Multiple Myeloma and Related Disorders. Zsolt Nagy

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1 Multiple Myeloma and Related Disorders Zsolt Nagy

2 Outline Biology Plasma Cell Dyscrasia MGUS Plasmacytoma Multiple myeloma Smoldering POEMS Waldenstrom s Macroglobulinemia Amyloidosis

3 Classification of Monoclonal Gammopathies Monoclonal Gammopathy of Undetermined Significance "Benign"/idiopathic Associated with other diseases (autoimmune, infectious, non-heme cancer, etc) Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia Other lymphoproliferative disorders Multiple Myeloma Smolderimg Multiple Myeloma Plasma cell leukemia IgD myeloma POEMS Plasmacytoma Heavy Chain disease Amyloidosis

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6 The Continuum of Plasma Cell Disorders Normal MGUS Indolent Multiple Myeloma Myeloma

7 Myeloma, Malpas et al. 2004

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9 The hallmark of plasma cell disorders is the presence of a paraprotein in the serum and/or urine.

10 Paraproteinemias Normal immunoglobulin pattern Polyclonal reflects progeny of different plasma cells Paraproteinemia Monoclonal immunoglobulin band in sera reflects synthesis from single plasma cell clone

11 SPEP Polyclonal Gammopathy Monoclonal Gammopathy

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14 Normal Immunoelectrophoresis

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16 Presentation of Plasma Cell Disorders Increased protein on a routine chemistry panel Anemia Bone pain Renal dysfunction Hypercalcemia

17 Pathophysiology: Monoclonal B- Cells/Plasma Cell Dyscrasia Marrow replacement Cytopenias Constitutional symptoms Decreased quantitative immunoglobulins Infections Lytic bone lesions Fractures Hypercalcemia Extramedullary involvement Plasmacytomas Organomegaly

18 Pathophysiology: Monoclonal Immunoglobulin Proteins Heavy chains or Light chains in serum, urine, kidney or other tissues Renal insufficiency Neurologic disease Hyperviscosity Cold Agglutinin disease AL Amyloidosis POEMS: Polyneuropathy, Organomegaly, Endocrine disturbances, M-protein, Skin changes

19 M-protein at the Mayo Clinic Multiple Myeloma 18% (185) Amyloidosis (AL) 10% (106) Lymphoma 5% (50) Smouldering myeloma 4% (39) Solitary or extramedullary plasmacytoma 3% (27) Chronic lymphocytic leukaemia 2% (21) MGUS 56% (578) Waldenström s macroglobulinaemia 2% (20) RA Kyle in: Myeloma Biology & Management, 1995

20 MGUS Diagnosis Serum M-protein Usually IgG or IgA, usually <3 g/dl Stable over time Marrow plasma cells <10% No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency Incidence 1-2% of adults Increases with age 6% aged y/o, 14% >90 y/o

21 Other diseases associated with M-protein Autoimmune diseases (RA, SLE, scleroderma) Skin diseases (pyoderma gangraenosum) Liver disease (cirrhosis) Infectious diseases (m.tuberculosis, Hep C,HIV)..

22 MGUS Progression 1384 patients at Mayo MGUS: 1% per year progression Relative risk 25x (myeloma), 46x (Waldenstrom s), 8.4x (amyloid), 2.4x (lymphoma) IgM MGUS: 1.5% per year Predictors Size of M-spike (> 2.5 g/dl, 41% at 10 yr) Serum albumin NEJM 2002;346:564. Kyle ASH 2002 #384.

23 MGUS Progression: 1% per Year NEJM 2002;346:564

24 Diagnostic work-up MGUS LAB CBC Serum Ca/alb and creatinin Serum protein electrophoresis (EF) and immunofixation (IF) Quantification of immunoglobulins 24-hour urine albumin, EF +IF Skeletal X rays Bm aspirate/biopsy if M-protein > 15 g/l IgA or IgM M-protein Abnormal free light chain ratio CT thorax/abdomen if IgM paraprotein (m.waldenstrom)

25 MGUS: Management Testing CBC, calcium, creatinine, SPEP with immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive) If M-protein 2-3 g/dl, add bone marrow and skeletal survey F/U SPEP/H&P repeated in 6 months, then annually

26 Multiple Myeloma and Related Disorders Definition: A group of diseases that involve malignant proliferation of Ig-secreting cells of B-cell lineage that are usually associated with paraproteinemia or paraproteinuria.

