Epidemiology of plasma cell disorders

Transcription

1 Epidemiology of plasma cell disorders Ola Landgren, M.D., Ph.D., Senior Investigator Multiple Myeloma Section, National Cancer Institute, NIH London, UK, March 13, 2012

2 Disclosures: none

3 Overview Etiology and pathogenesis Second primary malignancies Survival patterns and beyond

4 Etiology and pathogenesis

5 Multiple myeloma Plasma cell malignancy, characterized by monoclonal protein in blood and/or urine 2 nd most common hematologic malignancy (20,000/year); 65,000 prevalent cases in US Average age of onset ~70 years

6 MGUS and smoldering myeloma Plasma cell precursor disorders, defined based on lab criteria ~5,000 SMM cases per year in US ~3% of 50+ y/o white population has MGUS (~3 to 5 million prevalent cases in US)

7 MGUS prevalence, by age and sex Kyle et al, NEJM 2006

8 Myeloma an increasing problem due to the aging population Many diagnosed at age year Proportion of patients 80+ years doubled from 16% to 31% Therefore, median age increased from 70 to 74 years Today, ~65,000 myeloma patients in the U.S. increasing! Turesson et al, Mayo Clin Proc 2010

9 Myeloma, racial disparity Landgren and Weiss, Leukemia 2009

10 MGUS, racial disparity Landgren et al, Blood 2010

11 MGUS, racial disparity Landgren et al, Blood 2010

12 Familial studies, using Swedish population databases Myeloma patients First-degree relatives of patients All myeloma pts, controls, and first-degree relatives Matched controls Any cancer Population controls First-degree relatives of controls Final database Cancer Registry Population Registry Multigenerational Registry

13 Familial aggregation, myeloma Kristinsson et al, Int J Cancer 2009

14 Earlier age of onset in African Americans, myeloma and MGUS Waxman et al, Blood 2010

15 Support for genetic factors in myeloma etiology Familial aggregation Racial disparity (more common in Blacks) Earlier age of onset in Blacks

16 Environmental factors, myeloma Odds ratio=1.9 (95% CI ) comparing MGUS positive in the Agricultural Health Study vs. Olmsted County, MN Landgren et al, Blood 2009

17 Obesity, MGUS and myeloma Landgren et al, Blood 2010

18 Chronic immune stimulation, MGUS and myeloma Lindqvist et al, Blood 2011

19 Support for environmental factors in myeloma etiology Pesticides Obesity Chronic immune stimulation Radiation? Chemicals? More??

20 What is our current focus?

21 Myeloma precursor disease: an opportunity to find a cure? Smoldering myeloma: ~10% annual risk of progression to multiple myeloma MGUS=monoclonal gammopathy of undetermined significance MGUS: ~1% annual risk of progression Kyle et al, New Engl J Medicine 2007

22 IMWG 2010 clinical guidelines for smoldering myeloma Baseline bone marrow biopsy and skeletal survey Repeat pertinent lab tests 2-3 months after initial recognition. If stable, repeat every 4-6 months for a year, and if stable every 6-12 months Treatment is not indicated unless it is part of a clinical trial. Consider clinical trials for selected patients; with the aim to delay and/or prevent progression to symptomatic myeloma Kyle et al. Int l Myeloma Working Group, Leukemia 2010

23 Is myeloma always preceded by a precursor state? Are there precursor patients at very high risk of progression?

24 Nationwide prospective PLCO Cancer Screening Trial Over 77,000 healthy men and women Age yrs at study enrollment Blood draw at baseline, repeated annually (up to 6 years) together with screening protocol Prospective follow-up for cancer Prorok et al, Clin Trials 2000

25 Patients who developed myeloma in the PLCO Trial Total number*, n 71 Age at diagnosis, mean (range) 70 (58 81) Male sex (%) 50 (71) Available annual samples, mean (range) 3 (1 6) Months between blood draw and myeloma dx, median (range) First pre-diagnosis blood draw 59 (29 118) Last pre-diagnosis blood draw 32 (24 84) *With available serum obtained 2 or more years prior to myeloma dx

