THE MANY FACES OF MONOCLONAL GAMMOPATHIES

Marion S. Sternbach, MD, FRCP(C), FACP

Presented at Medicine Grand Rounds, St Josephs Hospital Sept 19, 2007

Monoclonal Gammopathies Objectives. 1. Getting acquainted with varied aspects of clinical presentation of the Monoclonal Gammopathies (MG) and their association with different conditions. 2. Following the evolution and pathogenesis from MGUS to myelomas or lymphomas.

The immunoglobulin molecule

The basic structure of immunoglobulins
C C Fc Receptor Region Heavy Chain (gamma, miu, alpha Delta) C C Hinge or J region S-S bridges Light Chain ( kappa, lambda)

N N

N N Fab. Antibody binding site regions

The antibody producing and secreting cells

B-Lymphocytes ( CD19,20)

Immunoglobulins in cytosol and surface

Plasma cell

Monoclonal Gammopathies
Medicine involves a life time of learning, not only because treatments change and improve constantly, but because NO TWO PATIENTS ARE IDENTICAL & THE SAME DIAGNOSIS PLAYS ITSELF OUT DIFFERENTLY IN EVERY PATIENT.

Monoclonal Gammopathies, Definition

A monoclonal expansion of a single NON FUNCTIONAL ANTIBODY, originating in a mutated MONOCLONAL B- LYMPHOCYTE or PLASMA CELL. Plasma cells are terminal non proliferating cells, secreting gamma globulins = functional antibodies. Once they mutated, they can proliferate producing the pathological antibody.

Monoclonal Antibodies Patient presentations

1. FH, 46 year old female, dental assistant , never exposed to toxic chemicals, fumes or pollutants. Experienced fatigue, full physical check up by family MD and investigations revealed an abnormal protein electrophoresis. Referred to Hematology. Physical Exam WNL, Past History non contributory, exc. For years of smoking, quit 2 years ago.

Monoclonal Gammopathies, Patient presentations ( 1. cont.)

Investigations: CBC, Renal, Hepatic functions N. Immune fixation: Monoclonal IgGK of 15 g/L. Bone Marrow aspirate and biopsy perfectly Normal. Skeletal survey, chest X ray, abdominal and pelvic US Normal. Pt. followed for 3 years with no change. Then sudden back pain in the T6-T7 area.

Monoclonal Gammopathies Patient presentation (1. cont.)

All tests from before unchanged, exc. IgGK now up to 21 g/l., Skeletal survey showed a collapsed T6 vertebra. Bone marrow aspirate and biopsy Normal. MRI of spine showed lytic lesion in T6, nowhere else. Vertebral biopsy confirmed Plasmacytoma. VAD chemotherapy administered for 6 cycles with monthly Pamidronate, followed by Autologous PBSC transplant. Successful.

Monoclonal Gammopathies Patient presentation 2.

2. 72 year old female from Poland, retired teacher. Suffered for years from Mixed Connective Tissue disorder. Got intermittent steroid therapy. Ref. to me for monoclonal gammopathy IgGL Initial investigations, including BM Bx, skeletal survey, CT-s all Neg. Two years later, followed regularly developed significant lymphadenopathy and splenomegaly.

Monoclonal Gammopathies Patient presentation (2. cont.)

Lymph node and Bone marrow biopsy revealed low grade diffuse lymphocytic lymphoma. Treated with Cyclophosphamide, Vincristine, Prednisone 8 cycles. Improved remarkably for over one year. Even the Mixed Conn. Tissue Dis. Symptoms abated. 18 months later huge lymph nodes, aggressive large cell lymphoma and Hypercalcemia. CHOP chemotherapy, short remission. Died in one year.

Monoclonal Gammopathies, Lymphocytic lymphoma, diffuse

Monoclonal Gammopathies Large Cell diffuse Lymphoma

Monoclonal Gammopathies Patient presentations 3.

43 year old African female from Congo, immigrated to Canada to 25 year old daughter. Ref. because of extreme weight loss, weakness, diarrheas, peripheral lymphadenopathy and IgGK of 32 g/l. Exam: confirmed diffuse lymphadenop., large tonsils, splenomegaly. Bone marrow: heavy infiltration with plasma cells with mostly kappa surface immuno globulin. No skeletal lesions, HIV positive.

Monoclonal Gammopathies Patient presentations 3. (cont.)

Ref. by me to STD Clinic at McMaster. Started aggressive HIV therapy, since Myeloma could not be treated until HIV was not under control. Dramatic response to Anti-HIV DNA treatment: Clinically gained weight, felt well. Lab: PCR dramatic reduction of viral load and increase of Helper Lymphocytes. Reduction and final disappearance of monoclonal gammopathy.