27 Multiple Myeloma US Incidence: 15,000 new cases/year 1% of malignancies US Prevalence: 65,000 cases/year Double incidence rate in African Americans Median age 65 3% <40 years old Unknown cause Radiation, benzene, solvents, pesticides, insecticides

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29 Etiology Etiology is not known. Risk factors: Race, sex. Increased risk with ionizing radiation and exposure to pesticides like Dioxin. Recently viruses like HHV-8 and SV-40, have been linked to myeloma development.

30 Pathogenesis Bone marrow microenvironment very important for proliferation and chemotherapy resistance. BM stromal cells produce IL-6, responsible for pathogenesis and progression. IL-6 inhibits apoptosis of plasma cells. IL-6 contributes to bone loss by stimulating osteoclasts and inhibiting bone formation. Interaction with extracellular matrix proteins protect cells from chemo and radiation.

31 MM: Clinical Features Disease of the elderly (7th decade) Bone pain most commonly vertebra and long bones lytic lesions fractures

32 Myeloma: Clinical Features Bone pain: often with loss of height Constitutional: weakness, fatigue, and weight loss Anemia Renal disease: renal tubular dysfunction Infections: neutropenia/hypogammaglobulinemia Hypercalcemia: myeloma cells secrete osteoclast-activating factors Hyperviscosity: 2% with myeloma; 50% with macroglobulinemia Neurologic dysfunction: spinal cord or nerve root compression

33 Major Symptoms at Diagnosis Bone pain: 58% Fatigue: 32% Weight loss: 24% Paresthesias: 5% 11% of patients are asymptomatic or have only mild symptoms at diagnosis Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

34 Multiple Myeloma Typical Punched Out Lesions

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38 Multiple Myeloma

39 Diagnostic Criteria for Myeloma Patient Criteria MGUS [1,2] Smoldering Myeloma [1] M protein < 3 g/dl spike 3 g/dl spike and/or Monoclonal plasma cells in bone marrow, % End-organ damage *C: Calcium elevation (> 11.5 mg/l or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dl) A: Anemia (Hb < 10 g/dl or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) Active Myeloma In serum and/or urine [2] < [2] None None 1 CRAB* feature [3] Only patients with symptomatic MM should be treated 1. IMWG. Br J Haematol. 2003;121: Kyle RA, et al. N Engl J Med. 2002;346: Durie BG, et al. Hematol J. 2003;4:

40 Multiple Myeloma Diagnosis (1 major+1 minor or 3 minor) Major Criteria Plasmacytoma on tissue biopsy 30% Marrow plasmacytosis M-protein 3.5 g/dl IgG 2 g/dl IgA 1g/24 hr urine Bence Jones Minor Criteria 10-29% Marrow plasmacytosis M-protein Less than major Lytic bone lesions Low immunoglobuins IgM <50 mg/dl IgA <100 mg/dl IgG <600 mg/dl

41 Newly Diagnosed Multiple Myeloma: N=1027 Median age: 66 years Median survival: 33 months Did not improve 1985 through 1998 Multivariate analysis Age, plasma cell labeling index, thrombocytopenia, serum albumin, creatinine (log value) Kyle, Mayo Clin Proc, 2003.

42 Newly Diagnosed Multiple Myeloma: % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Ca Cr >2 Anemia Skel Surv UPEP SPEP Kyle, Mayo Clin Proc, 2003.

43 Myeloma Diagnostic Work-Up SPEP and UPEP (24 collection) with immunofixation 3% nonsecretory: check serum free light chains Skeletal survey (not a bone scan) Quantitative serum immunoglobulins (IgA, IgG, IgM) Bone Marrow Aspirate and Biopsy Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis

44 M-Protein Tests Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA) Screening (SPEP/UPEP) Gamma-globulins Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/cll Monoclonality Immunofixation with monospecific antibodies Immunoelectrophoresis Immunoassay for serum free light chains (Mayo Clinic)

45 Myeloma Prognostic Work-Up Hemoglobin Calcium Serum creatinine Beta-2 microglobulin Albumin Bone Marrow cytogenetics FISH chromosome 13 and 11? C-reactive protein?? Plasma cell labeling index?? Serum IL-6??

