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Multiple Myeloma Joan Bladé Asunción, 8 de julio de 2011.

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Presentation on theme: "Multiple Myeloma Joan Bladé Asunción, 8 de julio de 2011."— Presentation transcript:

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

2 MONOCLONAL GAMMOPATHIES I. MALIGNANT 1. Multiple myeloma 2. Variants of myeloma Smoldering myeloma Non-secretor Plasma cell leukemia POEMS 3. Localized plasmacytomas Solitary plasmacytoma (bone) Extramedullary plasmacytoma 4. Waldenström’s macroglobulinemia 5. Primary amyloidosis II. NON-MALIGNANT 1. Monoclonal gammopathy of undetermined significance 2. 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 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 FeatureRR 95% Confidence Interval p-value Evolving vs non-evolving < IgA vs others M-protein (≥15 g/L)

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 <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 * The International Myeloma Working Group. Br J Haematol 2003; 121:

12 MONTHS MONTHS SMM. Evolution of the M-protein EvolvingNon-evolving g/L

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 SMM MGUS “EVOLVING” “NON EVOLVING” “NON EVOLVING” 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 β 2 -microglobulin Organ damage Renal function Hb

24 Author, yearParametersOther Durie and Salmon, 1975Hb, Ca, M-protein, bone lesionsRenal function Merlini et al, 1980 %PC, Cr, and Ca (IgG) Hb, Ca, M-protein (IgA) MRC, 1980Hb, urea, PS Cavo et al, 1989D & S, platelet count Greipp et al, 1988  2-microglobulin, LI Bladé et al, 1989Albumin, urea San Miguel et al, 1989Hb, 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. Main Staging Systems in MM

25 StageOverall 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 International Prognostic System (IPS) 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 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 High-resolution Genomic Profiles* (aCGH/mRNA microarray/FISH/novel bioinformatics) * 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 can overcome drug resistance in poor cytogenetic subgroups New therapies should target specific molecular pathways Novel Drugs and New Molecular Targets



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) P= CR Median: 6.1 yrs PR Median: 1.3 yrs 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 p= 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 sizeCR (%)P-value Serum* - < 10 g/L  10 g/L 15 Serum and urine** - < 10 g/L and < 0.5 g/24h – 20 g/L and / or 0.5 to 1 g/24h > 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* RegimenPre-ASCTPost-ASCT Dexa/VAD5%35% Cyclophospha mide/Dexa 7%32% VBMCP/VBAD10%35% *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* RegimenPre-ASCTPost-ASCT Thal/Dex6%23-34% Vel/Dex12%33% PAD-124%43% VTD21-30%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 RC (%)P-value TD vs. VTD (GIMEMA) <10 vs. ~35*0.001 VBMCP/VBAD+bortezomib vs. TD vs. VTD (PETHEMA) 23 vs. 0 vs VAD vs. VD (IFM ) 3 vs. 18*0.07 Cavo et al, Lancet 2010; Rosiñol et al, IMW 2011; Harousseau et al, JCO Bortezomib and high-risk cytogenetics (t (4;14) and or del 17p). PETHEMA-GEM05 *CR + nCR

49 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) EMP29%40%14% No EMP13%18%6% Rosiñol et al. IMW 2011


51 Pre- and post-ASCT CR rate according to the induction regimen. PETHEMA-GEM05. Pre-ASCTPost-ASCT VBMCP/VBAD + Bortezomib (%) 2138 TD (%)1424 VTD (%)3546 Rosiñol et al. IMW 2011

52 Consolidation / maintenance therapy

53 Consolidation/maintenance therapy Thalidomide EFS/PFSOS Pamidronate+thal vs pamidronate vs observation 52% vs. 37% vs. 36% Longer survival if suboptimal response postransplant Thal+PDN vs PDN42% vs. 23% Longer survival 86% vs 75% Thal vs observation6 vs. 4.1 yrs Shorter OS after relapse Longer OS in patients with cytogenetic abnormalities Thal vs. IFN33 vs. 22mShorter OS after relapse 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 Bortezomib (x 6 cycles) – Increase the postrasplant CR/nCR Lenalidomide (x 2 cycles) – Improved postrasplant response Consolidation/maintenance therapy 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 High molecular tumor burden (n=13) 11 Relapses MRD (-) correlates with a very low probability of relapse Ladetto et al, JCO 2010;28: Very low molecular tumor burden (N=19) 3 relapses

