaneous bortezomib substantially decreases 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 doseFor 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 activitiesof daily living), or grade 4
Discontinue bortezomib
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
– Magnesium for muscle cramps
– Potassium (ie, apple cider vinegar, bananas, oranges) for muscle cramps
FDA-approved drugs for diabetic neuropathy
– Duloxetine
– Pregabalin
Amino acid supplements
– Acetyl-carnitine
– 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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Multiple Myeloma: Case-Based Workshops With the Experts
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: Case-Based Workshops With the Experts
Multiple Myeloma: Risk Categories
Risk Factors Standard Risk(Expected OS: 6-7 Yrs)
High Risk(Expected OS: 2-3 Yrs)
FISH t(11;14)t(6;14)
del(17p)t(4;14)*t(14;16)
Cytogenetics Hyperdiploidy Hypodiploidydel(13q)
β2-M* Low (< 3.5 mg/L) High (≥ 5.5 mg/L)
PCLI < 3% High (≥ 3%)
Isotype -- IgA
Gene expression profile Good risk High risk
*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;23:2210-21. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-88. Munshi N, et al. Blood. 2011;117:4696-4700.
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Multiple Myeloma: Case-Based Workshops With the Experts
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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Multiple Myeloma: Case-Based Workshops With the Experts
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
What would you do now?
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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
What would you do now?
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Overview of Phase III Trials With Len and Bortezomib in Relapsed/Refractory MM
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.
Regimen Trial ORR, %
CR or nCR, %
≥ VGPR, %
DOR, Mos
TTP or PFS, Mos
Median OS, Mos
Len + dex MM-009[1] 61 24 NE16
1135[5]
Len + dex MM-010[2] 60 25 NE 17 11
Bortezomib APEX[3] 43 16 NE 86
30
VdoxMMY-3001[4] 44 13 27
109 NE
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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)
What would you recommend now?
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Carfilzomib
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
5967
Relapsed/ refractory
1-3 42 52
17/2212/15
8.3NR
006 (combo with len/dex)[5] 50 Relapsed/refractory
1-3 78 2/8 --
Neuropathy from phase II experience: 9.6% grades 1/2 and 1.4% grade 31. 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.
*Evaluable for response.
Approved for patients who progress within 60 days of last therapy and have received ≥ 2 therapies including bortezomib and an IMiD.
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PX-171-003A1: Phase II Trial of Carfilzomib in Relapsed/Refractory MM
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.
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
Neuropathy: Grade 1 or 2 without pain
Cycle 1: 20 mg/m2 IV
Cycles 2-12: 27 mg/m2 IV
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003A1: Overall Response Rate
Siegel DS, et al. Blood. 2012;120:2817-2825.
Median DOR: 7.8 months (95% CI: 5.6-9.2)
Response Category, n (%)All Patients
(n = 257)
Patients With Unfavorable Cytogenetics/FISH Markers
(n = 71)
ORR 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)
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003A1: Progression-Free Survival
Siegel DS, et al. Blood. 2012;120:2817-2825.
100
75
50
25
0
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5Mos From Start of Treatment
Pro
po
rtio
n o
f P
atie
nts
Aliv
ean
d W
ith
ou
t P
rog
ress
ion
(%
)
Median PFS: 3.7 mos (95% CI: 2.8-4.6)
Censored observationsConfidence band
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003A1: Overall Survival (N = 266)
Siegel DS, et al. Blood. 2012;120:2817-2825.
100
75
50
25
0
0 3 6 9 12 15 18 21 24 27Mos From Start of Treatment
Pro
po
rtio
n o
f P
atie
nts
Aliv
e (%
)
Median OS: 15.6 mos (95% CI: 13.0-19.2)
Censored observationsConfidence band
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003A1: Common Hematologic AEs
Siegel DS, et al. Blood. 2012;120:2817-2825.
AEs Regardless of Relationship, % All Grades Grade 3 Grade 4
Anemia 46 22 2
Thrombocytopenia 39 17 12
Lymphopenia 23 18 2
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003A1: Common Nonhematologic AEs
Siegel DS, et al. Blood. 2012;120:2817-2825.
Nonhematologic AE, n (%) All Grades Grade 3/4Fatigue 130 (49.0) 20 (7.5)Nausea 119 (45.0) 5 (1.9)Dyspnea 90 (34.0) 9 (3.4)Diarrhea 86 (32.0) 2 (0.8)Pyrexia 83 (31.0) 4 (1.5)Headache 74 (28.0) 5 (1.9)Upper respiratory tract infection 71 (27.0) 12 (4.5)Increased serum creatinine 67 (25.0) 7 (2.6)Vomiting 59 (22.2) 2 (0.8)Peripheral neuropathy 33 (12.4) 3 (1.1)Hypophosphatemia 32 (12.0) 16 (6.0)Pneumonia 32 (12.0) 25 (9.4)Hyponatremia 31 (11.7) 22 (8.3)Renal failure (acute) 13 (4.9) 9 (3.4)Febrile neutropenia 2 (0.8) 2 (0.8)Tumor lysis syndrome 1 (0.4) 0 (0)
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Results: Cardiac Analysis003-A0 (n = 46)
003-A1 (n = 266)
004 (n = 164)
005 (n = 50)
All Patients(N = 526)
SMQ grouping, n (%)
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)
Ischemic heart disease 3 (6.5) 11 (4.1) 4 (2.4) 0 18 (3.4)
Grade 3 1 (2.2) 6 (2.3) 0 0 7 (1.4)
Patient disposition in response to cardiac AEs
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)
*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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PX-171-004: PFS With Carfilzomib in Bortezomib-Naive Patients
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30
Mos From the Start of Treatment
Pts at Risk 59 33 19 7 4
(n) 67 38 33 1 0
Cohort 1: 20 mg/m2
Cohort 2: 20/27 mg/m2
59
67
8.2
NR
6.0-12.3
11.3-NE
n Median 95% CI
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
Vij R, et al. Blood. 2012;119:5661-570.
