Plasma Cell Disorders

Monoclonal Gammopathies

Kristi McIntyre M.D.

Texas Oncology

2004

A Cluster of Malignant Plasmablasts Bataille, R. et al. N Engl J Med 1997;336:1657-1664

Classification of Monoclonal Gammopathies

• • • • • •

Monoclonal Gammopathy of Undetermined Significance Malignant Monoclonal Gammopathies

Multiple Myeloma Smolderimg Multiple Myeloma Plasma cell leukemia IgD myeloma POEMS

Plasmacytoma Malignant Lymphoproliferative disorders Heavy Chain disease Amyloidosis

Patient Profile

• 61 year old female presented with rash to dermatologists in 2001. SPEP revealed 0.2 IgGlambda M-protein. Asymptomatic otherwise.

2

Breast ca

M-protein 1 2001 2002 2003 2004

MGUS

Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder

•M-protein < 3g/dL • < 10% plasma cells in bone marrow •No or small amounts of M-protein in urine •Absence of lytic bone lesions,anemia,hypercalcemia or renal insufficiency •No evidence of B cell lymphoproliferative disorder •Stability of M-protein over time

MGUS

Monoclonal Gammopathy of Undetermined Significance •1

% of adults in US

•

3% of adults over age 70 years

•

11% of adults over age 80 years

•

14% of adults over age 90 years

MGUS

MGUS can progress to monoclonal disease:

IgA or IgG Multiple Myeloma Primary Amyloidosis or related plasma cell disorder IgM NHL CLL Waldentroms macroglobulinemia

MGUS

• 1,384 patients MGUS

Heavy chain IgG : 70% IgM :15% IgA :12% Light chain Kappa : 61% Lambda : 39% Concentration of uninvolved immunoglobulins reduced in 39% Kyle, R. A. et al. N Engl J Med 2002;346:564-569

MGUS

prognosticators( predictors of progression):

1. Age 2. sex 3. Size of initial M-protein 4. Type of immunoglobulins 5. Hemoglobin 6. # of bone marrow plasma cells 7. Reduction of uninvolved imunoglobulins 8. Urinary light chains

Kyle, R. A. et al. N Engl J Med 2002;346:564-569

Initial Monoclonal Protein Values in 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance Was Diagnosed from 1960 through 1994 Kyle, R. A. et al. N Engl J Med 2002;346:564-569

Probability of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance (MGUS) Was Diagnosed from 1960 through 1994 Kyle, R. A. et al. N Engl J Med 2002;346:564-569



Risk of progression to serious disease 1% per year

Patterns of Increase in Monoclonal Protein among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy Was Diagnosed in 1960 through 1994 Kyle, R. A. et al. N Engl J Med 2002;346:564-569

MGUS

• The size of the M-protein at the time of recognition of MGUS is the most important predictor of progression • IgM & IgA monoclonal proteins have a greater risk of progression than an IgG M-protein • Reduction in uninvolved immunoglobulins & urine protein not significant

MGUS

Management: •

Periodic monitoring of serum protein electrophoresis

•

Interval of monitoring based on initial M-protein level

•

Monitoring should be at least annually LIFELONG

•Risk does not go away with time “cumulative” probability of progression ( 10% at 10 years , 25% at 25 years)

Patient Profile

•

64 year old female hospitalized with severe low back pain for 3 weeks. Spine films negative MRI scan showed path fracture at L2 . Fatigue x 2 months

ESR: 28mm/hr Creat : 0.6

Calcium 9.4

SPEP : M-protein : IgG kappa 4.8 g/dl

SPEP

Multiple Myeloma

3-4 % patients have no serum or urine M-protein “non-secretory myeloma”

Multiple Myeloma

Patient Profile

• Skeletal survey : diffuse osteoporosis • Bone marrow : 48% atypical plasma cells • L2 biopsy: plasmacytoma

Multiple Myeloma

Diagnostic definition:

Minimal criteria for diagnosis include a bone marrow containing > 10% plasma cells (or plasmacytoma) plus at least one of the following:

•

M-protein in serum >3 g/dL

•

M-protein in urine

•

Lytic bone lesions

Multiple Myeloma

International Myeloma Working Group: •Presence of an M-protein in serum •Presence of bone marrow clonal plasma cells •Presence of related tissue or organ impairment (“CRAB”)

C calcium R renal failure A anemia B bone lesions

Multiple Myeloma

Bone Disease Conventional radiographs abnormal 80% of patients who present with multiple myeloma Osteopenia or osteoporosis 20% Focal lytic bone 57%% Pathologic fractures 20% Vertebral body compression fractures 20%

Multiple Myeloma

MRI scan: 

MRI scans of spine are an excellent assessment of bone marrow and myelomatous involvement.



