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Multiple Myeloma

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Title: Multiple Myeloma


1
Multiple Myeloma
  • Joan Bladé
  • Asunción, 8 de julio de 2011

2
MONOCLONAL GAMMOPATHIES
  • MALIGNANT
  • Multiple myeloma
  • Variants of myeloma
  • Smoldering myeloma
  • Non-secretor
  • Plasma cell leukemia
  • POEMS
  • Localized plasmacytomas
  • Solitary plasmacytoma (bone)
  • Extramedullary plasmacytoma
  • Waldenströms macroglobulinemia
  • Primary amyloidosis
  • NON-MALIGNANT
  • Monoclonal gammopathy of undetermined
    significance
  • Transient MG HIV infection, bone marrow
    trasplant, organ trasplant (liver, kidney)

3
Monoclonal Gammopathy of Undetermined
Significance (MGUS) Diagnostic Criteria
  • Serum M protein size lt3g/dL
  • Bone marrow plasma cells lt10
  • No clinical manifestations or other laboratory
    abnormalities attributable to the monoclonal
    gammopathy

The International Myeloma Working Group. Br J
Haematol 2003 121 749-757.
4
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5
Malignant Transformation of MGUS
  • Actuarial probability
  • 1 per year (30 at 25 yrs)
  • Actual probability
  • (considering competing causes of death)
  • 11 at 25 yrs

6
Factors Predicting Malignant Transformation in
MGUS
  • M-protein size
  • IgA type
  • Abnormal free-light chain ratio
  • Aberrant phenotype (gt95)
  • Evolving vs Non-evolving

7
MGUS. Predictors of Malignant Transformation
Feature RR 95 Confidence Interval p-value
Evolving vs non-evolving 12.14 5.80-25.40 lt0.0001
IgA vs others 2.92 1.36-6.28 0.006
M-protein (15 g/L) 2.18 1.02-4.66 0.044
8
Evolving vs. Non-evolving MGUS
Evolving
Non-evolving
9
MGUS Serum Free Light Chain (FLC) Ratio an
Independent Risk Factor for Progression
Risk at 20 years
HIGH-RISK
Abnormal FLC ratio, non-IgG and M-protein ?15g/L 58
LOW-RISK
Normal FLC ratio, IgG-type and M-protein lt15 g/L 5
Rajkumar et al. Haematologica / The Hematology
Journal 2005 S1 194. Rajkumar et al. Blood
2005 106 812-817.
10
  • Smoldering Multiple Myeloma (Asymptomatic
    Myeloma)

11
Smoldering Multiple Myeloma (Asymptomatic
Myeloma) Diagnostic Criteria
  • Serum M protein size 3g/dL
  • and/or urine light chain 1g/24 hours
  • and/or bone marrow clonal plasma cells 10
  • No related organ tissue impairment (no end organ
    damage including bone lesions) or symptoms

The International Myeloma Working Group. Br J
Haematol 2003 121 749-757.
12
SMM. Evolution of the M-protein
g/L
g/L
Evolving
Non-evolving
13
Evolving Smoldering Multiple Myeloma
  • Rising M-protein
  • Previously recognized MGUS
  • Chromosomal losses, 1q gains
  • Response to therapy (?50)
  • Short time to symptomatic MM

Rosiñol et al, Br J Haematol 2003 Rosiñol et al,
Br J Haematol 2005
14
Monoclonal Gammopathies
MM
EVOLVING
SMM
NON EVOLVING
NON EVOLVING
MGUS
Rosiñol et al. Br J Haematol 2003 123
631-36. Rosiñol et al. Mayo Clin Proc 2007 82
428-34.
15
SMM Factors Predicting Progression
  • M-protein size 30 g/L and 10 BMPC
  • Abnormal free-light chain ratio
  • Aberrant phenotype (gt95)
  • Pattern of MRI
  • Evolving vs Non-evolving

16
  • Symptomatic Multiple Myeloma

17
Symptomatic Multiple Myeloma
  • M-protein in serum and / or urine
  • Bone marrow (clonal) plasma cells or
    plasmacytoma
  • Related organ or tissue impairment (end organ
    damage, including bone lesions)

Some patients may have no symptoms but have
related organ or tissue impairment If flow
cytometry is performed, most plasma cells (gt90)
will show a neoplastic phenotype
18
Myeloma-related organ or tissue impairment (end
organ damage) (ROTI) due to the plasma cell
proliferative process
  • Increased serum Calcium
  • Renal insufficciency
  • Anaemia haemoglobin 2 g/dL below the lower
    normal limit
  • Bone lesions lytic lesions or osteoporosis with
    compression fractures (MRI or CT may clarify)
  • Other symptomatic hyperviscosity (rare),
    amyloidosis, recurrent bacterial infecitons (
    episodes in 12 months), extramedullary
    plasmacytomas.