26 Multiple myeloma is consistently preceded by a precursor state Yrs prior myeloma dx n/n Prevalence (95% CI) 2 27/ (87 100) 3 57/58 98 (91 100) 4 47/48 98 (89 100) 5 35/37 95 (82 99) 6 25/ (86 100) 7 14/15 93 (68 100) > 8 14/17 82 (57 96) Based on all MM patients with available serum obtained 2 yrs prior to MM diagnosis (n = 71). Landgren et al, Blood 2009

27 Risk stratification for smoldering myeloma (precursor disease) High-risk patients median time to multiple myeloma is <2 years No. of risk factors No. of patients, n (%) Progression at 5 years 1 76 (28) 25% (42) 51% 3 82 (30) 76% No. of risk factors No. of patients, n (%) Progression at 5 years 0 28 (31) 4% 1 22 (25) 46% 2 39 (44) 72% Risk factors: BMPCs >10% M-protein >3 g/dl FLC-ratio <0.125 or >8 Dispenzieri et al. Blood 2008 Risk factors: 95% abnormal plasma cells* Immunoparesis *Incl decreased CD38 expression, expression of CD56, and absence of CD19 and/or CD45 Pérez-Persona et al. Blood 2007

28 Bone marrow vascularity in myeloma precursor disease DCE MRI measuring Kep* CD 34 stains (microvessel density) Early Plasma Cell Dyscrasia * Kep is the rate on contrast agent moving from extravascular space to intravascular space mean kep=2.16 1/sec L3 vertebral body, measured Sagittal T2W TSE Sagittal T2W SPAIR TSE * Sagittal ktrans map * Sagittal kep map L3 vertebral body, measured mean kep=13.6 1/sec Late Plasma Cell Dyscrasia Sagittal T2W TSE Sagittal T2W SPAIR TSE * * Sagittal ktrans map Sagittal kep map No statistical difference in vascularity (MVD and DCE MRI) between smoldering myeloma and multiple myeloma patients Berg et al, unpublished data

29 High-risk smoldering myeloma patients have aggressive biology Plasma Cell Clustering Figure 4. Plasma cell sheeting is predictive of malignant progression in SMM Number of patients Plasma cell clusters Plasma cell sheets Plasma Cell Sheeting Risk profile Risk stratification based on PETHEMA model IHC staining CD138 positive plasma cells Berg et al, unpublished data

30 What are we doing in the clinic for patients with high-risk myeloma precursor disease?

31 Regulation of NK cell activity Equilibrium between activating and inhibiting signals received from the target cell through activatory receptors and inhibitory receptors (Killer-cell Immunoglobulin-like Receptors; KIR)

32 Using the patient s own immune system to kill myeloma cells MHC from allogeneic transplanted patient is not recognized by KIR of NK cells from donor due to genetic difference between donor and recipient. NK cell is activated. Mimicking mismatch situation with a blocking antibody targeting KIR. NK cell is activated.

33 Patients NK cell response to matched myeloma cells Spe ecific IFNγ expr ression (%) KIR2D SP NK cells (+IPH2101) KIR2D SP NK cells n=8 (Mean & SEM) Day Korde et al, unpublished data

34 Our treatment goals for high-risk smoldering myeloma Landgren et al, Clin Cancer Research 2011

35 Ongoing prospective natural history and molecular profiling study at NIH/NCI Baseline 6 months 12 months 1 year Group risk scores) Primary Objective To prospectively characterize the natural history and prognosis of MGUS and smoldering myeloma (including both Mayo Clinic and PETHEMA Study 2 years 3 years 4 years 5 years Secondary Objective To obtain and store primary blood and tissue samples for molecular profiling of tumor cells and bone marrow microenvironment (e.g., gene expression, sequencing, microrna, methylation, cytokines)

36 Using genome sequencing (RNA-Seq) to define mechanisms of progression Precursor disease Precursor disease Precursor disease Multiple myeloma Platform to discover somatic mutations and chromosomal translocations as well as to provide digital gene expression. Aim is to identify treatment targets delay or prevent multiple myeloma

37 Second primary malignancies

38 IFM : study design Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR Consolidation: Lenalidomide alone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Placebo (N=307) until relapse Lenalidomide (N=307) mg/d until relapse Attal et al; ASH 2010 (abstract 310)

