plasma cell disorders kristi mcintyre m.d. texas oncology 2004 monoclonal gammopathies

Plasma CellDisorders

Kristi McIntyre M.D.Texas Oncology2004

Monoclonal Gammopathies

Bataille, R. et al. N Engl J Med 1997;336:1657-1664

A Cluster of Malignant Plasmablasts

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.

2001 2002 2003 2004

2

1M-proteinBreast ca

MGUSDenotes 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 MyelomaPrimary Amyloidosis

or related plasma cell disorder

IgM

NHLCLL

Waldentroms macroglobulinemia

MGUS

• 1,384 patients MGUS

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

IgG : 70%IgM :15%IgA :12%

Heavy chain Light chain

Kappa : 61%Lambda : 39%

Concentration of uninvolved immunoglobulins reduced in 39%

MGUSprognosticators( predictors of progression):

1. Age2. sex3. Size of initial M-protein4. Type of immunoglobulins5. Hemoglobin6. # of bone marrow plasma cells7. Reduction of uninvolved imunoglobulins8. Urinary light chains

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

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

Risk of progression to serious disease 1% per year

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

Patterns of Increase in Monoclonal Protein among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy Was Diagnosed in 1960 through 1994

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/hrCreat : 0.6Calcium 9.4SPEP : 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:

•M-protein in serum >3 g/dL• M-protein in urine•Lytic bone lesions

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

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 calciumR renal failureA anemiaB bone lesions

Multiple Myeloma

Bone DiseaseConventional 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 marrowFocal bone marrow lesionsHeterogeneous bone marrow

Multiple Myeloma

Stimulation of osteoclastic activity

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

Inhibition of osteoblastic activity

IL-6

NEJM Tian,E Dec 2003

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

Gene expression analysis

Multiple Myeloma

Bone disease: mechanism for osteolytic lesions

BM microenvironmentMyeloma cell overexpress

DKK1

osteoblast OsteoclastsTian,EDec 2003 NEJM

Multiple MyelomaOncologic emergency

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

Managed with urgent:1. Corticosteroids2.neurosurgical intervention (laminectomy or anterior decompression) + radiation therapy to preserve neurological function3. 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

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

MGUSMultiple myelomaSMM

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.

21% 41%Skeletal events

Pamidronate* Placebo

Also reduces bone pain

Multiple Myeloma

ManagementMultiple Myeloma

Age <70Transplant eligible

Age > 70Transplant ineligible

Melphalan 0.15mg/kg x 7 dPrednisone 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

IMiDs (immunomodulatory agent )with antiangiogenic properties

•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)

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 MyelomaProteosome 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

•Allogeneic transplantation-insufficient evidence currently nonmyeloblative “mini” transplants as salvage

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

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