CRAB (calcium, renal insufficiency, anaemia or
bone lesions)
19
  • Am J Med, 42 937-948, June 1967

20
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21
Prognostic Factors in MM
  • Prognostic value
  • A new prognostic factor
  • A simple reliable marker
  • An easily available parameter
  • An independent prognostic factor
  • A new staging system
  • Proposal for a novel prognostic index

22
Prognostic Factors in MM
  • Clinical and laboratory features
  • Staging systems
  • Malignant clone molecular genetic status
  • Response to therapy
  • Mechanisms of disease control/progression

23
Prognostic Factors in MM Clinical and Laboratory
Features
  • Host characteristics
  • Age
  • PS
  • Tumor burden
  • ß2-microglobulin
  • Organ damage
  • Renal function
  • Hb

24
Main Staging Systems in MM
Author, year Parameters Other
Durie and Salmon, 1975 Hb, Ca, M-protein, bone lesions Renal function
Merlini et al, 1980 PC, Cr, and Ca (IgG) Hb, Ca, M-protein (IgA)  
MRC, 1980 Hb, urea, PS  
Cavo et al, 1989 D S, platelet count  
Greipp et al, 1988 ?2-microglobulin, LI  
Bladé et al, 1989 Albumin, urea  
San Miguel et al, 1989 Hb, Cr, PS, PI  
San Miguel et al, 1995 S-phase, ?2-microglobulin, age, PS  
IMWG, 2005 ?2-microglobulin, albumin  
MRC Medical Research Council IMWG
International Myeloma Working Group Hb
haemoglobin Ca calcium PC plasma cells Cr
creatinine Ig Immunoglobulin PS performance
status LI labelling index PI paraprotein
index.
25
International Prognostic System (IPS)
Stage Overall Survival (months)
I ?-2M lt 3.5 mg/L and albumin 3.5 g/dL 62
II ?-2M lt 3.5 mg/L and albumin lt 3.5 g/dL or ?-2-m 3.5 5.4 mg/L 44
III ?-2M 5.5 mg/L 29
Greipp P et al. J Clin Oncol 2005 23 3412-20.
26
Cytogenetic Prognostic Subgroups in Multiple
Myeloma
  • Good/average prognosis
  • Hyperdiploidy
  • t(1114)(q32q32) cyclin D1 upregulation
  • Bad prognosis
  • Hypodiploidy
  • t(414)(p16.3q32) FGFR3MMSET upregulation
  • t(1416)(q32q23) c-MAF upregulation
  • Chromosome 1 abnormalities 1q gains
    (overexpression CKS1B)
  • 17p deletions, 13q deletions

27
13q Deletion as Single Abnormality
  • No independent prognostic impact
  • Gutiérrez N et al. Leukemia 2007 21 541-9.
  • Avet-Loiseau H et al. Blood 2007 109 3489-95.

28
Molecular Myeloma Subgroups Gene Expression
Profiling
  • Translocation/Cyclin D classification
  • 8 groups
  • Recurrent translocations/hyperdiploidy
  • 7 entities

Bergsagel PL et al. Blood 2005 106
296-303. Zhan F et al. Blood 2006 108 2020-8.
29
High-resolution Genomic Profiles (aCGH/mRNA
microarray/FISH/novel bioinformatics)
  • 4 different MM subtypes
  • (recurrent DNA copy number changes), i.e.
  • Hyperdiploid, 11q gains good outcome
  • Hyperdiploid, 1q gains and/or 13 losses poor
    outcome

Carrasco R et al. Cancer Cell 2006 4 313-25.
30
  • GEP of tumor biology / chemotherapy sensitivity
    can refine the ISS classification

31
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32
Response to Therapy as Prognostic Factor
  • Stabilization of disease
  • Impact of CR
  • With primary therapy
  • After HDT/SCT

33
Imaging Techniques with Prognostic Interest
  • MRI number of focal lesions (FL)
  • FDG-PET/CT
  • FDG suppression (SUV-FL) prior ASCT
  • Metastatic spread (EMD)

Walker R, et al. J Clin Oncol 2007 25
1121-1128 Bartel TB, et al. Blood 2009 114
2068-2076
34
Novel Drugs and New Molecular Targets
  • Novel drugs can overcome drug resistance in poor
    cytogenetic subgroups
  • New therapies should target specific molecular
    pathways

35
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36
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37
First-line treatment for MM in 2010
  • Patients eligible for HDT/SCT
  • Patients non-eligible for HDT/SCT

38
Patients eligible for HDT/SCT
39
  • The crucial step for long-lasting response and
    prolonged survival is the achievement of CR
    postrasplant.