39 IFM : survival outcomes Improvement in progression-free survival (placebo arm 24 months vs. lenalidomide arm 42 months) No overall survival improvement P=n.s p< Placebo Revlimid Placebo Revlimid PFS OS Attal et al; ASH 2010 (abstract 310)

40 IFM : second malignancies 19 second malignancies (hematologic and solid tumors) following myeloma 16 lenalidomide arm vs. 3 placebo arm; 10 in lenalidomide arm were hematologic (AML, MDS, ALL, HD) Attal et al; ASH 2010 (abstract 310)

41 CALGB : study design Registration Restaging Days Randomizatio n S-D Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better 1 yr from start of therapy > 2 x 10 6 CD34 cells/kg Mel 200 ASCT CR PR SD Placebo Lenalidomide 10 mg/d with (5 15 mg) Patient stratification based on diagnostic β-2m and thalidomide and lenalidomide therapy during induction McCarthy et al; ASH 2010 (abstract 37)

42 CALGB : study design 568 pts, <70 yrs, post-asct with stable disease. Randomized to lenalidomide vs. placebo Unblinded in December 2009; placebo arm closed; ~80% crossover; April 2008 median follow-up 28 mo McCarthy et al; ASH 2010 (abstract 37); Int l Myeloma Workshop 2011 (abstract)

43 CALGB : survival outcomes Median TTP: 42 mo Median TTP: 22 mo At median follow-up 28 months; better overall survival (lenalidomide 90% vs. placebo 83%; p=0.018) McCarthy et al; ASH 2010 (abstract 37); Int l Myeloma Workshop 2011 (abstract)

44 CALGB : second malignancies 21 second malignancies (hematologic and solid tumors) following myeloma Second malignancies: 15 lenalidomide and 6 placebo arm (5/21 were AML or MDS) McCarthy et al; ASH 2010 (abstract 37); Int l Myeloma Workshop 2011 (abstract)

45 MM-015: study design Cycles (28-day) 1-9 Cycles 10+ ION MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Continuous Lenalidomide Treatment 10 mg/day days 1-21 RANDOMIZATI MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MP Placebo Disease Progression Lenalidomide (25 mg/day) +/- Dexamethasone M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 Placebo PBO: days 1-21 Palumbo et al; ASH 2010 (abstract 620)

46 MM-015: survival outcomes 13 mo 14 mo 31 mo Second tumors MP (n=2), MPR (n=6*), MPR-R (n=4**) *2 AML; **2 AML and 2 MDS Palumbo et al; ASH 2010 (abstract 620)

47 What else is known about second malignancies following myeloma? 375 myeloma pts treated with melphalanbased therapy; 14 developed AML 1 Representing 17.4% actual risk of developing AML at 50 mo Bergsagel et al. N Engl J Med 1979

48 What are the mechanisms? Bergsagel et al. N Engl J Med 1979

49 What are the mechanisms? Mailankody et al. Blood 2011

50 What are the mechanisms? Mailankody et al. Blood 2011

51 What are the clinical implications? Based on small numbers, 3 randomized studies show more hematologic malignancies in the treatment arm ASH 2010 (abstracts): Attal et al.; McCarthy et al.; Palumbo et al.

52 What are the clinical implications? Landgren et al, NEJM 2011

53 What are the clinical implications? At median follow-up of 28 months, CALGB study shows better overall survival (lenalidomide 90% vs. placebo 83%; p=0.018) McCarthy et al. Int l Myeloma Workshop 2011 (abstract)

54 Clinical implications in summary Currently, we lack clear answers (due to small numbers and study limitations) Benefits versus risks We have to discuss these facts with our patients and stay updated Key question for the future: What are the mechanisms?

55 Survival patterns and beyond

56 Advances in the treatment of myeloma Waxman et al, Blood 2010

57 Overall survival has increased dramatically the past decades Newly diagnosed patients 65 years old (n=242). Periods of diagnosis: , , , , , and Turesson et al, J Clin Oncol 2010

58 However, we still have a lot to do in multiple myeloma Remains an incurable fatal disease, average overall survival ~6-7 years About 25% of patients only survive 1-3 years

59 Genome sequencing in multiple myeloma Chapman et al, Nature 2011

60 Genome sequencing in multiple myeloma Parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs Several oncogenic mechanisms suggested by pattern of somatic mutations Chapman et al, Nature 2011

