Scleromyxedema

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Scleromyxedema

• A 70-year-old patient presented with a one-year
  history of progressive tightening of the skin.
• Physical examination showed generalized
  sclerodermoid induration and discoloration of the
  skin, as well as decreased motility of the mouth
  and joints.
• Examination of a deep-skin biopsy specimen showed
  fibrosis, proliferation of fibroblasts, and
  interstitial deposits of mucin in the dermis.

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Scleromyxedema

• Serum electrophoresis showed a monoclonal
  gammopathy of the IgG type, with lambda light
  chains.
• The patient died three months later owing to
  respiratory and cardiac failure.
• Scleromyxedema is a primary dermal mucinosis that
  is almost always associated with a monoclonal
  gammopathy.

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Frequency Monoclonal Gammopathies

• MGUS 64
• Smouldering MM 2
• Multiple Myeloma 14
• PCL lt1
• Immunocytom 6
• Waldenströms Macroglobulinemia 2
• CLL 2
• NHL lt1
• Amyloidosis Primary 8
• POEMS lt1
• Other diseases ?

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MONOCLONAL GAMMOPATHY

• Hans E Johnsen MD DMSc
• Professor in Medicine
• Department of Hematology
• Herlev Hospital
• University of Copenhagen
• Denmark

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Normal B Cell differentiation

• Memory B Cells
• Plasma Cells
• Ig Heavy Light chain gene rearrangement
• Somatic hypermutations
• Isotype Switch genes

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Normal B Cell differentiation

• Memory B Cells
• Plasma Cells
• Ig Heavy Light chain gene rearrangement
• Somatic hypermutations
• Isotype Switch genes

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Pathogenesis Monoclonal Gammopathies

• Expansion of clonal B cells (Plasma Cells)
• Expression of monoclonal protein
• M component in plasma and/or urine.

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Diagnosis Monoclonal Gammopathies
Serum Protein Electrophoresis Showing an M
Component Migrating in the Slow Gamma Globulin
Region. A normal result of protein
electrophoresis is also shown.
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Frequency Monoclonal Gammopathies

• MGUS 64
• Smouldering MM 2
• Multiple Myeloma 14
• PCL lt1
• Immunocytom 6
• Waldenströms Macroglobulinemia 2
• CLL 2
• NHL lt1
• Amyloidosis Primary 8
• POEMS lt1
• Other diseases ?

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Mechanisms of Progression in Monoclonal
Gammopathies.
N Engl J Med 20043511860-1873.Multiple Myeloma
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Probability of Progression in Monoclonal
Gammopathy of Undetermined Significance (MGUS)

• The top curve shows the probability of
  progression to a plasma-cell cancer or of an
  increase in the monoclonal protein concentration
  to more than 3 g per deciliter or the proportion
  of plasma cells in bone marrow to more than 10
  percent.
• The bottom curve shows only the probability of
  progression of MGUS to multiple myeloma, IgM
  lymphoma, primary amyloidosis, macroglobulinemia,
  chronic lymphocytic leukemia, or plasmacytoma.

N Engl J Med 2002346564-569.A Long-Term Study
of Prognosis in Monoclonal Gammopathy of
Undetermined Significance
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MULTIPLE MYELOMA

• Hans E Johnsen MD DMSc
• Professor in Medicine
• Department of Hematology
• Herlev Hospital
• University of Copenhagen
• Denmark

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Frequency Monoclonal Gammopathies

• MGUS 64
• Smouldering MM 2
• Multiple Myeloma 14
• PCL lt1
• Immunocytom 6
• Waldenströms Macroglobulinemia 2
• CLL 2
• NHL lt1
• Amyloidosis Primary 8
• POEMS lt1
• Other diseases ?

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Myelomatosis (myelon marv, osis
tilstand) Von Rustizky 1873 (McBeans Disease
with Macintyres proteinuria) Multiple
Myeloma Bergsagel DE et al 1962 Korst DR et al
1964 Monoclonal Gammopathies
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Multiple Myeloma Heterogenous Disease Spectrum
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Pathology

• Bone Marrow Disease
• Abnormal Plasma Cells
• Lytic Bone Destruction
• Monoclonal Immunoglobulin

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Pathogenesis

• Cell Biology
• Cellular hierarchy
• Plasma cell development

• Molecular Genetic
• Oncogenesis
• IgH translocations
• Chromosome 14

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Plasma Cell development
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Pathogenesis

• Cell Biology
• Cellular hierarchy
• Plasma cell development

• Molecular Genetic
• Oncogenesis
• IgH translocations
• Chromosome 14

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Chromosome 14 Translocations
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Translocations in IgH switch
Poulsen TS, Silahtaroglu AN, Gisselo CG et al.
Detection of illegitimate rearrangement within
the immunoglobulin locus on 14q32.3 in B-cell
malignancies using end-sequenced probes. Genes
Chromosomes.Cancer 2001 32 265-74.
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Frequency of IgH translocation Partner genes
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Pathogenesis

