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Multiple Myeloma: a Pathobiological review




Enviado por Dr. Peter Ubah Okeke



  1. Abstract
  2. Introduction
  3. Diagnosis
  4. Prognosis
  5. Intermediate risk disease
  6. Management
  7. Chemotherapy
  8. References

Abstract

This paper presents multiple myeloma with
current information on diagnosis, prognosis, and risk
stratification using the International staging system as the
standard. The Major prognostic factors remain on the level of
Beta -2- Microglobulin and Albumin. It also covers the general
aspects of management of patients using novel therapeutic
approach. This paper adds to the existing literature reviews on
multiple myeloma, and further clinical trials on both autologous
and allogeneic transplantation, its conditioning system, and
novel gene therapy are fundamental to improve the quality of life
of patients with multiple myeloma.

Keywords: Myeloma, Diagnosis, Prognosis,
Risk stratification, Management

Introduction

Multiple Myeloma (MM) is a malignant
disorder characterized by the proliferation of a single clone of
plasma cells originated from B cells in the bone marrow. However,
the massive proliferation of plasma cells invades adjacent bone
and infiltrates multiple organs resulting in a variety of
symptoms; anemia, skeletal bone pain and fractures. The plasma
cell clonal production leads to monoclonal (M) protein that in
turn leads to renal failure as a result of light chains (Bence
Jones protein) or hyperviscocity of blood from excessive
accumulation of M protein.

Multiple Myeloma accounts for about 10
percent of hematological malignancies. It is twice as common in
African- Americans as in white population, and is slightly more
common in men than women. Multiple Myeloma is generally the
disease of the elderly people with a median age at onset of about
69 years, and only 2 percent of patients are younger at
diagnosis. MM evolves from a premalignant condition called
monoclonal gammopathy of Undetermined Significance (MGUS), thus,
about half of patients of MGUS showed primary translocation of
immunoglobulin heavy chain (IgH) locus on chromosome 14 q32.
Secondary genetic abnormalities change, changes in the bone
marrow microenvironment, suppression of cell mediated immunity,
and changes in various cytokines also played a role in the
mechanisms by which MGUS evolves.

Diagnosis

Multiple Myeloma should be suspected in an
elderly above 40 years with unexplained bone pain or fractures,
osteoporosis, osteolytic lesions, lethargy, anemia, red cell
rouleaux, high erythrocyte sedimentation rate, hypercalcaemia,
renal dysfunction, proteinuria or recurrent infection. It is
characterized by bone marrow plasmacytosis, lytic bone lesions on
skeletal radiology, and the presence of M protein in the serum or
urine. However, after patient clinical evaluation, Full blood
count and blood films should be made immediately. Other tests
include; Erythrocyte Sedimentation Rate(ESR), Urea or Creatinine,
Calcium phosphates, Alkaline phosphatase, Uric acid, serum
protein electrophoresis assay of serum immunologlobulins,
Urinalysis, Urine electrophoresis for Bence Jones proteins,
Immunofixation; Skeletal survey, bone marrow aspirate and
biopsy.

Normochromic normocytic anemia is often
seen, neutropenia and thrombocytopenia indicates an advanced form
of disease. The blood films show rouleaux and plasma cells could
be visualized in about 5 percent of cases. The ESR is increased
but sometimes could be normal. About 20 percent of cases of MM
have increased serum calcium, urea, and creatinine concentration.
Renal dysfunction due to cast nephropathy is common. Low serum
Albumin reflects advanced form of disease. Serum beta-2-
Microglobulin and protein C- reactive could be employed in
prognostic index monitoring.

Skeletal radiology is a critical diagnostic
point, and this shows lytic alterations, pathological fracture
and generalized bone rarefaction in about 80 percent of cases.
However, osteoporosis only is seen in about 10 percent of MM
cases. Note that bone scans are typically useless in MM cases,
why? This is because despite extensive bone damage, the bone scan
remains negative. Magnetic Resonance Imaging (MRI) is the most
sensitive imaging diagnostic tool for cases of MM, and is
indispensable in suspected cases of cord compression
disease.

Furthermore, among patients with MM, 3
percent have no detectable M protein in serum or urine
immunofixation, and are known to have nonsecretory MM; hence, in
these patients, serum free light chain (FLC) assay becomes
imperative for diagnosing and monitoring response to therapy. A
diagnosis of MM requires 10 percent or more plasma cells on bone
marrow films (or biopsy proven plasmacytoma), M protein in the
serum or urine (except in patients with true nonsecretory
Myeloma), evidence of end organ damage (hypercalcemia, renal
insufficiency, anemia, or bone lesions) suspected to be due to
secondary underlying plasma cell infilteration.

The most important differential diagnosis
includes; MGUS, Smoldering (asymptomatic) MM, Primary
Amyloidosis, and Solitary plasmacytoma. There is no single test
that could differentiate all these disorders. However, a serum
IgG concentration test greater than 30 g/l or IgA concentration
test greater than 20 g/l, suggests strongly a diagnosis of
Myeloma rather than MGUS. The term Smouldering Multiple Myeloma
is used to describe patients in whom M protein and bone marrow
(plasma cells) criteria exists for Myeloma diagnosis, but anemia,
renal dysfunction, and skeletal lesions are not
present.

