MULTIPLE MYELOMA

Multiple myeloma is the malignant proliferation of a single clone of plasma
cells. A solitary collection of plasma cells is known as plasmacytoma.

INCIDENCE
Multiple myeloma is a hematological neoplasm and accounts for less than
1% of adult cancers. The incidence of myeloma increases with advancing age. In
India, multiple myeloma accounts for about 10%of hematological malignancies and
1% of all forms of cancer. It is slightly more common in males than females.

ETIOLOGY AND PATHOPHYSIOLOGY
The exact etiology of multiple myeloma is unclear. However significant
advances have been made in the understanding of its pathophysiology . The most
important development has been an appreciation of the role of the bone-marrow
microenvironment in the progression of this disease in addition to the known role of
malignant plasma cells. The myeloma plasma cells originate from the postfolicullar
B cells that have already undergone immunoglobulin gene rearrangement and
somatic hypermutation. Cytogenetic and molecular genetic studies have recently
shown that these plasma cells are characterized by complex chromosomal
abnormalities. The most important chromosomal aberrations involve translocations
of the immunoglobulin heavy-chain gene locus on chromosome 14 that lead to
dysregulation of many different partner genes on other chromosomes. In addition to
these abnormalities, deletion of 13q14 locus have been proven to have a very
important adverse prognostic implication.
Bone destruction is clinical hallmark of myeloma. Bone marrow stromal
cells and plasma cells have been shown to engage in a complex web of reciprocal
interactions (both positive and negative) that eventually leads to activation of
osteoclastic resorption of the bone and plasma cell proliferation. The mediators of
this complex interaction between the plasma cell and its microenvironment are
cytokines like interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP 1α),

renal failure. Besides skeletal complaints other clinical features may include : . Extramedullary plasmacytoma are usually detected in nasopharynx and paranasal sinuses or gastrointestinal tract and usually do not progress to multiple myeloma. Solitary osseous plasmacytoma can occur in 3% of patients with solitary osteolytic lesions. Other patients may manifest only light chains the urine without a corresponding M band in the serum. The elucidation of the role of these factors in progression of myeloma is one of major achievements of recent times. IgD and other myelomas are rare. osteoprotegerin. the RANK ligand. Sometimes marked osteoporosis is the only finding. In very few cases sclerotic bone lesions are noted. Some of these patients progress to the full clinical picture of multiple myeloma. about 60% have IgG paraproteins while IgA is present in about 24%. vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF1). The patients usually present with complaints of bone pains. About one-third of these patients elaborate M-protein. recurrent infections and neurological abnormalities. tumor necrosis factor alpha (TNFα). Uncommonly distal long bones may also be involved. The pain is well-localized and aggravated by movement. bone marrow suppression. These patients with light chain myeloma have poorer prognosis compared to those in whom complete immunoglobulin molecules are present. Of all the patients with myeloma. hypercalcemia.receptor activator of nuclear factor kappa B (RANK). Biclonal myeloma is rare but when present IgG and IgA are found together more commonly than IgG and IgM type. Monoclonal M band may be absent in the serum and urine in some patients with multiple myeloma and these patients have a non-secretory multiple myeloma. sometimes due to compression fractures of thoracic or lumbar vertebrae. CLINICAL FEATURES Multiple myeloma is largely a disease of elderly population and is characterized by osteolytic lesions. The exact roles and interactions of these and other cytokines is fascinating subject but beyond the scope of this chapter.