40
TTP according response to transplant (CR vs. PR)
CR Median 6.1 yrs
PR Median 1.3 yrs
P0.000001
Rovira et al., EBMT 2009 (abstract P592)
41
Overall survival according response to transplant
(CR vs. PR)
CR Median 9.6 yrs
PR Median 4 yrs
p0.0001
Rovira et al., EBMT 2009 (abstract P592)
42
Impact of Induction
  • CR postransplant depends on the effectiveness of
    the induction therapy

43
CR after HDT According to Tumor Burden
Pretransplant
M-protein size CR () P-value
Serum
- lt 10 g/L 52 0.01
- ? 10 g/L 15
Serum and urine
- lt 10 g/L and lt 0.5 g/24h 67
- 10 20 g/L and / or 0.5 to 1 g/24h 21 0.03
- gt 20 g/L and / or gt 1 g/24h 7
Alexanian et al, BMT 2001 27 1037-1043
Nadal et al, BMT 2004 33 61-64
44
Treatment options for patients eligible for
transplantation
Induction
Bortezomib-based VelDex VTD PAD
IMiD-based Thal/Dex TAD CTD Rd VRD
Traditional VAD CyDex
Stem cell harvest High-dose melphalan Stem cell
infusion
45
  • Which is the best induction regimen?

46
Pre and Post-ASCT CR Rate with old Regimens
Regimen Pre-ASCT Post-ASCT
Dexa/VAD 5 35
Cyclophosphamide/Dexa 7 32
VBMCP/VBAD 10 35
Bladé et al. Blood 20101153655-63 Bladé et
al. Haematologica 201095702-4 Harousseau et
al. JCO 2010 Mellqvist et al. Cancer
2008112129-35 Rosiñol et al, IMW 2011
47
Pre and Post-ASCT CR Rate with Novel Induction
Regimens
Regimen Pre-ASCT Post-ASCT
Thal/Dex 6 23-34
Vel/Dex 12 33
PAD-1 24 43
VTD 21-30 43-52
Total Therapy III - 56 at 2 yrs
Cavo et al, Lancet 2010 Rosiñol et al, IMW
2011 Harousseau et al, Haematologica 2006 91
1498-05 Rosiñol et al, JCO 2007 251498-05
Popat et al, BJH 2008 141 512-6 Barlogie et
al, BJH 2007 138176-85.
VTD-PACE Tandem ASCT VTD/TD
48
Bortezomib and high-risk cytogenetics (t (414)
and or del 17p). PETHEMA-GEM05
RC () P-value
TD vs. VTD (GIMEMA) lt10 vs. 35 0.001
VBMCP/VBADbortezomib vs. TD vs. VTD (PETHEMA) 23 vs. 0 vs. 42 0.003
VAD vs. VD (IFM 2005-01) 3 vs. 18 0.07
CR nCR
Cavo et al, Lancet 2010 Rosiñol et al, IMW 2011
Harousseau et al, JCO 2010.
49
Progressive Disease in Pre-transplant Induction
According to the Presence or Absence of
EMP (PETHEMA-GEM05)
  • 27 vs. 12, p0.01

VBCMP/VBAD bortezomib (n14) TD (n20) VTD (n21)
EMP 29 40 14
No EMP 13 18 6
Rosiñol et al. IMW 2011
50
TO TRANSPLANT OR NO TO TRANSPLANT... THIS IS THE
QUESTION!!!
51
Pre- and post-ASCT CR rate according to the
induction regimen. PETHEMA-GEM05.
Pre-ASCT Post-ASCT
VBMCP/VBAD Bortezomib () 21 38
TD () 14 24
VTD () 35 46
Rosiñol et al. IMW 2011
52
Consolidation / maintenance therapy
53
Consolidation/maintenance therapy Thalidomide
EFS/PFS OS
Pamidronatethal vs pamidronate vs observation 52 vs. 37 vs. 36 Longer survival if suboptimal response postransplant
ThalPDN vs PDN 42 vs. 23 Longer survival 86 vs 75
Thal vs observation 6 vs. 4.1 yrs Shorter OS after relapse Longer OS in patients with cytogenetic abnormalities
Thal vs. IFN 33 vs. 22m Shorter OS after relapse
Attal et al. Blood 2006108328994 Spencer et
al. J Clin Oncol 200927178893 Barlogie et al.
N Engl J Med 2006354102130 Blood
2008112311521 Lokhorst et al. Blood
20101151113-20
54
Consolidation/maintenance therapy
  • Bortezomib (x 6 cycles)
  • Increase the postrasplant CR/nCR
  • Lenalidomide (x 2 cycles)
  • Improved postrasplant response