Monoclonal Gammopathies at the Mayo Clinic 1998. 1149 patients

3% 2 % 4%

1% 3%
MGUS Myeloma Amyloid SMM Lymphom Macrogl. Extramed other

10% 14 % 63%

Classification of Monoclonal Gammopathies 1. Monoclonal gammopathies of undetermined significance (MGUS):

IgG, IgA, IgM, IgD almost always will evolve into aggressive Myeloma. Idiopathic light chain Bence Jones proteinuria.

Classification of Monoclonal Gammopathies ( 2 cont. ) Bi- & triclonal Gammopathies, A. Malignant Monoclonal Gammopathies:
1. Myeloma, 2. Smoldering myeloma, 3. Plasma cell leukemia, 4. Non secretory myeloma. 5. Osteosclerotic myeloma (POEMS)

Classification of Monoclonal Gammopathies ( cont.3 ) B. Plasmacytoma:

1. Solitary Plasmacytoma of bone 2. Extramedullary plasmacytoma.

C. Lymphoproliferative disorders :
1. Waldenstroms Macroglobulinemia, 2. Heavy chain diseases (HCD): gamma, alpha, miu (u) 3. Primary Amyloidosis. 4. CLL and other B- cell Lymphomas, PTLD

IgG Myeloma in bone marrow

Classification of Monoclonal Gammopathies ( cont. 4 ) D. Connective Tissue disorders:

SLE, Rheumatoid Arthritis, Sjogren syndrome and Mixed conn. Tissue Disorders, Scleroderma, Psoriatic Arthritis, Polymyalgia rheumatica, Cryoglobulinemia.

Cryoglobulinemia rash on legs

Classification of Monoclonal Gammopathies ( cont. 5 ) E. Associated with infections:

Hepatitis C virus, HIV/AIDS

F. Dermatologic disorders:
Scleredema, Lichen myxoedematosus, Diffuse plane xanthomatosis, Urticaria and IgM ( Schnitzlers syndrome ) Subcorneal pustular dermatosis, Necrobiotic xantogranuloma. Pyoderma gangrenosum

Classification of Monoclonal Gammopathies, ( cont. 6 ) G. Miscellaneous:

Acquired von Willebrands syndrome with Anti Factor VIII Ag. Activity . Acquired C 1 esterase deficiency ( angioedema ) Eosinophilic Fasciitis, Myelodysplasia, Chronic Neutrophilic Leukemia, CIDP with MGUS, Capillary Leak syndrome, T-cell large granular lymphocyte leukemia.

Monoclonal antibody Anti-F.X

Course of 241 pts. With MGUS from Kyle, RA: JAMA 251:1849, 1984
Group Description F/U 24-38 yrs
No. of pts. 1 No substantial increase of serum or urine monoclonal protein 2 Monoclonal protein =>3.0g/dl, but no myeloma or related disease 3 Died of unrelated causes 4 Development of Myeloma, macroglob. Amyloidosis or related disease %

25

10

26 127

11 53

63

26 100

Total

241

Monoclonal Gammopathies of undetermined significance (MGUS)

Diagnostic Criteria: 1.Presence of a Monoclonal antibody : IgG, A, or M at a concentration of < 3.0 g/dl. 2. Less than 10% plasma cells in bone marrow. 3. Absence of: Predilection of developing myeloma Anemia, or related malignancy at a rate of Lytic bone lesions, 1% per year. Renal impairment, Hypercalcemia No evidence of underlying plasma or lymphoproliferative disorder.

Monoclonal Gammopathies Serum Protein Electrophoresis.

M-protein

Albumin

alpha1 alpha2 beta

gamma globulins

Monoclonal Gammopathies, Incidence and Clinical Characteristics

MGUS is found in 1-2% of adults in studies from Sweden, US, France and Japan. It becomes higher after the age of 70 yrs and 3-4 X higher in African Americans than Caucasians. Prevalence of MGUS in Olmsted county, Minnesota: Immunofixation in 21,463/ 28,038 residents (77%) of persons > 50 yrs. Jan.1.1995:

Prevalence of MGUS in Olmsted county Minnesota

=> 50 years 3.2% => 70 years 5.3% => 85 years 7.5% Men : Women ratio = 4.0 : 2.7% MGUS concentration: < 1.0 g/dl in 63% IgG - 69% IgA - 11% =>2.0 g/dl in 4.5% IgM 17% Biclonal 3%
kappa -62 and lambda 38%

Monoclonal Gammopathies Clinical course by Mayo Clinic

Derived from long term F/U of 1,384 patients with MGUS 11,009 person-years during which 70% pts. Died. 115 -8.3% developed Myeloma, Macroglob., Amyloidosis or Lymphoma. Cumulative probability of progression to one of those dis. was: 10 yrs 10%, This is where the average 20 yrs. - 21% of 1% per year was calculated . 25 yrs 26%

Monoclonal Gammopathies Clinical Course continued

Number of pts. With MGUS progressing to plasma cell or lymphoid neoplasia was 7.3 X that expected in the general population. Median interval from Dg. Of MGUS to one of its complications was 10.4 years. 32 pts. (2.3%) had a serum M-protein of =>3.g/dl and >10% plasma cell in the bone marrow without developing Myeloma. Only 6 pts.(0.4%) had MGUS, that spontaneously disappeared.