Occasionally false hyponatremia can occur due to marked increased in M-protein (pseudohyponatremia). Neurological involvement Neurological abnormalities are common in multiple myeloma and all patients should be evaluated for the same. M-protein. Streptococci. and mental status changes (hypercalcemic encephalopathy). The skin changes in . The neurological abnormalities can manifest as mental status changes. Escherichia coli and other gram-negative organisms are some common pathogenetic organisms identified in these patients. vomiting. Staphylococcus aureus. Infections Patients with multiple myeloma have defects in both cell-mediated and humoral immunity. light chain nephropathy amyloidosis of the kidneys. These patients are prone to repeated infections. constipation.Renal Dysfunction and Electrolyte Abnormalities. Patient with multiple myeloma are prone to renal failure which is multifactorial in etiology. dehydration. Anemia Anemia is a common finding in multiple myeloma and its frequency increases with the progression and duration of disease. uric acid nephropathy. The common causes of renal impairment are hypercalcemia. Approximately 50% of patients with anemia due to multiple myeloma have low serum erythropoietin levels. particularly pneumococcal pneumonia. Endocrinopathy. anemia of chronic disease. POEMS (Polyneuropathy. Skin changes) syndrome is associated with osteosclerotic myeloma. and renal dysfunction. septicemia. infection. Organomegaly. and administration of nephrotoxic drugs. Klebsiella pneumoniae. Hypercalcemia is a common finding in myeloma and often manifests as nausea. cord compression or peripheral neuropathy. It is multifactorial origin – direct involvement of marrow by tumor cells or amyloid.

In advanced cases pleural effusion may be seen. Amyloidosis Amyloidosis is develops in about 15% of patients with multiple myeloma and may manifest as nephritic syndrome. hyperpigmentation and skin thickening. skin nodules. Pulmonary involvement due to multiple myeloma/ plasmacytomas is rare. carpal tunnel syndrome. periorbital purpura and macroglossia. protein losing enteropathy. peripheral neuropathy. Involvement Other Systems Cardiac involvement is rare but can be due to amyloid changes in the heart. Diagnostic Evaluation of Multiple Myeloma  History and physical examination  Complete blood count with differential  Erythrocyte sedimentation rate  Blood urea and serum creatinine  Serum electrolytes  Serum calcium  Serum albumin and globulin levels  Serum Immunoelectrophoresis and immunofixation .POEMS syndrome usually manifest as hypertrichosis. Occasionally the patient can have coagulation defect and bleeding tendency. Diagnostic Evaluation The diagnostic of multiple myeloma should be suspected from the clinical picture. Rarely plasmacytoma can be detected in the gastrointestinal tract. It manifests as cardiomyopathy and congestive cardiac failure. It can present as a pulmonary mass. renal failure. malabsorption. restrictive cardiomyopathy. skin infiltrates. polyarthropathy. The following table shows the recommended investigations in a newly diagnosed patient with multiple myeloma.

The bone marrow biopsy and aspirate show increased plasma cells (Figure.  24 hour urine for electrophoresis and immunofixation  Skeletal survey for lytic lesions (skull. the severity of which worsens as the disease progresses. cytogenetics and plasma cell labeling index)  Serum β-2 microglobulin  Serum lactate dehydrogenase levels A detailed history and physical examination is an essential part of the work- up with emphasis on neurological findings. normocytic anemia.1) some of which may have abnormal morphology. long bones and pelvis)  Bone marrow aspiration and biopsy (morphology. Examination of peripheral smear usually shows increased rouleaux formation. Very high erythrocyte sedimentation rate (ESR) can be seen in multiple myeloma and this diagnosis should be suspected in such patients. the condition is referred to as plasma cell leukemia. spine. . When this occurs. Patients with multiple myeloma usually have a normochromic. The plasma cells are not usually seen in the peripheral smear examination.

