Supportive Treatment of Multiple Myeloma

Supportive Treatment of Multiple Myeloma

• Supportive treatment is the treatment that aim to treat the signs & symptoms or reduce them; it is not aim to treat the disease itself.

Renal Impairment :-

• Rehydrate.
• Treat the underlying cause (e.g. hypercalcemia, hyperuricemia).
• Dialysis.
• Drink at least 3 Liter of fluid daily (all multiple myeloma cases).

Bone disease and hypercalcemia :-

• Bisphosphonates (such as pamidronate, clodronate or zoledronic acid) reduce the progression of bone disease.
• Rehydration with isotonic saline, a diuretic and corticosteroids followed by a biphosphonate (to treat acute hypercalcemia).

Compression paraplegia :-

• Use decompression laminectomy or irradiation. 
• Also corticosteroid therapy may help.

Anemia :-

• Erythropoietin.
• Transfusion.

Bleeding (Bleeding caused by paraprotein interference with coagulation and hyperviscosity syndrome) :-

• May be treated by repeated plasmapheresis.

Infections :-

• Must treated rapidly.
• Prophylactic infusions of immunoglobulin concentrates together with oral broad - spectrum antibiotics and antifungal agents may be needed for recurrent infections.

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Multiple Myeloma: An Overview

Multiple Myeloma: An Overview

Definition:-

• Multiple myeloma (MM) is a malignant bone marrow–based, plasma cell neoplasm associated with abnormal protein production.

• Multiple myeloma also called myelomatosis.

Epidemiology:-

• 1~2% of all types of malignant diseases
• ~10% of hematological malignancies.
• 15% of lymphoid malignancies.
• ~ 50 cases per million.
• Twice common in black than white people.
• Slightly more common in males than in females.
• 98% of cases occur over the age of 40 years with a peak incidence in the 7th decade.

Etiology (Causes):-

- Exact cause is unknown, but the following are suspects:

• Radiation.
• Viral infections.
• Toxins.
• Chemicals.
• Chromosomal abnormalities ( 8 % - 35 % of MM patients ).

- MM patients with chromosomal damage have a worse prognosis, a higher rate of disease acceleration, and decreased survival. 

Clinical Signs & Symptoms:-

• Fatigue: caused by anemia
• Excessive thirst and urination: caused by excess calcium.
• Nausea: caused by excess calcium.
• Bone pain in back and ribs: caused by plasma cell acceleration.
• Bone fractures: caused by calcium leeching from bones into circulation.
• Unexpected infections: caused by compromised immunity.
• Weakness and numbness in the legs: caused by vertebrae compression. 
• Renal insufficiency.(Myeloma kidney).
• Hypercalcemia.
• Amyloidosis (in 5% of cases).
• Weight loss & night sweats (in advanced cases).
• Abnormal bleeding tendency: myeloma protein may interfere with platelet function and coagulation factors
• Thrombocytopenia (in advanced cases).

Laboratory Findings:-

• Anemia (2/3 of cases). ( Normocytic normochromic anemia ).
• Leukopenia (1/3 of cases).
• Thrombocytopenia.
• ESR > 100 mm/hr.
• Blood film shows rouleaux with a bluish background staining.
• Bone marrow shows >10% plasma cells.
• ↑ Total protein.
• ↑ Uric Acid.
• ↑ LDH.
• Hypercalcemia.
• Protein electrophoresis (monoclonal spike in the gamma region).
• Bence-Jones protein (immunoglobulin light chain) in urine. (in some cases).
• Serum β₂ microglobulin (β₂M) often raised and higher levels correlate with worse prognosis.

Radiology:-

X-rays, CT scan, MRI or PET.

Prognostic Data:-

Prognostic data include:-

• Hb.
• β₂M.
• Creatinine.
• Albumin. &
• Extent of skeletal disease.

Treatment:-

• Chemotherapy.
• Supportive.
• Radiation.
• Transplantation (bone marrow; stem cell).

Prognosis:-
 

• The prognosis of MM is poor.
• Median survival of only 6 months without therapy.
• The median survival can be increased to 3 years with chemotherapy.
• Increased survival has been reported with autologous bone marrow & peripheral blood stem cell transplants.
• Infection is a major cause of death.

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Hemophilia: An Overview

Hemophilia A (Classic Hemophilia; Factor VIII Deficiency)

Ø   The most common inherited coagulation disorder (after Von Willebrand Disease).

Ø     The factor VIII gene is on the X chromosome so inheritance is sex-linked with the severe disease occurring in males.

Ø     Hemophilia A accounts for 80–85% of all cases of hemophilia with a prevalence of approximately 1 in 5,000–10,000 male births.

Ø     Genetic changes of the factor VIII gene.

Ø     Each son has a 50% chance of inheriting the affected gene.

