Multiple Myeloma(Plasma Cell Myeloma)

血液腫瘤科 林棟樑12 January , 2010

Introduction– An incurable plasma cell neoplasm– Originating in early B-cell precursors with idiotypic pre-

switch rearrangements of the immunoglobulin gene– About 1% of all cancers, 10% of hematologic

malignancies– CGMH (1999-2005): 0.4% of all cancers; 9.8% of

hematologic malignancies (not including myelodysplatic syndrome and myeloproliferative neoplasms)

Etiology

• Pesticides: agriculture workers• Viruses: herpes virus 8, HIV, hepatitis C virus?• Radiation• Genetic predisposing factors• Chronic antigen stimulation: infection, inflammation,

connective tissue disorders, autoimmune diseases

Epidemiology

• Age: most > 40 years, peak: 65 – 70• Race: highest in African-Americans and native Pacific

Islanders, lowest in Asians• Prevalence in blacks twice than in whites• Male: Female = 2:1; CGMH: 1.2:1

History

• Morse et al (1974): discrete lytic lesions with sharply demarcated borders in American Indian skeletons from AD 200-1300.

• Samuel Solly (1844)– 39-year-old Sarah Newbury in 1840– Severe back pain; progression with multiple bone

fractures– “Morbid action of blood vessels”– Treatment: Rhubarb ( 大黃 ) and orange peel

Bull N Y Acad Med 1974;50:447-458

Br J Haematol 2000;111:1035-1044

Sarah Newbury

Sarah Newbury: destruction of femurs by myeloma tumor

Br J Haematol 2000;111:1035-1044

Clinical Manifestations

• Anemia• Bone disease• Monoclonal proteins (M-proteins)• Hypercalcemia• Renal insufficiency• Infection• Hemostasis abnormalities• Plasmacytoma

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

Bartel, T. B. et al. Blood 2009;114:2068-2076

Untreated myeloma patient with time-concordant X-ray, MRI, and FDG-PET/CT studies

Histopathology

• Plasma cells: abnormal in number and morphology– Clonal plasma cells– Flaming cells– Mott cells (grape cell, morula cells)– Russell bodies– Inclusion bodies

Flaming cell

Grape cell

Mott cell

Dutcher body

Russell body

Grape cell

Rouleaux formation of RBCs

Plasma cells

Laboratory findings

• Hematology• Biochemistry• Immunoglobulins and others• Cytogenetics

Hematology

• Bone marrow failure– Anemia (Hb < 10g/dl: 72.3%)– Thrombocytopenia (platelet < 100x109/l: 22.7%)– WBC: usually normal

• Circulating plasma cells• Hemostasis

– Prolonged PT, APTT, bleeding time

• Increased erythrocyte sedimentation rate

Biochemistry

• Reversed albumin to globulin ratio• Renal insufficiency

– Cr ≥2.0 mg/dl: 43.1%• Hypercalcemia

– Corrected Ca ≥10 mg/dl: 49.4%• Hyperuricemia

– Uric acid > 8.0 mg/dl: 50.0%• Elevated lactate dehydrogenase

Immunoglobulins

• Monoclonal gammopathy– M-protein: monoclonal protein; malignant protein;

myeloma protein– Present in 97% of patients (serum or urine)

• protein electrophoresis (PEP)• immunofixation electrophoresis (IFE)• immunoelectrophoresis (IEP)

• Non-secretory myeloma: no detectable M-protein

Bence Jones ProteinFree Light Chain

• Dr. Thomas Watson (leading general practitioner of London) wrote a letter to Dr. Bence Jones (31-year-old physician) in 1845.– The tube contains urine of very high specific

gravity. When boiled it becomes slightly opaque. On the addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite clear; but as it cools, assumes the consistence and appearance which you see. Heat reliquifies it. What is it?

Bence Jones Protein

• Patient: Thomas Alexander McBean• Doctors

– William MacIntyre– Thomas Watson– Henry Bence Jones

• Autopsy– Mr. Shaw

• Microscopic examination– Dr. John Dalrymple

Bence Jones Protein

• Hydrated deutoxide of albumen• “I need hardly remark on the importance of

seeking for this oxide of albumen in other cases of mollities ossium.”

• Soluble in urine at room and body temperature• A white cloud at 40℃, precipitate at 60℃;

disappeared on boiling; reappeared on cooling• 1956, Korngold and Lapiri: 2 types of Bence Jones

protein (kappa and lambda)

Henry Bence Jones (From Serum Free Light Chain Analysis, 5th Edition)

Br J Haematol 2001;115:13-18

Henry Bence Jones and his home at 84 Brook Street in London

84 Brook Street in London; Five Star Argyll Business Centre group

Grade II Listed Building

Listed Building

• Grade I: buildings of outstanding architectural or historic interest.