pelvis and rarely the long bones. The lesional tissue gives a low-intensity signal on T-1 and brighter signals on T-2. Positive test for Bence-Jones proteinuria by heat test should always be confirmed by electrophoresis and immuno-electrophoresis of the concentrated urine. vertebrae. Isotope bone scans are not sensitive in detection of bone lesions in myeloma and are not recommended. MRI is more accurate in the assessment of intra-osseous and soft tissue extents of the disease. The skeletal survey characteristically shows multiple lytic lesions usually involving the skull. In patients with otherwise solitary skeletal plasmacytoma MRI of the spine may help to uncover more extensive disease. Diagnostic Criteria . The urinary proteins precipitate on heating at 56˚ to 60˚C and dissolve at 90˚ to 100˚C. The dipstick test for urinary albumin does not detect Bence-Jones proteins. The quantification of M band in the serum and urine at baseline is important for response evaluation after treatment.2). Immunofixation studies using monospecific antisera helps to identify the type of immunoglobulin. The serum and urine electrophoresis reveal a characteristic M (monoclonal) band in the gamma region (Fig.

Recently the International Myeloma Working Group has proposed new criteria for diagnosis of monoclonal gammopathies. The following combination of the above criteria are regarded as diagnostic : 1 + (b or c or d) 2 + (a or b) or (c or d) 3+a 4+a a+b+c However some patients with low disease burden may not fit into these criteria despite having symptomatic myeloma. Bone marrow pasmacytosis of to greater than 30% 10 to 30% 2. Monoclonal serum globulin by c. Monoclonal serum globulin less plasmacytoma than the levels for major criteria 3. The criteria are as follows :  In monoclonal gammopathy of underminated significance (MGUS). Biopsy confirmation of b. Bone marrow plasmacytosis of a. IgA less than 100 mg%. Discrete lytic bone lesions electrophoresis greater than 3 d. Requires 24-hour urine total protein estimation and electrophoresis.The criteria for the diagnosis of myeloma (Salmon and Durie) are as follows : MAJOR CRITERIA MINOR CRITERIA 1. 4. 24-hour urine excretion of greater or IgG less than 600mg%. Reduction of normal serum gm% (IgG) or greater than 2 immunoglobulin to IgM less than gm% (IgA) 50mg%. . than 1 gm of kappa (K) or lambda (A) light chains. other B-cell proliferative disorders or amyloidosis. the monoclonal protein is <3 gm/dL and the bone marrow plasma cells <10% with no evidence of multiple myeloma.

Bence-Jones proteins are not specific to multiple myeloma and can be detected in patients with amyloidosis. which is typically manifested by increased calcium.5 gm/dL Serum calcium <85 mg% 8. quantity of M- protein and hypercalcmia.5 – 12 mg% >12 mg% Number of bone lesions 0–1 2 -3 >3 Monoclonal protein IgG <5 gm/dL 5 – 7 gm/dL >7 gm/dL IgA <3 gm/dL 3 – 5 gm/dL >5 gm/dL Urinary light-chains <4 gm 4 – 12 gm >12 gm (24 hrs) Patients are further sub-grouped as stage A (normal serum creatinine) or Stage B (serum creatinine concentration >2 mg/dL). and amyloidosis). renal insufficiency.  In asymptomatic (smouldering) myeloma the M-protein is ≥3 g/dL and/or bone marrow plasma cells ≥10% but there is no related organ or tissue impairment or end-organ damage. Differential Diagnosis Metastatic carcinoma can also present with lytic bone disease and can be confused with multiple myeloma. or bone lesions attributed to the plasma cell proliferative process. adult Fanconi syndrome. . recurrent infections. Stage 1 Stage 2 Stage 3 Hemoglobin >10 gm/dL 8. anemia.5 – 10 gm/dL <8. renal failure. Staging of Multiple Myeloma Patients of myeloma are staged on the basis of hemoglobin. hyperviscocity. hypercalcemia.  Symptomatic multiple myeloma is characterized by serum and/or urine M protein. bone lesions. clonal plasmacytosis in the bone marrow or solitary plasmacytoma and related organ or tissue impairment (anemia.