Ø     Approximately 30% of the affected individuals have no positive family history of the disease.

Clinical Features

Ø     These range from severe spontaneous bleeding, especially into joints (hemarthroses) and muscles, to mild symptoms, depending on the factor VIII level.

Ø     Generally individuals with > 30% activity do not have hemophilia symptoms.

Ø     Onset in early childhood (e.g. post-circumcision).

Ø     Pseudotumours as a result of extensive bleeds.

Ø     Hemarthrosis (usually in severe cases) is the most common feature of severe hemophilia.

Ø     Joint bleeds, particularly into the knee and ankle.

Ø     Chronic debilitating joint disease caused by repeated bleeds.

Ø     Increased risk of post-operative or post-traumatic hemorrhage.

Ø     Subcutaneous hematomas can begin with slight trauma and spread to involve a large mass of tissue, causing purple discoloration of the skin.

Ø     Epistaxis is rare in hemophilia.

Ø     Hematuria.

Ø     Deep muscle bleeding.

Ø     Excess bleeding from dental extractions.

Ø     Bleeding with intramuscular injections.

Ø     Delayed bleeding after minor cuts.

Ø     The most common cause of death (after exclusion of viral infections transmitted by the replacement product) is intracranial hemorrhage, which can occur spontaneously or after trauma.

Ø     Mild deficiencies can be asymptomatic and unsuspected until a surgical procedure or major traumatic injury results in severe bleeding.

Laboratory Data

Ø     APTT >> ↑

Ø     PT >> N

Ø     PFA-100 test >> N

Ø     Plasma Factor VIII >> ↓

Ø     Von Willebrand factor (vWF) >> N

Ø     Carriers have factor VIII levels in plasma approximately 50% of normal. If the levels are <40% they may have clinical features of mild hemophilia. DNA analysis is helpful in carrier detection and antenatal diagnosis.

Treatment

Ø     Infusions of factor VIII (either recombinant or concentrate from normal donated plasma “Cryoprecipitate”).

Ø     Avoid aspirin, other antiplatelet drugs and intramuscular injections.

Ø     Gene Therapy.

Complications of Treatment

Ø     Infections.

Ø     Neutralizing antibodies (inhibitors) to factor VIII in 15% of severe patients may require:

§        Immunosuppressive therapy,

§        Treatment with porcine factor VIII, or

§        Plasma exchange.

Hemophilia B  (Factor IX Deficiency; Christmas Disease)

Ø     15–20% of hemophilia.

Ø     ~1 in 30.000 males.

Ø     Factor IX is coded by a gene close to the gene for factor VIII.

Ø     Specific Factor IX Assay.

Ø     Bleeding episodes are treated with high - purity factor IX concentrates. Because of its longer biological half-life, infusions do not have to be given as frequently as do factor VIII concentrates in haemophilia A.

Ø     Recombinant factor IX.

Ø     Gene Therapy.

Ø     Clinical features & other laboratory data are same as in hemophilia A.

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The Role of 2,3-Diphophoglycerate

The Role of 2,3-Diphophoglycerate

     The major function of the hemoglobin molecule is the transport of oxygen to the tissues. The oxygen affinity of the hemoglobin molecule is associated with the spatial rearrangement of the molecule and is regulated by the concentration of phosphates, particularly 2,3-DPG in the erythrocyte. The manner in which 2,3-DPG binding to reduced hemoglobin (deoxyhemoglobin) affects oxygen affinity is complex. Basically, 2,3-DPG combines with the beta chains of deoxyhemoglobin and diminishes the molecule’s affinity for oxygen. 

    When the individual heme groups unload oxygen in the tissues, the beta chains are pulled apart. This permits the entrance of 2,3-DPG and the establishment of salt bridges between the individual chains. These activities result in a progressively lower affinity of the molecule for oxygen. With oxygen uptake in the lungs, the salt bonds are sequentially broken; the beta chains are pulled together, expelling 2,3-DPG; and the affinity of the hemoglobin molecule for oxygen progressively increases.

     In cases of tissue hypoxia, oxygen moves from hemoglobin into the tissues, and the amount of deoxyhemoglobin in the erythrocytes increases. This produces the binding of more 2,3-DPG, which further reduces the oxygen affinity of the hemoglobin molecule. If hypoxia persists, depletion of free 2,3-DPG leads to increased production of more 2,3-DPG and a persistently lowered affinity of the hemoglobin molecule for oxygen.

