1. Joan Bladé Asunción, 8 de julio de 2011
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
Waldenström’s 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 <3g/dL
Bone marrow plasma cells <10%
No clinical manifestations or other laboratory abnormalities attributable to the monoclonal gammopathy
En ausencia de IR, anemia, hipercalcemia, lesiones osteolíticas u otras manifestaciones atribuibles a la gammapatía monoclonal
The International Myeloma Working Group. Br J Haematol 2003; 121:

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 (>95%)
“Evolving” vs “Non-evolving”

7. MGUS. Predictors of Malignant Transformation
Feature RR
95% Confidence Interval
p-value
Evolving
vs non-evolving
12.14
<0.0001
IgA vs others
2.92
0.006
M-protein
(≥15 g/L)
2.18
0.044

8. Evolving vs. Non-evolving MGUS

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 <15 g/L 5%
Rajkumar et al. Haematologica / The Hematology Journal 2005; S1: 194.
Rajkumar et al. Blood 2005; 106:

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
I finalment parlaré més breument de les dues GM que a diferència del MM no s’han de tractar: el MQ o MM asimptomàtic i la GMSI que per ser la GM més freqüent, m’hi extendré una mica més. Unicament dir del MQ quins són els seus criteris diagnòstics:.....En ausencia de IR, anemia, hipercalcemia, lesiones osteolíticas u otras manifestaciones atribuibles a la gammapatía monoclonal. Aqueesta entitat queda doncs entre la definició de MM i la de GMSI.
* The International Myeloma Working Group. Br J Haematol 2003; 121:

12. SMM. Evolution of the M-protein
g/L
MONTHS 20 30 40 50 60 70 80 6 12 18 24 36 42 48 54 66 72 78 84 90
g/L
MONTHS 25 35 45 55 65 75 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
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
“EVOLVING”
SMM
“NON EVOLVING”
“NON EVOLVING”
MGUS
Rosiñol et al. Br J Haematol 2003; 123:
Rosiñol et al. Mayo Clin Proc 2007; 82:

15. SMM: Factors Predicting Progression
M-protein size ≥ 30 g/L and ≥10% BMPC
Abnormal free-light chain ratio
Aberrant phenotype (>95%)
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 (>90%) 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: , June 1967

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
β2-microglobulin
Organ damage
Renal function Hb

24. 2-microglobulin, albumin
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 < 3.5 mg/L and albumin ≥ 3.5 g/dL 62 II
-2M < 3.5 mg/L and albumin < 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:

26. Cytogenetic Prognostic Subgroups in Multiple Myeloma
Good/average prognosis
Hyperdiploidy
t(11;14)(q32;q32): cyclin D1 upregulation
Bad prognosis
Hypodiploidy
t(4;14)(p16.3;q32): FGFR3&MMSET upregulation
t(14;16)(q32;q23): 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:
* Avet-Loiseau H et al. Blood 2007; 109:

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:
** Zhan F et al. Blood 2006; 108:

29. High-resolution Genomic Profiles
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:

30. GEP of tumor biology / chemotherapy sensitivity can refine the ISS classification

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:
Bartel TB, et al. Blood 2009; 114:

34. Novel Drugs and New Molecular Targets
Novel drugs can overcome drug resistance in poor cytogenetic subgroups
New therapies should target specific molecular pathways

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)
Median: 6.1 yrs PR
Median: 1.3 yrs P=
Rovira et al., EBMT 2009 (abstract P592)

41. Overall survival according response to transplant (CR vs. PR)
Median: 9.6 yrs PR
Median: 4 yrs
p=0.0001
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*
- < 10 g/L 52
0.01
-  10 g/L 15
Serum and urine**
- < 10 g/L and < 0.5 g/24h 67
- 10 – 20 g/L and / or 0.5 to 1 g/24h 21
0.03
- > 20 g/L and / or > 1 g/24h 7
*Alexanian et al, BMT 2001; 27:
** Nadal et al, BMT 2004; 33: 61-64

44. Treatment options for patients eligible for transplantation
Induction
‘Traditional’
VAD
CyDex
Bortezomib-based:
VelDex
VTD
PAD
IMiD-based:
Thal/Dex
TAD
CTD Rd
VRD
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*
Pre-ASCT
Post-ASCT
Dexa/VAD 5%
35%
Cyclophosphamide/Dexa 7%
32%
VBMCP/VBAD
10%
*Bladé et al. Blood 2010;115: ; Bladé et al. Haematologica 2010;95:702-4; Harousseau et al. JCO 2010; Mellqvist et al. Cancer 2008;112:129-35; Rosiñol et al, IMW 2011

47. Pre and Post-ASCT CR Rate with “Novel” Induction Regimens*
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: ; Rosiñol et al, JCO 2007; 25: ; Popat et al, BJH 2008; 141: 512-6; Barlogie et al, BJH 2007; 138:
**VTD-PACE + Tandem ASCT + VTD/TD

48. Bortezomib and high-risk cytogenetics (t (4;14) and or del 17p)
Bortezomib and high-risk cytogenetics (t (4;14) and or del 17p). PETHEMA-GEM05
RC (%)
P-value
TD vs. VTD
(GIMEMA)
<10 vs. ~35*
0.001
VBMCP/VBAD+bortezomib
vs. TD vs. VTD
(PETHEMA)
23 vs. 0 vs. 42
0.003
VAD vs. VD
(IFM )
3 vs. 18*
0.07
*CR + nCR
Cavo et al, Lancet 2010; Rosiñol et al, IMW 2011; Harousseau et al, JCO 2010.