Prognosis

The easiest way to estimate prognosis of MM
is based on blood levels of; beta-2-Microglobulin and Albumin.
Higher levels of beta-2- Microglobulin and lower levels of
Albumin are associated with a poorer prognosis. This staging
system is called the International Staging System (ISS). The
Durie – Salmon staging system ( no longer in use) is an
older system that divides patients into three stages: Stage I,
Stage II, a Stage III, corresponding to low, intermediate, and
high cell mass, this in turn depends upon the severity of anemia,
calcium level, kidney function, presence or absence of bone
lesions and the quantity of abnormal proteins. This staging
system is best used to estimate the overall amounts of malignant
plasma cells present in the patient, but is less important in
estimating prognosis.

Risk stratification

The aggressiveness of MM depends upon
several variables that impact pathobiology. Genetic abnormalities
seen in MM cells are one of the strongest predictors of tumor
aggressiveness. However, patients diagnosed newly are classified
into high, intermediate or standard risk disease based on tumor
genetics.

High risk disease

About 15 percent of subjects with MM have
high risk disease on cytogenetic testing: translocation t (14;
16), t (14; 20) and deletion chromosome 17p. This type of MM is
aggressive and may shorten survival. Patients with high risk
disease are treated best with more aggressive
chemotherapy.

Intermediate risk
disease

About 10 percent of patients with MM have
intermediate risk disease on cytogenetic examination. And this
class of patients include: translocation t (4; 14) and with good
therapy, patients with these classes of disease have approached
that of standard risk MM.

Standard risk disease

All subjects with MM that are not high or
intermediate risk genetic abnormalities are considered to have
standard risk MM. However, with modern therapy, patients with
standard risk MM have an estimated median survival of about 10
years.

Summary of major independent prognostic
factors in Multiple Myeloma

  • Performance status

  • International staging system
    stage

  • Conventional cytogenetics ( deletion of
    chromosome 13 & hypodiploidy)

  • Fluorescence In Situ Hybridization
    (FISH); t (4; 14), t (14; 16) or del (17p)

  • Lactate Dehydrogenase (LDH)

  • Plasmablastic Morphology

  • Plasma cell labeling index (limited
    availability)

Management

Without adequate treatment, a patient with
MM is likely to experience progressive bone damage, anemia and
renal failure. In managing this disease therefore, general
aspects of care are imperative. Infection is the most common
cause of death, so initial treatment should include;

  • Infection : Broad spectrum antibiotics
    is necessary

  • Pain control: analgesia and local
    radiotherapy should be instituted.

  • Limitations of renal damage:
    rehydration, dialysis, plasmapheresis and
    chemotherapy.

  • Hypercalcaemia:Rehydration, diuresis
    and bisphosphonate is administered.

  • Bone disease: radiotherapy, longterm
    bisphosphonates and fixation of potential
    fractures.

  • Anemia: blood transfusion and sometimes
    erythropoietin therapy is needed.

  • Cord Compression disease: MRI scanning
    to localize lesion and perform radiotherapy.

  • Hyperviscosity syndrome: Plasmapheresis
    and chemotherapy is necessary.

Chemotherapy

Initial chemotherapy in myeloma should
include melphalan with or without prednisolone. Blood counts are
monitored for 3 weeks after the starting of therapy and the
melphalan dose adjusted to produce mild cytopenic effects.
Combination therapy is more effective in younger patients with
high tumor loads; this may be more toxic in the elderly. The
combination of Vincristine, Adriamycin, dexmethasone (VAD)
produces a high response rate of 80 percent and well tolerated in
renal impairment, requires 4 to 6 months of treatment to achieve
maximum response and produces a higher proportion of complete
responses up to 20 percent. This treatment option is less toxic
to hemopoetic progenitors than standard melphalan or other
alkylator containing regimes. It is widely used in subjects under
65 years old in whom autologous stem cell collection is
programmed.

Autologous Stem cell transplantation
(ASCT)

This method of treatment is not curative,
but there is improvement in complete response rates, and prolongs
median overall survival in myeloma for about one year with a
mortality rate of 1 to 2 percent. For conditioning regime for
ASCT, melphalan is the most widely used. This system of ASCT is
favorable especially in subjects younger than 65 years with
adequate renal function.

Allogeneic transplantation

This method has advantages of lack of graft
contamination with tumor cells and the presence of a graft versus
MM effect. However, age factor makes it to be available for 5 to
10 percent of subjects, and availability of Human Leukocyte
Antigen (HLA) matched sibling donor, and adequate organ function
restricts this method of treatment. Furthermore, high rate of
treatment related mortality has made conventional allogeneic
transplants completely unacceptable for most patients with
MM.

References

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serum immunoglobulin free light chain quantification with urinary
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Bataille R et al (1983): Serum beta-2-
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Dingli D et al (2006): Immunoglobulin free
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Drew Provan et al (2003): ABC of Clinical
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Durie BGM et al (2006): International
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Fonseca R et al (2003): Clinical and
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Mehta J Singhals (1998): Graft versus
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Rajkumar SV et al (2002): Myeloma, Amyloid,
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Autor:

Dr. Peter Ubah Okeke,

AIMLS (Nig), M.S, PhD.

 

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