61 MEK/Erk pathway in myeloma cell growth and differention Cell proliferation, cell motility and stress response

62 What is our current focus?

63 Proposed molecular classification of multiple myeloma MAF 16q23 c-maf 20q11 mafb 8q24.3 mafa NONE G1 Phase OFF MMSET/ FGFR3 4p16 CYCLIN D2 Cyclin D2 CDK 4, 6 CYCLIN D1 + D2 Cyclin D1 CYCLIN D1 Hyperdiploid CDK 4, 6 Rb E2F CYCLIND1 11q13 Cyclin D3 CDK 4, 6 P P P Rb P CYCLIN D3 6p21 p16 p15 p18 p19 E2F ON INK4a INK4b INK4c INK4d S phase Bergsagel and Kuehl, J Clin Oncol 2005

64 Both MAF and MMSET/FGFR3 myeloma have increased MAF transcription MAF mrna MAF signature* MAF MAF MMSET/FGFR3 MMSET/FGFR3 N=451 *Average expression of MAF and its 3 target genes (cyclind2, integrin beta-7, chemokine receptor 1) Annunziata et al, Blood 2011

65 MEK inhibition induces apoptosis in MAF expressing myeloma MAF MMSET/FGFR3 Annunziata et al, Blood 2011

66 MEK 1/2 inhibition in relapse/refractory multiple myeloma: multicenter phase 2 AZD6244, oral MEK 1/2 inhibitor, 75 mg twice daily on a 28-day cycle At least 2 prior lines of therapy 37 patients enrolled in trial 1, 12 consented to correlative sampling 1 Holkova et al, ASH 2011

67 Correlative assays based on CD138+ cells qrt-pcr: c-maf, MAFB, MAFA RT-PCR: JH-MMSET Pyrosequencing: RAS, BRAF NanoPro immunoassay: pperk1/2

68 Up-regulated c-maf, MAFB and MAFA expression in 3/12 (25%), 6/12 (50%), and 1/12 (8%) pts, respectively MAF relative mrna expression (log2) c-maf MAFB MAFA A B C D MAF qrt-pcr on CD138+ cells Zingone et al, ASH 2011

69 Kb 1.0 Kb 0.5 Kb 0.3 Kb RT-PCR on CD138+ cells to detect presence of JH-MMSET hybrid Zingone et al, ASH 2011 No template 2 OCI-MY5 (neg control) 1 XG-7 (pos control) Presence of MMSET translocation in 1/12 (8%) patient

70 Presence of RAS (n=5/11; 45%) and BRAF (n=1/11; 9%) mutations Patients with mutation, n/n (%) K-RAS 3/11 (27) N-RAS 2/11 (18) BRAF 1/11 (9) Pyrosequencing on CD138+ cells WT K-RAS codon 12 WT K-RAS codon 61 Zingone et al, ASH 2011

71 Mutations and translocations activating MEK/ERK pathway and clinical outcome Pt # Age Sex Prior lines of therapy, MAF RAS Best response Duration of response Comment 1 53 M Vel/Doxil, HDM/ ASCT, Rev/Dex MMSET, c-maf K-RAS VGPR 8 months 2 70 M Mel/Thal/Pred, Vel/Pred, Vel/Rev 3 66 F Thal/Dex. Vel, Vel/Doxil MAFB - SD 13 months MAFB - SD 9 months 4 57 F Rev/Vel/Dex, MAFB - SD 5 months Generalized skeletal pain Rev gone after 1 cycle 5 73 M Mel/Pred, VAD, HDM/ASCT, Thal, Rev/Dex, CTD, CRD, CVD, Bend/Vel/Dex, Pom 6 49 M Rev/Dex, HDM/ASCT, Thal, Rev, Rev/Dex, Allo, Mel - N-RAS PD 1 month Toxicity, dose reduction, disease progression - BRAF PD 1 month Toxicity, dose reduction, disease progression 7 72 M Vel/Dex, Vel/Rev/Dex MAFA K-RAS PD 1 month Toxicity, dose reduction, disease progression 8 57 F Thal/Dex, Rev/Dex Vel/Dex, Vel/Doxil c-maf, MAFB - PD 2 months Toxicity, dose reduction, disease progression