Figure: Hemoglobin molecular changes

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Alterations in Myeloid:Erythroid Ratio

     

     The M:E ratio is sensitive to hematologic factors that may impair red blood cell life span, inhibit overall production, or cause dramatic increases in a particular cell line. Each of these conditions reflects bone marrow dynamics through alterations of the M:E ratio. Many observations in the peripheral smear can be traced back to the pathophysiologic events at the level of bone marrow. A perfect example of this is the response of the bone marrow to anemia. As anemia develops and becomes more severe, the patient becomes symptomatic, and the kidney senses hypoxia secondary to a decreased hemoglobin level. Tissue hypoxia stimulates an increased release of erythropoietin (EPO), a red blood cell-stimulating hormone, from the kidney. EPO travels through the circulation and binds with a receptor on the youngest of bone marrow precursor cells, the pronormoblast. Bone marrow has the capacity to expand production 6-8 times in response to an anemic event. Consequently, the bone marrow delivers reticulocytes and nucleated red blood cells to the peripheral circulation prematurely if the kidney senses hypoxic stress. What is observed in the peripheral blood smear is polychromasia (stress reticulocytes, large polychromatophilic red blood cells) and nucleated red blood cells. Both of these cell types indicate that the bone marrow is regenerating in response to an event, a dynamic that represents the harmony between bone marrow and peripheral circulation.

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Bone Marrow & Myeloid:Erythroid Ratio

     

     The bone marrow is one of the largest organs of the body, encompassing 3% to 6% of body weight and weighing 1500 g in an adult. It is hard to conceptualize the bone marrow as an organ because it is not a solid organ that one can touch, measure, or weigh easily. Because bone marrow tissue is spread throughout the body, one can visualize it only in that context. It is
composed of yellow marrow, red marrow, and an intricate supply of nutrients and blood vessels. Within this structure are erythroid cells (red blood cells), myeloid cells (white blood cells), and megakaryocytes (platelets) in various stages of maturation, along with osteoclasts, stroma, and fatty tissue. Mature cells enter the peripheral circulation via the bone marrow sinuses, a central structure lined with endothelial cells that provide passage for mature cells from extravascular sites to the circulation. The cause and effect of hematologic disease are usually rooted in the bone marrow, the central factory for production of all adult hematopoietic cells. In the first 18 years of life, bone marrow is spread throughout all of the major bones of the skeleton, especially the long bones. As the body develops, the marrow is gradually replaced by fat until the prime locations for bone marrow in an adult become the iliac crest (located in the pelvic area) and the sternum (located in the chest area).
     In terms of cellularity, there is a unique ratio in the bone marrow termed the myeloid:erythroid (M:E) ratio. This numerical designation provides an approximation of the myeloid elements in the marrow and their precursor cells and the erythroid elements in the marrow and their precursor cells. The normal ratio of 3:1 to 4:1 reflects the relationship between production and life span of the various cell types. White blood cells have a much shorter life span than red blood cells (6 to 10 hours for neutrophils as opposed to 120 days for erythrocytes) and must be produced at a much higher rate for normal hematopoiesis.

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Iron Distribution

Iron-containing compounds in the body are one of two types:

1. Functional compounds that serve in metabolic (hemoglobin, myoglobin, iron-responsive element-binding protein) or enzymatic (cytochromes, cytochrome oxygenase, catalase, peroxidase) functions
2. Compounds that serve as transport (transferrin, transferrin receptor) or storage forms (ferritin and hemosiderin) for iron. 

     A poorly understood iron compartment is the intracellular “labile pool.” Iron leaves the plasma and enters the intracellular fluid compartment for a brief time before it is incorporated into cellular components (heme or enzymes) or storage compounds. This labile pool is believed to be the chelatable iron pool. The total iron concentration in the body is 40–50 mg of iron/kg of body weight. Men have higher amounts than women.

    Iron is found primarily in erythrocytes, macrophages, hepatocytes, and enterocytes (absorptive cells at the luminal [apical] surface of the duodenum). Hemoglobin constitutes the major fraction of body iron (functional iron) with a concentration of 1 gm iron/kg of erythrocytes, or about 1 mg iron/mL erythrocytes. Iron in hemoglobin remains in the erythrocyte until the cell is removed from the circulation. Hemoglobin released from the erythrocyte is then degraded in the macrophages of the spleen and liver, releasing iron. Approximately 85% of this iron from degraded hemoglobin is promptly recycled from the macrophage to the plasma where it is bound to the transport protein, transferrin, and delivered to developing normoblasts in the bone marrow for heme synthesis. The macrophages recycle 10 to 20 times more iron than is absorbed in the gut. This iron recycling provides most of the marrow’s daily iron requirement for erythropoiesis.

      Iron in hepatocytes and intestinal enterocytes is stored and utilized as needed to maintain iron homeostasis. The hepatocytes store iron that can be released and utilized when the amount of iron in the plasma is not sufficient to support erythropoiesis. Enterocytes that absorb dietary iron can either export it to the plasma or store it. Iron stored in enterocytes is lost when the cells are sloughed into the intestine. 

 

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