• Cell Biology
• Cellular hierarchy
• Plasma cell development

• Molecular Genetic
• Oncogenesis
• IgH translocations
• Chromosome 14
• Multistep proces

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Multi-step molecular pathogenesis of multiple
myeloma
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Pathogenesis

• Cell Biology
• Cellular hierarchy
• Plasma cell development
• Disease progression

• Molecular Genetic
• Oncogenesis
• IgH translocations
• Chromosome 14
• Multistep proces

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Disease Progression
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Bone Disease
Receptor activator of nuclear factor- B ligand
(RANKL) acts to stimulate osteoclast formation
and activity leading to bone erosion, whereas
dickkopf1 (DKK1) appears to inhibit osteoblasts,
thus preventing repair of the lesions.
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Diagnosis of Multiple Myeloma
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Clinical criteria at diagnosis

• Diagnostic criteria
• AC, AD or BCD
• High level of a monoclonal protein
• Low level
• Plasma cell infiltration
• Osteolytic bone disease

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Clinical presentation at diagnosis
Bone pain often with loss of height
Constitutional weakness, fatigue, weigth
loss Susceptibility to infections immune
paresis Hyperviscosity isotype dependent
(IgM) Neurologic dysfunction spinal cord
compression

• Associated findings
• 1. Anemia
• 2. Renal insufficiency
• Hypercalcemia

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Prognostic factors survival
At diagnosis Beta2-Microglobulin Plasma cell
labeling index Cytokines and soluble
receptors Regulatory cells Oncogenes Tumor
suppressor genes Serum markers DNA
aneuploidy Cytogenetics Cytology Phenotyping by
flowcytometry Blood myeloma cells Level of B
cells Immune paresis
Following therapy CR is the most important
single factor
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Therapy of Multiple Myeloma
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Proposed Mechanism of Action of Drugs
In myeloma cells, alkylating agents,
corticosteroids, and bortezomib inhibit cell
growth and induce apoptosis. The effect of
bortezomib on myeloma cells is mediated in part
by the inhibition of nuclear factor- B.
Thalidomide and bortezomib inhibit the
interaction between myeloma cells and stromal
cells as well as the production of cytokines such
as tumor necrosis factor and interleukin-6.
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Forrest Plot Showing the Odds Ratios and 99
Percent Confidence Intervals (CIs) for the
Current Study and Two Other Published Studies
Comparing Conventional Treatment with High-Dose
Treatment in Patients with Myeloma.
N Engl J Med 20033481875-1883.High-Dose
Chemotherapy with Hematopoietic Stem-Cell Rescue
for Multiple Myeloma
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WALDENSTRÖMSMACROGLOBULINEMIA

• Hans E Johnsen MD DMSc
• Professor in Medicine
• Department of Hematology
• Herlev Hospital
• University of Copenhagen
• Denmark

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Frequency Monoclonal Gammopathies

• MGUS 64
• Smouldering MM 2
• Multiple Myeloma 14
• PCL lt1
• Immunocytom 6
• Waldenströms Macroglobulinemia 2
• CLL 2
• NHL lt1
• Amyloidosis Primary 8
• POEMS lt1
• Other diseases ?

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A 65-year-old man had an 18-month history of
slowly progressive swelling and discoloration of
both ears, fatigue, night sweats, weight loss,
occipital headaches, and photophobia.
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AMYLOIDOSIS

• Hans E Johnsen MD DMSc
• Professor in Medicine
• Department of Hematology
• Herlev Hospital
• University of Copenhagen
• Denmark

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Frequency Monoclonal Gammopathies

• MGUS 64
• Smouldering MM 2
• Multiple Myeloma 14
• PCL lt1
• Immunocytom 6
• Waldenströms Macroglobulinemia 2
• CLL 2
• NHL lt1
• Amyloidosis Primary 8
• POEMS lt1
• Other diseases ?

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Diagnostic Algorithm for Amyloidosis. A biopsy
of tissue that shows amyloid deposits on
Congo-red staining is the first step.
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Characteristics of the Systemic Amyloidoses.
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Clinical Features of Amyloidosis. All patients
had AL amyloidosis.
Panel A shows ecchymoses around the eyes with a
characteristic absence of soft-tissue swelling.
Panel B shows an enlarged tongue (macroglossia)
with prominent indentations caused by the teeth.
Panels C show soft-tissue deposits of amyloid in
the submandibular glands and synovial tissues,
the "shoulder-pad sign." Panel D shows nail
dystrophy.
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Distribution of Organ Involvement in 445
Patients with Light-Chain Amyloidosis.
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MONOCLONAL GAMMOPATHY?

• Hans E Johnsen MD DMSc
• Professor in Medicine
• Department of Hematology
• Herlev Hospital
• University of Copenhagen
• Denmark