56 p<10 -7 P < IFM : 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 VTD? ASCT MEL-200 Consolidation VRD? Maintenance Len+glucocorticoids ±bortezomib

60 Patients non-eligible for HDT/SCT

61 Multiple myeloma in the elderly Results with “old” regimens MP – CR: <5% – Median overall survival: 2-3 yrs Dex-based – CR <5% – 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 RegimenCR rate (%) MPT 1,2 15 MPR MPV 4 30 Rev/Dex 5 or BIRD Palumbo et al. Blood 2008; 112:3107–14 2 Facon et al. Lancet 2007; 370:1209–18 3 Palumbo et al. JCO; 25: San Miguel et al. N Engl J Med 2008; 359: Lacy et al. Mayo Clin Proc 2007;82: Niesvizky et al. Blood 2008;111:1101-9

64 MPT vs. MP CR (%) PFS (%) OS (mos.) Palumbo et al, vs vs vs (p=NS) Facon et al, vs vs vs (p=0.0006) Hulin et al, vs vs vs (p=0.03) Wijermans et al, vs vs. 11 (PFS) 13 vs. 9 (EFS) 40 vs. 31 (p=0.05) Waage et al, vs. 415 vs vs. 32 (p=NS) 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 TreatmentO/NOverall survial time (months) median (SE) MP128/ (3.2) MPT62/ (4.5) MEL10078/ (2.7) 84 Proportion of surviving patients Time from randomisation (months) Median follow-up time = 51.5 months Facon et al, Lancet 2007; 370:

66 VISTA trial: VMP vs. MP VMP (%)MP (%) ORR7135 CR304 Median time to first response (mos) Median duration of response all responders (mos) patients achieving CR (mos) San Miguel et al. N Engl J Med. 2008; 359:906-17

67 VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR=0.483, p< Number of patients at risk: VMP: MP: Time (months) Patients without event (%) VMP MP San Miguel et al. N Engl J Med. 2008; 359: Time to progression: ~52% reduced risk of progression with VMP

68 OS: Confirmed survival benefit with VMP ~35% reduced risk of death with VMP Median follow-up 36.7 months Median OS: VMP: not reached MP: 43.1 months P= year OS: VMP: 68.5%, MP: 54% Mateos et al. J Clin Oncol 2010;28: VMP MP

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

71 PETHEMA-GEM05. Response rate to induction and maintenance therapy InductionMaintenance VMPVTPVTVP CR (IF-) CR(IF+) PR MR10621 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” diseaseMPV “Non-aggressive” diseaseMPT Poor cytogeneticsMPV Renal failureVel/Dex History of peripheral neuropathyLen-based Very elderlyMPT (Thal 100 mg/d) LogisticsMPT/ Len-based

74 Treatment of MM: ultimate goal Refined “Total Therapy”  Increase the cure fraction Individualized sequential approach  long-term disease control Young patients 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 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 Treatment of Relapsed/Refractory Myeloma. General Considerations (II)

78 Main randomized trials on treatment of relapsed/refractory myeloma RegimenORR(%)CR(%)TTPOS Bort. vs. Dex 1 38 vs. 186 vs vs vs. 66% at 1 yr Bort.+ Doxil vs. Bort 2 44 vs. 414 vs vs vs. 65% at 15 months Len/Dex vs. Dex 3 61 vs vs vs vs months Len/Dex vs. Dex vs vs vs. 4.7 Not reached vs months 1 Richardson et al., 2005 APEX trial; 2 Orlowski et al., 2007; 3 Weber et al., 2007; 4 Dimopoulos et al., 2007

79 Disease Evolution Sequential Therapy M/P Dex Vel Len/Dex IF- IF+ EP+


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