46 Myeloma Renal Disease Myeloma kidney Normal glomerular function Concentrated light chains precipitate in tubules Monoclonal light chains seen in UPEP with immunofixation Glomerular lesions Deposits of amyloid or light chain deposition disease Nonselective leakage of all serum proteins UPEP preponderance of albumin

47 Renal Manifestations Myeloma Kidney Cast Formation Light chain Deposition Amyloidosis Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):

48 Pathology

49 Myeloma: Durie-Salmon Staging Stage I Hemoglobin >10 g/dl Normal calcium No lytic bone lesions Low M-protein IgG <5 g/dl IgA <3 g/dl Bence Jones <4 g/24h Stage II (not Stage I/III) Stage III Hemoglobin <8.5 Calcium >12 (adjusted) >3 lytic bone lesions High M-protein IgG >7 g/dl IgA >5 g/dl Bence Jones >12 g/24h A) Creatinine <2 B) Creatinine >2

50 Myeloma: Median Survival Durie-Salmon stage Stage I Stage II Stage III 60 months 40 months 15 months

51 International Myeloma Working Group Staging System Stage 2 Microglobulin Albumin I < 3.5 > 3.5 II < <3.5 any III > 5.5 any

52 Therapy of Newly Diagnosed Multiple Myeloma: Kyle, Mayo Clin Proc, 2003.

53 OS (%) Multiple Myeloma in Session: Basics of Multiple Myeloma clinicaloptions.com/oncology No Improvement in Therapy for Patients With Myeloma in 30 Yrs Until... Prospective, randomized study of autologous bone marrow transplantation plus chemotherapy 100 Type of Response Patients, n Conventional Dose (N = 100) High Dose (N = 100) CR 5 22 Very good PR 9 16 PR MR Conventional dose High dose PD patients in high-dose group received autologous transplantation Mos Attal M, et al. N Engl J Med. 1996;335:91-97.

54 Myeloma: Therapy Principles Observation for stage I Incurable despite conventional chemotherapy and high-dose therapy Bisphosphonates Chemotherapy Conventional High-dose with stem cell rescue New agents Graft-versus-myeloma

55 Myeloma: Therapy Alkylating agents Melphalan: low-dose oral to high-dose myeloablative Steroids Alone (pulse Dexamethasone) or combination (M&P, VAD, Thal/Dex) Cyclophosphamide Thalidomide and the IMiD s Bortezomib (Velcade): proteosome inhibitor Graft-versus-myeloma effect Mini-allogeneic transplantation Interferon: maintenance

56 Therapy of Multiple Myeloma Chemotherapy pulse dexamethasone pulse dexamethasone+ thalidomide pulse dexamethasone +lenalidomide (revlimid) pulse dexamethasone + bortezimib (velcade) melphalan+prednisone + imid (not transplant candidate) Autologous stem cell transplant Radiation

57 Major Classes of Drugs Used in the Treatment of Myeloma Kyle, R. A. et al. N Engl J Med 2004;351:

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59 Autologous Transplantation NEJM 2003; 348: 1875.

60 Myeloma: Supportive Therapy Bisphosphonates Phase III: monthly pamidronate (JCO 1998;16:593) Skeletal-related events 38% versus 51%, p=0.015 Median survival 21 versus 14 months Compression fractures: vertebroplasty DVT risk: steroids, steroids + thalidomide Hypercalcemia Renal insufficiency:?plasmapheresis Infections Anemia: Eyrthropoietins

61 Myeloma Bone Marrow Interactions Microenvironment Myeloma cell adhesion molecules react with stroma Release of osteoclast activating factors (IL-1B, IL-6, TNFB) Vascular endothelial growth factor (VEGF) secreted by myeloma cells Myeloma Bone Disease

62 New Agents

63 Smoldering Myeloma Serum M-protein >3 g/dl Marrow plasma cells >10% No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency Evolve to overt multiple myeloma 3.3% per year Greatest for IgA JCO 2002;20:1625.