>95% of patients with multiple myeloma have MRI abnormalities:

Diffuse involvement of bone marrow Focal bone marrow lesions Heterogeneous bone marrow

Multiple Myeloma

Osteolytic lesions occur through 2 mechanisms via production of cytokines by myeloma cells adjacent to bone: Stimulation of osteoclastic activity

IL-6

Inhibition of osteoblastic activity

The Role of Wnt-Signaling Antagonist DKK1 on the development of Osteolytic Lesions in Multiple Myeloma

Gene expression analysis

NEJM Tian,E Dec 2003

Multiple Myeloma

Bone disease: mechanism for osteolytic lesions

BM microenvironment Myeloma cell overexpress DKK1 osteoblast Osteoclasts Tian,EDec 2003 NEJM

Multiple Myeloma

Oncologic emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma

Managed with urgent: 1. Corticosteroids 2.neurosurgical intervention (laminectomy or anterior decompression) + radiation therapy to preserve neurological function 3. Radiation therapy alone

Multiple Myeloma

Normochromic /normocytic anemia occurs in 75% patients at diagnosis

Multiple Myeloma

Renal disease •

Serum creatinine increased in > 50% at diagnosis

•

Creatinine >2g/dL in 20% of patients

•

Renal failure may be presenting manifestation

Major causes: •

Myeloma cast nephropathy

•

Hypercalcemia

•

Amyloidosis

•

Radiocontrast dye in a patient with myeloma

Multiple Myeloma

Multiple Myeloma

Multiple Myeloma

Prognosticators: •

Serum beta2 microglobulin small protein synthesized by all nucleated cells;light chain moiety of HLA antigen

•

LDH reflects cell turnover

•

C-reactive protein reflects IL-6 levels

Multiple Myeloma

• Cytogenetics

Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

Multiple Myeloma

Management

MGUS SMM Multiple myeloma

SMM –smoldering multiple myeloma : M-protein >3g/dl ,bone marrow plasma cells >10%, but asymptomatic with no organ related problems

SMM requires no intervention but close surveillance to assess stability

Multiple Myeloma

•

Treatment:Bisphosphonates: Pamidronate given monthly IV has been demonstrated to significantly reduce skeletal events in patients with Multiple Myeloma.

Skeletal events Pamidronate* 21% Placebo 41%



Also reduces bone pain

Multiple Myeloma

Management

Multiple Myeloma Age <70 Transplant eligible Age > 70 Transplant ineligible Melphalan 0.15mg/kg x 7 d Prednisone 20mg po tid x 7d MP produces reponse rates of 50-60% & median survival of 2-3 years

Multiple Myeloma

Conventional chemotherapy for induction: VAD -Vincristine Adriamycin Dexamethasone

ORR CR* 84% 27%

Modification of this regimen now with VDD(pegylated lipasomal doxirubicin )

*Anderson,H:Br J Cancer 1995

Multiple Myeloma

Thalidomide •

old drug 1950’s for sedation & pregnancy induced nausea/vomiting

•

Withdrawn 1961-tetratogenic causing phocomelia

•

Deformities later found to be due to inhibition of developing fetal limbs vessels (anti-angiogenic)

IMiDs (immunomodulatory agent )with antiangiogenic properties

Multiple Myeloma

Thalidomide & dexamethasone •

Myeloma patients with refractory disease underwent clinical trials producing 50% response rate (CR =PR )

•

Median survival from start of therapy 38 months

•

Relatively minor side effects and taken orally

•

Major clinical trials now testing thalidomide /Dex as induction regimen

Multiple Myeloma

Proteosome inhibitors (Velcade) FDA approval May 2003

Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis

Multiple Myeloma

•

Autologous transplantation

– recommended for advanced stage myeloma after induction therapy = age <70, good PS, normal renal function

Tandem double better than single (41 vs 21 mos OS) •

Allogeneic transplantation -

insufficient evidence currently nonmyeloblative “mini” transplants as salvage

Poems(osteosclerotic myeloma)

• Polyneuropathy dominating feature(100%),motor • Organomegaly -hepatosplenomegaly (50%) • Endocrinopathy hypogonadism, hypothyroidism (66%) • Monoclonal gammopathy • Skin changes hyperpigmentation, hypertrichosis

Sclerotic bone lesions –97%

Etiology of symptoms related to proinflammatory cytokines (VEGF)

Poems(osteosclerotic myeloma)

Treatment : 5000cGy to osteosclerotic bone lesion

Patient Profile

•

54 year old high profile male trial attorney went skiing with the “firm” in March 2002. Fell & fractured left humerus. Saw orthopedic surgeon on return to Dallas.”Pathologic fracture”bone survey otherwise negative: MRI spine negative.

Lab: BM : <10% plasma cells SPEP 0.52% IgGkappa UPEP -negative

DX : Solitary Plasmacytoma left humerus

Solitary plasmacytoma

• Presence of single plasmacytoma without evidence of multiple myeloma • Younger median age at presentation (55yrs) • 50-60% will convert multiple myeloma within 10 years • Treatment: tumoricidal radiation to site (5000cGy) • Possible bone marrow collection/storage