72 Patient #1: treatment history 52 y/o African American male; dx with multiple myeloma in January 2005: IgG lambda, M-spike 9 g/dl, Hgb 8.8g/dl, renal failure, lytic bone lesions Jan 2005: Velcade/Doxil, High-dose melphalan/asct (response: VGPR) March 2008: Relapse Elevated M-protein concentration FDG PET-CT revealed multiple new lytic lesions Right inguinal plasmacytoma April 2008: Plasmacytoma was excised, Revlimid/dexamethasone (response: CR), Revlimid maintenance (15 mg daily) June 2010: Relapse Elevated M-protein concentration (1.0 g/dl) Right inguinal plasmacytoma (2-3 cm diameter) July 2010: MEK inhibitor (AZD6244)

73 Patient #1: MEK inhibition down-regulates expression of MAF and its target* genes Patient #1 has MMSET translocation, c-maf up-regulated and K-RAS mutation Baseline Day 2 c-maf CCND2 ITGB7 CCR1 *CyclinD2 (CCND2), Integrin beta-7 (ITB7), Chemokine receptor 1 (CCR1) Zingone et al, ASH 2011

74 Patient #1: MEK inhibition reduces perk and pperk Baseline Day 2 Phosphorylation state of ERK1/2 detected by NanoPro Immunoassay Zingone et al, ASH 2011

75 Patient #1: M-protein concentration (g/dl) in relation to cycles of therapy Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Zingone et al, ASH 2011

76 Patient #1: Removed plasmacytoma treated with AZD6244 ex vivo Untreated 6 hours post treatment (10 um) 24 hours post treatment (10 um) 48 hours post treatment (10 um) Zingone et al, ASH 2011

77 Patient #1: Plasmacytoma shows activation of other MAPK cascade genes MAPK pathway gene expression array JUN CDK KRAS D1 D2 FOS GRB2 MAPK cascades MEK/ERK ERK5 p38/mapk JNK Also we found: - Mono-allelic deletion of Rb1-10% of cells have one copy of p53 Zingone et al, ASH 2011

78 Patient #6 (non-responder): low perk and pperk levels at baseline Baseline Day 2 Phosphorylation state of ERK1/2 detected by NanoPro Immunoassay

79 Functional imaging, disease activity

80 Molecular imaging to assess minimal bone disease in myeloma 18 F-NaF PET/CT to detect early bone lesions Exchange of hydroxyl ions in the hydroxy- apatite crystal; an indicator of bone mineralization 18 F-FDG PET/CT Dynamic contrast-enhanced-mri to visualize microcirculation patterns from MGUS to myeloma 18 F-FDG whole body PET/MRI Tan et al, ASH 2011

81 Carfilzomib-based study for high-risk smoldering multiple myeloma CRd CRd CRd CRd # CRd CRd CRd CRd C=36 mg/m 2, d 1, 4, 8, 11, 15, 18 R=25 mg, d 1-21/28 d=40 mg/week #=Harvest of stem cells (for eligible patients) R=10 mg, d 1-21/28, 12 cycles PET/CT Molecular characterization Correlative science PET/CT MRD (if CR) Correlative science Outcome PET/CT MRD (if CR) Correlative science Outcome CR

82 Labs and collaborators Landgren Lab Dr. Korde Dr. Kwok Dr. Zingone Mr. Costello RN Yancey RN Mulquin Mr. Cherry Dr. Mailankody Dr. Manasanch NIH Labs Dr. Staudt - Molecular pathogenesis and targeted therapy Dr. Choyke - Molecular imaging program Drs. Maric, Calvo, Bryant, and Jaffe Hematopathology Dr. Childs - NK cell immunotherapy Dr. Stetler-Stevenson - Flow cytometry Dr. Raffeld Molecular pathology Dr. Trepel - Pharmacodynamic assay development Dr. Annunziata - Molecular therapy Dr. Mock - Molecular therapy Dr. Robey - Bone marrow microenvironment Dr. Kuehl - Molecular pathogenesis Navy/Walter Reed Medical Center Mayo Clinic Dana-Farber Cancer Institute Karolinska Institute

83 Thank you for your attention! Ola Landgren, M.D., Ph.D. Mary Ann Yancey, R.N. Phone Marcia Mulquin, R.N. Phone