64 Plasmacytoma

65 Extramedullary Plasmacytoma ~3% of plasma cell neoplasms Isolated plasma cell tumors of soft tissues Upper respiratory tract common Uninvolved marrow, negative skeletal survey M-protein present ~25% cases Disappears following treatment Curable with local radiation therapy

66 Solitary Plasmacytoma of Bone ~3% of plasma cell neoplasms One isolated bony lesion of plasma cells Uninvolved marrow <5% plasma cells M-protein present ~25% cases Disappears following treatment Curable with local radiation therapy Median OS 10 years Multiple myeloma develops in 50-60%

67 Osteosclerotic Myeloma (POEMS) Polyneuropathy Sensorimotor peripheral neuropathy in 75% Organomegaly Lymphadenopathy, hepatomegaly, splenomegaly Endocrinopathy Adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic M-Protein Skin changes Hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails

68 Osteosclerotic Myeloma

69 Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009

70 30-50% of patients: deletion 6q by FISH

71 Lymphoplasmacytic Lymphoma (Waldenstrom s Macroglobulinemia) Malignant proliferation of plasmacytoid lymphocytes secreting IgM M-protein 1400 cases/year Organomegaly/Peripheral neuropathies Cryoglobulinemia Type I: Raynaud s phenomenon, cold urticaria, etc. Type II: Purpura, arthralgias, renal failure, mononeuritis IgM tissue infiltration/al amyloidosis Coagulation abnormalities

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73 Consensus recommendations of the 4th International WM meeting First Line therapy: Combination therapy (RCD or CPR; Cytoxan+nucleoside analogues+r; R-CHOP, R-CVP) Rituximab single agent Nucleoside analogues Alkylators Salvage therapy: Re-use therapies Bortezomib Thalidomide+steroids Alemtuzumab AHSCT Dimopoulos, JCO 2009, Treon et al Clin Lymph and Myeloma 2009

74 Hyperviscosity Usually IgM >5 g/dl, viscosity >4.0 Eyes Sausage link conjunctival and retinal veins Retinal hemorrhages, Papilledema CNS Ataxia, nystagmus, vertigo, confusion, altered consciousness Increased intravascular volume Dilutional anemia Risk congestive heart failure with transfusion Therapy: plasmapheresis/chemotherapy

75 Waldenstrom s Macroglobulinemia: Therapy Plasmapheresis for hyperviscosity 2-Chlorodeoxyadenosine (2-CdA, cladribine) Fludarabine Rituximab Other myeloma-like therapies

76 Monoclonal IgM: DDx MGUS Multiple myeloma Waldenstrom s CLL Chronic cold agglutinin disease No evidence of neoplasia Hemolytic anemia aggravated by cold exposure 90% have kappa light chains

77 Amyloidosis Extracellular tissue deposition of low molecular weight fibrils Beta-pleated sheets, bind Congo red Precursor proteins involved Monoclonal immunoglobulin light chains: Primary (AL) Amyloidosis Serum amyloid A protein: Reactive or Secondary (AA) Amyloidosis Beta-2 microglobulin: Dialysis (DA) Amyloidosis Transthyretin, apolipoprotein A-I, Alzheimer amyloid precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin

78 The Past 1854 Virchow: Amyloid 1922 Bennhold: Congo red 1959 Cohen & Calkins Fibrillar structure 1968 Eanes & Glenner cross- pleated struct. X-ray diffraction pattern

79 The Beginning of AL Amyloidosis 1931 Magnus-Levy (Mount Sinai Hospital, New York) Bence Jones protein is "Mother Substance 1961 Kyle & Bayrd Abnormal plasma cells in all 1964 Osserman Bence Jones protein 1971 Glenner Fibril & Bence Jones protein were the same

80 Amyloidosis: Protein Misfolding Diseases ~30 proteins localized Amyloidosis systemic Amyloidosis Merlini & Bellotti NEJM 2003 Sipe et al, 2012

81 Amyloid fibrils Misfolded FLC Small dangerous clone 1 (BMPC 7%) 53% LC only 75% l proteotoxicity structural damage λ1* λ6** Early detection of amyloid heart involvement is vital 1 Merlini & Stone, Blood. 2006; *Perfetti et al, Blood. 2012; **Comenzo et al, Br J Haematol. 1999

