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

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)

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: 749-757.

Malignant Transformation of MGUS Actuarial probability: 1% per year (30% at 25 yrs) Actual probability (considering competing causes of death): 11% at 25 yrs

Factors Predicting Malignant Transformation in MGUS M-protein size IgA type Abnormal free-light chain ratio Aberrant phenotype (>95%) “Evolving” vs “Non-evolving”

MGUS. Predictors of Malignant Transformation Feature RR 95% Confidence Interval p-value Evolving vs non-evolving 12.14 5.80-25.40 <0.0001 IgA vs others 2.92 1.36-6.28 0.006 M-protein (≥15 g/L) 2.18 1.02-4.66 0.044

Evolving vs. Non-evolving MGUS

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: 812-817.

Smoldering Multiple Myeloma (Asymptomatic Myeloma)

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: 749-757.

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

“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

Monoclonal Gammopathies “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.

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”

Symptomatic Multiple Myeloma

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

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)

Am J Med, 42: 937-948, June 1967

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…

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

Prognostic Factors in MM Clinical and Laboratory Features Host characteristics Age PS Tumor burden β2-microglobulin Organ damage Renal function Hb

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.

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: 3412-20.

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

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.

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.

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: 313-25.

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

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

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

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

First-line treatment for MM in 2010 Patients eligible for HDT/SCT Patients non-eligible for HDT/SCT

Patients eligible for HDT/SCT

The crucial step for long-lasting response and prolonged survival is the achievement of CR postrasplant.

TTP according response to transplant (CR vs. PR) Median: 6.1 yrs PR Median: 1.3 yrs P=0.000001 Rovira et al., EBMT 2009 (abstract P592)

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)

Impact of Induction CR postransplant depends on the effectiveness of the induction therapy

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: 1037-1043 ** Nadal et al, BMT 2004; 33: 61-64

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

Which is the best induction regimen?

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;115:3655-63; 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

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: 1498-05; Rosiñol et al, JCO 2007; 25:1498-05; Popat et al, BJH 2008; 141: 512-6; Barlogie et al, BJH 2007; 138:176-85. **VTD-PACE + Tandem ASCT + VTD/TD

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 2005-01) 3 vs. 18* 0.07 *CR + nCR Cavo et al, Lancet 2010; Rosiñol et al, IMW 2011; Harousseau et al, JCO 2010.

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

TO TRANSPLANT OR NO TO TRANSPLANT... THIS IS THE QUESTION!!!

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

Consolidation / maintenance therapy

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;115:1113-20

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)

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;28:2077-81

IFM 2005-02: PFS from randomization Attal et al, ASCO 2010 (abstract 8018)

Best treatment for younger patients Refined “Total Therapy”

Refined Total Therapy

Refined “Total Therapy” Triple induction regimen ASCT Consolidation Maintenance VTD? MEL-200 VRD? Len+glucocorticoids ±bortezomib

Patients non-eligible for HDT/SCT

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

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)

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; 25:4459-65 4San Miguel et al. N Engl J Med 2008; 359:906-17 5Lacy et al. Mayo Clin Proc 2007;82:1179-84 6Niesvizky et al. Blood 2008;111:1101-9

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

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 12 24 36 48 60 72 84 Time from randomisation (months) Facon et al, Lancet 2007; 370: 1209-18

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

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<0.000001 10 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; 359:906-17

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;28:2259-66

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; 11:29-37

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

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

GIMEMA. VMP vs. VMPT (weekly bortezomib dosing)  Peripheral neuropathy Maintain efficacy Bringhen S et al. Blood 2010

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

Treatment of MM: ultimate goal Refined “Total Therapy”  Increase the cure fraction Young patients Individualized sequential approach  long-term disease control Elderly patients

Treatment of Relapsed Myeloma Backbone of Treatment Thalidomide Bortezomib Lenalidomide HDT/Stem Cell Transplant (sensitive relapse)

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)

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

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

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