Monoclonal Gammopathies Predictors of progression

1. 2. 3. 4. 5. 6. 7. A. Low risk: M-protein < 1.5 g/dl Marrow plasma cells < 5.0% No reduction in polyclonal immunoglobulins. No light chain proteinuria. ESR < 40 mm/hr High IgA and IgM monoclonal protein have a significant risk for progression. K or L light chains dont seem to impact on progression.

Monoclonal Gammopathies Risk stratification model.

B. Free Light Chain (FLC) proteinuria or in serum carries a high risk of progression to MM, or Amyloidosis, confirmed in a cohort of 1,148 pts. Hazard ratio: 3.5; 95% CI 2.3 5.5 Indep. Of size and type of serum M protein. 3 adverse risk factors:
Serum M protein > 1.5 g/l Abnormal FLC ratio Non-IgG MGUS

1. 2. 3.

Monoclonal Gammopathies Risk stratification model (cont.) 3 risk factors ( high risk MGUS )- 58% 2 risk factors ( high-interm. MGUS) 37% 1 risk factor ( low-interm. MGUS ) - 21% No risk factor ( low risk MGUS ) 5 %

The higher the M-protein concentration the higher the risk of progression to plasma cell or lymphoid neoplasias.

Immuno fixation of MGUS on Agarose Gel

Alb. Serum prot. Eph.
Alpha 1, +2 beta, M-prot gamma

Ig G

Kappa IgA Lambda

Monoclonal Gammopathies Evaluation of Asymptomatic MGUS

CBC Urea, Creatinine, Calcium, Phosphorus and Uric Acid Serum protein Electrophoresis and immunofixation Quantitative Immunoglobulins 24 hour urine for total protein and light chains. Bone marrow biopsy and aspiration if MGUS is => 1.5 g/dl Metastatic skeletal survey. Monitoring every 6 months with careful history and phisical exam, lab. Testing for the rest of the pts. Life.

Monoclonal Gammopathies Speculation on their pathogenesis.

1. Chronic Antigenic stimulation as in HIV Hepatitis or other longstanding chronic infections and skin diseases. 2. Environmental Factors: Osserman had an inbred mouse highly susceptible to develop Plasmacytomas. If these mice were kept in a strictly sterile environment from birth, they did not develop the plasmacytoma.

Monoclonal Gammopathies Speculation on their pathogenesis.2

3. Evolution from auto-antibodies in autoimmune diseases or from hyperpolyclonal gamma globulinemia to MGUS. 4. As age progresses immune surveillance diminishes. 1 in 1.0 X 10^6 cells is usually mutated, but gets eliminated by our cytotoxic lymphocytes and mono-macrophages. These defenses start failing with age and neoplasia is more frequent in elderly.

IgA Myeloma in bone marrow

Current Therapies for Myeloma

1. Induction therapy with Vincristine, Adriamycine and Dexamethasone, 2. Harvesting of peripheral blood stem cells (PBSC) through apheresis, 3. High dose chemotherapy with Melphalan +/TBI only if necessary. 4. After relapse Thalidomide and Prednisone, followed by 5. Bortezomib (Velcade) have been very successful.

Monoclonal Gammopathies Summary 1.

1. The prevalence of MG is high and increases with age after the 6-th decade. 2. Its potential and susceptibility to evolve at 1.0 to 1.5 % per year into a plasmacytoid or lymphoid neoplasia is high: 7.3 X from the base line in an unaffected population of the same age group.

Monoclonal Gammopathies (MG) Summary 2.

3. MG is often associated with underlying nonlympho-plasmacytoid disorders, which when treated successfully, lead also to the disappearance of the MG. 4. Diff. Dg. Of MGUS from Myeloma : MG < 30 g/l Plasma cells in bone marrow < 10 % NO Anemia, NO Hypogammaglobulinemia, NO renal failure and urine light chain proteinuria. NO hypercalcemia , NO lytic bone lesions. NO CD 56 markers on plasma cells.

Monoclonal Gammopathies Summary 3.

Life long periodic monitoring of MG, as well as searching for an underlying or associated disorder is extremely important, since when they evolve into lymphomas or myelomas these diseases can be very successfully treated.