82 Amyloidosis: Presentation Nephrotic syndrome Refractory CHF, Arrhythmia, Heart block Orthostatic hypotension, Peripheral neuropathy Bleeding diathesis (Raccoon eyes) Factor X deficiency, liver disease GI bleeding, Gastroparesis/Dysmotility, Malabsorption Macroglossia, Shoulder pad sign, Carpal tunnel syndrome, Organomegaly Skin thickening/waxy, easy bruising

83 Amyloidosis

84 Diagnosis of Amyloidosis Merlini et al, Blood :

85 Amyloidosis: Work-up Biopsy Involved organs or bone marrow Fat pad, salivary glands, rectal mucosa: 50-70% success for diagnosis Echocardiography suggestive Speckled myocardium Interventricular septal thickening Distinguish from hereditary forms (10%) Evaluate for myeloma (rare)

86 AL Amyloidosis: Course Rare progression to multiple myeloma (0.4%) Poor long-term prognosis Cardiac, renal, hepatic failure, and infection Prognostic factors: circulating plasma cells, high beta-2 microglobulin, marrow plasmacytosis >10%, dominant cardiac involvement High B2M, marrow plasmacytosis: median survival 0: 54 months 1: 19 months 2: 13.5 months

87 AL Amyloidosis: Therapy Chemotherapy Dexamethasone with Dex/IFN maintenance High-dose melphalan with Auto transplantation Risky with cardiac, renal, GI involvement Dhodapkar, Blood 2004;104:3520. Skinner, Annals 2004;140:85

88 Therapy Development in AL Amyloidosis % 1990 MP 1 ASCT 2-4 Dex MDex 8,9 TDex 10 CTD LDex 12,13 B 14 CyBorD 15,16 1. Kyle, et al. NEJM Comenzo, et al. Blood Gertz, et al. Leuk Lymphoma Cibeira, et al. Blood Gertz, et al. Am J Hematol Merlini, et al. Br J Haematol Dhodapkar, et al. Blood Palladini, et al. Blood Jaccard, et al. NEJM Palladini, et al. Blood Wechalekar, et al. Blood Sanchorawala, et al. Blood Dispenzieri, et al. Blood Reece, et al. Blood Mikhael, et al. Blood Venner, et al. Blood 2012 Survival at 5 years 1131 AL patients Pavia Center

89 New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes. Palladini et al, J Clin Oncol. 2012;30: FLC NT-proBNP Proportion surviving acr VGPR Negative s. & u.ife, normal FLR dflc <40 mg/l PR dflc decrease 50% NR p< Time (months) p<0.001 other p=0.01 CR (97 patients, 3.6 deaths/100 py) VGPR (233 patients, 9.6 deaths/100 py) PR (140 patients, 23.7 deaths/100 py) NR (179 patients, 47.2 deaths/100 py) Proportion surviving p<0.001 p<0.001 NT-proBNP progression (at least 300 ng/l and 30% increase), 169 patients NT-proBNP stable, 108 patients NT-proBNP response (at least 300 ng/l and 30% decrease), 100 patients Time (months) Renal insufficiency and IMiDs may alter NT-proBNP metabolism New cardiac response criteria reduction of NT-proBNP >30% and >300 ng/l Renal response criteria under validation

90 Therapy is Highly Individualized and Must be Risk-adapted Based on Cardiac Biomarkers and Response-tailored o Treatment endpoint: at least VGPR o Hematologic and cardiac response should be assessed frequently, every 1-2 cycles (or three months after ASCT) o Rapid switch if no response o Therapy can be continued for 1-2 cycles beyond best response for consolidation <VGPR Bortez if unexposed and no severe neuropathy Len, Pom 1, Benda 2 in resist. to alkyl/bortez/thal Len requires monitoring renal function New drugs, such as Ixazomib 3 1 Dispenzieri et al, Blood 2012;119 : Merlini et al, Blood. 2012;120(21) Abstr Merlini et al, Blood 2012;120(21) Abstr 731

91 Treatment Selection is Based on Cardiac Biomarkers Gertz et al, Bone Marrow Transplant. 2013;48: Wechalekar et al, Blood 2013;121: Merlini et al, Blood :

92 Summary Spectrum of mature B-cell neoplasms/plasma cell dyscrasias Clinical manifestations: Tumor growth, marrow and tissue infiltration M-protein accumulation or infiltration Immune dysfunction Kidney and bone disease Therapy not curative, but increasingly effective