49. VBCMP/VBAD + bortezomib (n=14)
Progressive Disease in Pre-transplant Induction According to the Presence or Absence of EMP (PETHEMA-GEM05)
27% vs. 12%, p=0.01
VBCMP/VBAD + bortezomib (n=14) TD
(n=20)
VTD
(n=21)
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
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
Pamidronate+thal vs pamidronate vs observation
52% vs. 37% vs. 36%
Longer survival if suboptimal response postransplant
Thal+PDN 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
Attal et al. Blood 2006;108:3289–94; Spencer et al. J Clin Oncol 2009;27:1788–93; Barlogie et al. N Engl J Med 2006;354:1021–30; Blood 2008;112:3115–21; Lokhorst et al. Blood 2010;115:

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 (n=6)
Continued remissions
Very low molecular tumor burden
(N=19)
3 relapses
High molecular tumor
burden (n=13)
11 Relapses
MRD (-) correlates with a very low probability of relapse
Ladetto et al, JCO 2010;28:

56. IFM 2005-02: PFS from randomization
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
ASCT
Consolidation
Maintenance
VTD?
MEL-200
VRD?
Len+glucocorticoids
±bortezomib

60. Patients non-eligible for HDT/SCT

61. Multiple myeloma in the elderly Results with “old” regimensMP
CR: <5%
Median overall survival: 2-3 yrs
Dex-based
CR <5%

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
1Palumbo et al. Blood 2008; 112:3107–14
2Facon et al. Lancet 2007; 370:1209–18
3Palumbo et al. JCO; 25:
4San Miguel et al. N Engl J Med 2008; 359:906-17
5Lacy et al. Mayo Clin Proc 2007;82:
6Niesvizky et al. Blood 2008;111:1101-9

64. MPT vs. MP CR (%) PFS (%) OS (mos.) Palumbo et al, 2008 16 vs. 4
(p=NS)
Facon et al, 2007
13 vs. 2
27.5 vs. 17.8
51.6 vs. 33.2
(p=0.0006)
Hulin et al,
2009
7 vs. 1
24.1 vs. 18.5
44 vs. 29.1
(p=0.03)
Wijermans et al, 2010
2 vs. 2
15 vs. 11 (PFS)
13 vs. 9 (EFS)
40 vs. 31
(p=0.05)
Waage et al, 2010
13 vs. 4
15 vs. 14
29 vs. 32
Palumbo et al. Blood 2008; 112:3107–3114
Facon et al. Lancet 2007; 370:1209–1218
Hulin et al. J Clin Oncol 2009; 27:3664–3670
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/ (3.2)
MPT 62/ (4.5)
MEL100 78/ (2.7)
0.8
0.6
Proportion of surviving patients
0.4
0.2
Median follow-up time = 51.5 months 12 24 36 48 60 72 84
Time from randomisation (months)
Facon et al, Lancet 2007; 370:

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; 359:906-17

67. Time to progression: ~52% reduced risk of progression with VMP
100 90
VMP MP 80 70 60
Patients without event (%) 50 40 30 20
VMP: 24.0 months (83 events)
MP: 16.6 months (146 events)
HR=0.483, p< 10 3 6 9 12 15 18 21 24 27
Time (months)
Number of patients at risk:
VMP:
MP:
San Miguel et al. N Engl J Med. 2008; 359:906-17

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
P=0.0008
3-year OS: VMP: 68.5%, MP: 54% MP
Mateos et al. J Clin Oncol 2010;28:

69. Thal/Dex vs. MP and Len/Dex vs. Len/dex
High dose dexamethasone
 responses
 toxicity
 survival
Ludwig et al, Blood 2009; 113:
Rajkumar et al, Lancet Oncol 2010; 11:29-37

70. Induction
Bort/Mel/Pred
(VMP)
Bort/Thal/Pred
(VTP) vs
(GEM05>65)
Multicenter, two-stage randomized trial in newly diagnosed MM patients older than 65 years (PETHEMA- GEM05)
Maintenance
Bort/Thal
(VT)
Bort/Pred
(VP)
Mateos et al, Lancet Oncol 2010

71. PETHEMA-GEM05. Response rate to induction and maintenance therapy
VMP
VTP VT VP
CR (IF-) 20 27 44 39
CR(IF+) 12 10 15 16 PR 48 46 MR 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
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
>2 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 months
Len/Dex vs. Dex4
60.2 vs. 24
15.9 vs. 3.4
11.3 vs. 4.7
Not reached vs 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+