Mellqvist et al, ASH 2009 (abstract 530) Attal et
al, ASH 2009 (abstract 529)
55
Consolidation with VTD
  • 39 patients in CR or VGPR post-ASCT
  • Consolidation with 4 cycles of VTD
  • Follow-up with RT-PCR
  • Median follow-up 32 months
  • Complete molecular remission (n6)
  • Continued remissions
  • High molecular tumor
  • burden (n13)
  • 11 Relapses

Very low molecular tumor burden (N19) 3
relapses
MRD (-) correlates with a very low probability of
relapse
Ladetto et al, JCO 2010282077-81
56
IFM 2005-02 PFS from randomization


plt10-7

P lt 10-7
Attal et al, ASCO 2010 (abstract 8018)
57
Best treatment for younger patients
Refined Total Therapy
58
Refined Total Therapy
59
Refined Total Therapy
Triple induction regimen
Maintenance
ASCT
Consolidation
VTD?
MEL-200
VRD?
Lenglucocorticoids bortezomib
60
Patients non-eligible for HDT/SCT
61
Multiple myeloma in the elderly Results with
old regimens
  • MP
  • CR lt5
  • Median overall survival 2-3 yrs
  • Dex-based
  • CR lt5
  • Median overall survival 2-3 yrs

62
Expanding Treatment Options for Front-line
Therapy of Elderly Patients with MM
  • Alkylating agent-based
  • MPT (GIMEMA, IFM,
  • NMSG, HOVON)
  • MPV (PETHEMA,
  • VISTA)
  • MPR (GIMEMA)
  • CTD (MRC IX)
  • Dexa-based
  • Thal/Dex (ECOG,
  • Celgene 003,
  • CEMSG)
  • Len/Dex (SWOG,
  • ECOG, Others)

63
Unprecedented CR Rate with Novel plus Old Drugs
in Non-transplant Candidates
Regimen CR rate ()
MPT1,2 15
MPR3 13-18
MPV4 30
Rev/Dex5 or BIRD6 22-37
4San Miguel et al. N Engl J Med 2008
359906-17 5Lacy et al. Mayo Clin Proc
2007821179-84 6Niesvizky et al. Blood
20081111101-9
1Palumbo et al. Blood 2008 112310714 2Facon et
al. Lancet 2007 370120918 3Palumbo et al. JCO
254459-65
64
MPT vs. MP
CR () PFS () OS (mos.)
Palumbo et al, 2008 16 vs. 4 21.8 vs 14.5 45 vs. 47.6 (pNS)
Facon et al, 2007 13 vs. 2 27.5 vs. 17.8 51.6 vs. 33.2 (p0.0006)
Hulin et al, 2009 7 vs. 1 24.1 vs. 18.5 44 vs. 29.1 (p0.03)
Wijermans et al, 2010 2 vs. 2 15 vs. 11 (PFS) 13 vs. 9 (EFS) 40 vs. 31 (p0.05)
Waage et al, 2010 13 vs. 4 15 vs. 14 29 vs. 32 (pNS)
Palumbo et al. Blood 2008 11231073114 Facon et
al. Lancet 2007 37012091218 Hulin et al. J
Clin Oncol 2009 2736643670
Wijermans et al. IMW 2009 (abstract
116) Wijermans et al. JCO 2010 Waage et al.
Blood 2010
65
IFM 99-06 overall survival
1.0
Treatment O/N Overall survial time (months)
median (SE) MP 128/196 33.2(3.2) MPT 62/125 51.
6(4.5) MEL100 78/126 38.3(2.7)
0.8
0.6
Proportion of surviving patients
0.4
0.2
Median follow-up time 51.5 months
0
72
60
84
12
24
36
48
0
Time from randomisation (months)
Facon et al, Lancet 2007 370 1209-18
66
VISTA trial VMP vs. MP
VMP () MP ()
ORR 71 35
CR 30 4
Median time to first response (mos) 1.4 4.4
Median duration of response
all responders (mos) 19.9 13.1
patients achieving CR (mos) 24 12.8
San Miguel et al. N Engl J Med. 2008 359906-17
67
Time to progression 52 reduced risk of
progression with VMP
100
90
80
70
60
50
Patients without event ()
40
30
20
VMP 24.0 months (83 events) MP 16.6 months (146
events) HR0.483, plt0.000001
10
0
0
3
6
9
12
15
18
21
24
27
Time (months)
Number of patients at risk VMP
344 295 272 245 185 111 65 31 17 MP
338 296 241 206 152 86 53 22 5
San Miguel et al. N Engl J Med. 2008 359906-17
68
OS Confirmed survival benefit with VMP 35
reduced risk of death with VMP
Median follow-up 36.7 months
VMP
Median OS VMP not reached
MP 43.1 months
P0.0008 3-year OS VMP 68.5, MP 54
MP
Mateos et al. J Clin Oncol 2010282259-66
69
Thal/Dex vs. MP and Len/Dex vs. Len/dex
  • High dose dexamethasone
  • ? responses
  • ? toxicity
  • ? survival