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Palumbo A, et al. Blood 2012;120:730
CCd: Time to Onset for Best Response in Newly Diagnosed MM Patients
Median treatment duration, cycles (range): 5 (1-9)
% o
f P
atie
nts
Months
PR
sCR/CR/nCR
VGPR
1.00
0.75
0.50
0.25
0.02.5 5.0 7.5 10.0 12.50.0
• 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%
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
What would you recommend now?
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Proposed Guidelines for Bortezomib Dose Modification for Management of PN
Subcutaneous bortezomib causes less peripheral neuropathy
Richardson PG, et al. Leukemia. 2011;26:595-608.
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 doseFor 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 activitiesof daily living), or grade 4
Discontinue bortezomib
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Risk Assessment for VTEs in Patients With MM Receiving Thal or Len VTE prophylaxis for individual risk factors or myeloma-
related 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
Thrombocytopenia
– For grade ≥ 3, monitor platelet count and consider interrupting treatment or dose reductions
Anemia
– Consider ESAs for Hb < 10 g/dL
Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.
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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 [package insert].
Category Renal Function(Cockcroft-Gault)
CLcr, mL/min
Dose
Moderate renal impairment 30-6010 mg
Every 24 hr
Severe renal impairment< 30
(not requiring dialysis)15 mg
Every 48 hr
End-stage renal disease< 30
(requiring dialysis)
5 mg Once daily
(on dialysis days, administer following
dialysis)
Lenalidomide Starting Dose Adjustment for Renal Impairment
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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
Response (N = 51) n (%)
CR/nCRVGPRPRMRSDORR
12 (24)9 (18)
19 (37)1 (2)3 (6)
40 (78)
Niezvizky R, et al. Clin Cancer Res. 2013;19:2248-2256.
Week 1 Week 2 Week 3 Week 4: rest
Carfilzomib20/27 mg/m2 IV
Dexamethasone40 mg/day PO
Lenalidomide D1-D2125 mg/day PO
D1/D2 D8/D9 D15/D16
D1 D8 D15 D22
20 mg/m2 cycle 1 Days 1 and 2 only,27 mg/m2 all days, all cycles thereafter
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MM-002: Study Design
Open-label, randomized phase I/II trial[1]
– Phase I portion previously presented[2]
1. Richardson PG, et al. ASH 2011. Abstract 634. 2. Richardson PG, et al. ASH 2010. Abstract 864.
Patients with relapsed/
refractory MM
(N = 221)
PD
*Option to add low-dose dexamethasone40 mg/wk in cases of PD or no response after 4 treatment cycles (n = 61).
Pomalidomide 4 mg on Days 1-21 +Low-Dose Dexamethasone 40 mg/wk
28-day cycle(n = 113)
Pomalidomide* 4 mg on Days 1-2128-day cycle
(n = 108)Primary endpoint: PFS
Secondary endpoints: ORR, duration of response, OS, safety
Anticoagulants and granulocyte colony-stimulating factor added after cycle 1
Erythroid growth factors, bisphosphonates, platelet, and/or RBC transfusions added as clinically indicated
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MM-002: Response and Survival Outcomes
Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.
Outcome Pomalidomide +Low-Dose Dexamethasone
Pomalidomide
Overall population (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
• For patients with PD as best response 5.4
Double-refractory population (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 4.6
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MM-002: Adverse Events
Richardson PG, et al. ASH 2011. Abstract 634. Reprinted with permission.
Grade 3/4 Adverse Event in ≥ 5% Patients, %
Pomalidomide +Low-Dose Dexamethasone
(n = 112)
Pomalidomide(n = 107)
Hematologic
Neutropenia 38 45
• Requiring dose reduction 4 7
Thrombocytopenia 19 21
• Requiring dose reduction 5 9
Anemia 21 17
Nonhematologic
Pneumonia 19 8
Fatigue 10 8
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MM-003: Pomalidomide and Low-Dose Dex in Relapsed/Refractory Myeloma Randomized, phase III trial
Dimopoulos, et al. ASH 2012. Abstract LBA-6.
Patients with relapsed/refractory multiple
myeloma with ≥ 2 previous treatments, incl failure of
lenalidomide and bortezomib
(N = 455)
PD or unacceptable toxicity
Pomalidomide 4 mg on Days 1-21 +Low-Dose Dex (LoDex)40 mg/day
Days 1, 8, 15, 22; 28-day cycles(n = 302)
Dex (HiDex) 40 mg/dayDays 1-4, 9-12, 17-20; 28-day cycles
(n = 153)
Primary endpoint: PFS
Secondary endpoints: ORR (≥ PR), duration of response, OS, safety
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MM-003: PFS (ITT Population)
Dimopoulos et al. ASH 2012, Abstract LBA-6. Reprinted with permission.
0 4 8 12 160.0
0.2
0.4
0.6
0.8
1.0
HR: 0.45; P < .001
Median PFS
POM + LoDEX: 3.6 mo
HiDEX: 1.8 mo
Months
Pro
po
rtio
n o
f P
atie
nts
W
ith
ou
t P
rog
ress
ion
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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 --
Median DOR (range)
10.1 mo(6.2 – 12.1)
NE --
Dimopoulos et al. ASH 2012. Abstract LBA-6. Reprinted with permission.