• Grade II*: particularly significant buildings of more than local interest.

• Grade II: buildings of special architectural or historic interest.

Immunoeletrophoresis (IgG-kappa)

NHS: normal human serum

Protein Electrophoresis

κ and λ FLC concentrations in 282 normal sera. A: axis at the normal κ/λ ratio of 0.6. B: axis at a κ/λ ratio of 1.00.

Serum Free Light Chain Analysis, 5th edition

κ/λ logarithmic plot of sFLCs showing samples that would be mis-identified as negative using PEP and serum IFE. (High pIgG: polyclonal hypergammaglobulinemia.

Serum Free Light Chain Analysis, 5th edition

Serum Free Light Chain

• A professor, a junior doctor, a medical student, a technician

D: Can you see that small band in the gamma region?

P: Pass me my other glasses… Yes, I can clearly see the band now.

S: I think there might two bands.D: We could test for serum free light chains.P: I’m not using those new-fangled methods. A

urine test will be fine. What was good enough for Henry Bence Jones is good enough for me.Serum Free Light Chain Analysis, 1st edition

2Y 1Y1R1G 1Y1R1G

Diagnosis, WHO 2008

• Symptomatic MM– M-protein in serum or urine– Bone marrow clonal plasma cells (usually > 10%) or

plasmacytoma– Related organ or tissue impairment

• C: hypercalcemia (Ca > 11 mg/dl)• R: renal insufficiency (Cr > 2 mg/dl)• A: anemia (Hb < 10 g/dl or decrease >

2 g/dl of normal lower limit)• B: bone lesions (lytic lesions or

severe osteopenia or compression fracture)

Diagnosis, WHO 2008

• Asymptomatic (smoldering) MM– M-protein in serum at myeloma level (> 3000

mg/dl) AND/OR 10% or more clonal plasma cells in bone marrow– No related organ or tissue impairment or no

myeloma-related symptoms (CRAB)

Monoclonal Gammopathy of Undetermined Significance (MGUS)

1. M-protein levels < 3000 mg/dl2. Bone marrow plasma cells <10% and low level

of plasma cell infiltration in a trephine biopsy

3. No myeloma-related organ or tissue impairment (CRAB)

4. No evidence of B-cell proliferative disorder

Treatment

• Supportive care: most important• Eligible for high dose chemotherapy and

autologous hematopoietic stem cell transplantation (ASCT)

• Not eligible for high dose chemotherapy and ASCT

Eligible for ASCT

• Autologous stem cell transplantation (ASCT)• Age < 65

– Age may not be an absolute limitation.

• No obvious comorbidities

Eligible for ASCT• Induction before ASCT

– Bortezomib (Velcade)-based– Thalidomide-based– Suggested: VTD (Velcade, thalidomide, dexan)

• Conditioning regimen before ASCT– Melphalan 200mg/m2

• Complete response (CR) or very good partial response (VGPR) before ASCT– Good overall survival (OS) and event-free survival (EFS)

Eligible for ASCT

• < VGPR after 1st ASCT– 2nd ASCT: suggested; allogeneic SCT: selected cases– Thalidomide?– Velcade?– VTD?

• Maintenance of response after ASCT: important (for 2 years after ASCT)– Thalidomide: suggested– Steroid– Thalidomide + steroid

Not eligible for ASCT

• Non-aggressive: MPT (melphalan, prednisolone, thalidomide)

• Aggressive: VMP (Velcade, melphalan, prednisolone)• Very old: MPT with T 100mg/day• Renal impairment: Velcade-based• Risk of thrombosis: Velcade-based• Poor risk cytogenetics: Velcade-based (VMP)• History of neuropathy: lenalidomide-based

Treatment of Myeloma Bone Disease• Radiation therapy

– Pain control: most common– Impending or actual pathological fracture– Spinal cord compression– Tumor causing local neurologic problems– Large soft tissue plasmacytoma

• Surgery– Actual pathological fracture– Unstable spine

• Drug therapy– Bisphosphonates: pamidronate, zoledronic acid

Treatment Response

• Southwest Oncology Group: SWOG criteria• European Group for Blood and Bone Marrow

Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR): EBMT criteria

• International Myeloma Working Group uniform response criteria: IMWG criteria

SWOG criteria• Objective response (all of the following criteria sustained

for at least 2 months)– Decrease in the synthetic index of serum M-protein to 25% of

less of the pretreatment value and to less than 2500mg/l– Decrease in light-chain urine protein excretion to less than 10%

of the pretreatment value and to less than 200mg/24h– Improvement in bone pain and performance status– In all responsive patients the size and number of lytic skull

lesions must not increase and serum calcium remain within normal limits

– Correction of anemia (Hb > 9.0mg/dl) and hypoalbuminemia (>3.0mg/dl) if they are considered to be secondary to myeloma

• Improvement:– Decline in the M-protein synthesis index to less than 50% but

not less than 25% of the pretreatment value)

Cancer 1972;30:382-389

EBMT response criteria• Complete response (CR) requires all of the following:

– Absence of the original M-protein in serum and urine by immunofixation, maintained for a minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR.

– < 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed. If absence of M-protein is sustained for 6 weeks it is not necessary to repeat the bone marrow, except in patients with non-secretory myeloma where the marrow examination must be repeated after an interval of at least 6 weeks to confirm CR.

– No increase in size or number of lytic bone lesions (development of a compression fracture does not exclude response).

– Disappearance of soft tissue plasmacytomas.Br J Haematol 1998;102:1115

EBMT response criteria• Partial response (PR) requires all of the following:

– >50% reduction in the level of the serum M-protein, maintained for a minimum of 6 weeks.

– Reduction in 24 h urinary light chain excretion either by >90% or to <200 mg, maintained for a minimum of 6 weeks.

– For patients with non-secretory myeloma only, >50% reduction in plasma cells in a bone marrow aspirate and on trephine biopy, if biopsy is performed, maintained for a minimum of 6 weeks.

– >50% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination).

– No increase in size or number of lytic bone lesions (development of a compression fracture does not exclude response).

Br J Haematol 1998;102:1115

EBMT response criteria• Minimal response (MR) requires all of the following:

– 25–49% reduction in the level of the serum M-protein maintained for a minimum of 6 weeks.

– 50–89% reduction in 24 h urinary light chain excretion, which still exceeds 200mg/24 h, maintained for a minimum of 6 weeks.

– For patients with non-secretory myeloma only, 25–49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks.

– 25–49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination).

– No increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response).

Br J Haematol 1998;102:1115

EBMT response criteria• No change (NC)

– Not meeting the criteria of either minimal response or progressive disease.

• Relapse from CR requires at least one of the following:– Reappearance of serum or urinary M-protein on

immunofixation or routine electrophoresis, confirmed by at least one further investigation and excluding oligoclonal immune reconstitution.

– >5% plasma cells in a bone marrow aspirate or on trephine bone biopsy.

– Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions (development of a compression fracture does not exclude continued response and may not indicate progression).

– Development of hypercalcemia (corrected serum calcium >11·5 mg/dl ) not attributable to any other cause.Br J Haematol 1998;102:1115

EBMT response criteria• Progressive disease (for patients not in CR) requires one or

more of the following:– >25% increase in the level of the serum M-protein, which must also

be an absolute increase of at least 500mg/dl and confirmed by at least one repeated investigation.

– >25% increase in the 24 h urinary light chain excretion, which must also be an absolute increase of at least 200mg/24 h and confirmed by at least one repeated investigation.

– >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10%.

– Definite increase in the size of existing bone lesions or soft tissue plasmacytomas.

– Development of new bone lesions or soft tissue plasmacytomas (development of a compression fracture does not exclude continued response and may not indicate progression).

– Development of hypercalcemia (corrected serum calcium >11·5 mg/dl) not attributable to any other cause.

Br J Haematol 1998;102:1115

Leukemia 2006;20:1467-1473IMWG response criteria

Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

Kyle, R. A. et al. Blood 2008;111:2962-2972

Timeline depicting the history and treatment of multiple myeloma from 1844 to the present

Overall Survival

• MP: 2-3 years• TMP: 29-52 months• VMP: 72%-87% at 3 years• VTP: 93% at 2 years• VMPT: 88% at 3 years• MPR (MP + lenolidomide): 91% at 2 years• ASCT: about 5-7 years

Mechanism of Thalidomide

Nature Reviews Cancer 2007;7:585-598

Multiple Myeloma

• An incurable malignancy?• Survival

– No treatment: about 6 months– MP: about 3 years– ASCT: about 5-7 years; some > 10 years in CR

• Curable?

Thanks for your attention.