Ludwig et al, Blood 2009 113 3435-42 Rajkumar
et al, Lancet Oncol 2010 1129-37
70
Multicenter, two-stage randomized trial in newly
diagnosed MM patients older than 65 years
(PETHEMA- GEM05)
Mateos et al, Lancet Oncol 2010
71
PETHEMA-GEM05. Response rate to induction and
maintenance therapy
Induction Induction Maintenance Maintenance
VMP VTP VT VP
CR (IF-) 20 27 44 39
CR(IF) 12 10 15 16
PR 48 46 39 44
MR 10 6 2 1
Mateos et al, Lancet Oncol 2010
72
GIMEMA. VMP vs. VMPT (weekly bortezomib dosing)
  • ? Peripheral neuropathy
  • Maintain efficacy

Bringhen S et al. Blood 2010
73
Choice of Treatment
Aggressive disease MPV
Non-aggressive disease MPT
Poor cytogenetics MPV
Renal failure Vel/Dex
History of peripheral neuropathy Len-based
Very elderly MPT (Thal 100 mg/d)
Logistics MPT/ Len-based
74
Treatment of MM ultimate goal
Refined Total Therapy ? Increase the cure
fraction
Young patients
Individualized sequential approach ? long-term
disease control
Elderly patients
75
Treatment of Relapsed Myeloma
  • Backbone of Treatment
  • Thalidomide
  • Bortezomib
  • Lenalidomide
  • HDT/Stem Cell Transplant (sensitive relapse)

76
Treatment of Relapsed/Refractory Myeloma.
General Considerations (I)
  • Components of initial therapy
  • Degree/duration of response to primary therapy
  • gt2 years? retreatment
  • Consider HDT/SCT (chemosensitive relapse)

77
Treatment of Relapsed/Refractory Myeloma. General
Considerations (II)
  • Type of relapse
  • aggressive ? bortezomib-based
  • non-aggressive ? IMiDs-based
  • Previous toxicity
  • Peripheral neuropathy? avoid bortezomib and
    thalidomide
  • Age and PS
  • Elderly and/or poor PS?gentle approach

78
Main randomized trials on treatment of
relapsed/refractory myeloma
Regimen ORR() CR() TTP OS
Bort. vs. Dex1 38 vs. 18 6 vs. 1 6.2 vs. 3.5 80 vs. 66 at 1 yr
Bort. Doxil vs. Bort2 44 vs. 41 4 vs. 2 9.3 vs. 6.5 76 vs. 65 at 15 months
Len/Dex vs. Dex3 61 vs. 19.9 14.1 vs. 0.6 11.1 vs. 4.7 29.6 vs. 20.2 months
Len/Dex vs. Dex4 60.2 vs. 24 15.9 vs. 3.4 11.3 vs. 4.7 Not reached vs. 20.6 months

1Richardson et al., 2005 APEX trial 2Orlowski et
al., 2007 3Weber et al., 2007 4Dimopoulos et
al., 2007
79
Disease Evolution Sequential Therapy
M/P
Dex
Len/Dex
Vel
IF
IF-
EP
80
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