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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.

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Autor:

Dr. Peter Ubah Okeke,

AIMLS (Nig), M.S, PhD.