However the diagnosis of monoclonal gammopathy does not represent an immediate mandate for treatment. smouldering myeloma and monoclonal gammopathy of unknown significance (MGUS) can be safely followed without treatment. Solitary plasmacytomas should be observed for progression to multiple myeloma. False positive test for Bence-Jones proteins can be encountered in connective tissue disorders like rheumatoid arthritis. or Wegener’s granulomatosis. Stage I patients with Bence-Jones proteinura 3. Severe bony pains 7. Prognostic Factors Untreated multiple myeloma patients have a median survival of 3. anemia. Refractory hypercalcemia 5.5 months while the median survival of the patients treated with melphalan and prednisolone regimen is about 3 years. Progressive lytic bony lesions 4. Vertebral compression fractures 6. and renal failure tend to do well compared to patients with these features. Patients with stage 1 myeloma. Management of Multiple Myeloma Multiple myeloma has a spectrum of manifestation and the disease course can vary from indolent (as in smouldering myeloma) to fulminant and rapidly fatal (as in plasma cell leukemia). poymyositis. Recurrent infections 8. lymphomas.hyperparathyroidism. hypercalcemia. Light chain myeloma has poorer prognosis than IgG and IgA myelomas. and benign monoclonal gammopathy. Patients without symptoms. All patients with stage II and stage III myeloma 2.5 – 11. Severe bone marrow suppression . The indication for treatment for multiple myeloma are as follows : 1. chronic renal insufficiency. leukemias and metastatic carcinoma. β2 microglobulin levels and deletion of 13q14 have been shown to have very important independent adverse prognostic implications.

The VAD regimen involves continuous intravenous administration over 96 hours necessitating an infusion pump and central venous line. renal failure. Rising M component levels or doubling of M component levels in <1 year 10. All patients are at risk of developing tumor-lysis syndrome after the start of chemotherapy. 9. and various dyselectrolytemias. alkalinization of urine and administration of allopurinol should be implemented in all patient to prevent this complication. A high index of suspicion and early initiation of empirical broad spectrum antibiotics is of vital importance. Patients are also at significant risk of developing serious infection. This syndrome is characterized by hyperuricemia. It is preferred in younger patients and those who are candidates for autologous transplantation in the future. The alkylating agents melphalan and cyclophosphamide have shown significant activity in multiple myeloma. It has the advantages of faster onset of action. the primary approach to its treatment is systemic antineoplastic chemotherapy. They have been use in the standard as well as high doses in the management of this disease. . Presence of renal failure Chemotherapy Since MM is disseminated plasma cell neoplasm. Multiagent combination chemotherapy regimens have also been routinely used. M-P has the advantage of oral administration and same overall survival compared to combination regimens. However melphalan is stem-cell toxic and this regimen cannot be used in patient with renal impairment. It is commonly preferred in older patients who are not candidates for autologous transplantation. The two most commonly used regimens in the initial treatment of patients are melphalan plus prednisolon (M- P) and vincristine plus doxorubicin plus dexamethason (VAD). Chemotherapy involves remission induction and maintenance phases. Standard preventive measure like hydration. being non-stem-cell toxic and appropriate for use in patient with renal failure. The mainstay of remission induction therapy in patients with multiple myeloma involves administration of cycotoxic drugs either singly or in combination with or without glucocorticoids.

Recently it was shown that thalidomide is an active agent in the treatment of advanced and refractory patients. cardiac failure and . Patients are typically treated for six or mor cycles of chemotherapy to attain the plateau state. methylprednisolone. carmustin. Supportive Care Multiple myeloma is the prototype of multi-system disease and appropriate supportive care is of vital importance in its management. In the last 15 years it has been shown that autologous stem-cell transplantation (ASCT) conducted as part of the initial management after several cycles of conventional chemotherapy. The value of continued therapy beyond this point (maintenance therapy) has been a matter of debate and is not standard. Rapid strides have been made in the use of this agent and it is increasingly being used (with good results) in earlier stages of this disease. Many other drugs like idarubicin. have comorbid illness and are vulnerable to infections. result in superior survival compared to no transplantation. hypercalcemia. etoposide posses anti-myeloma activity and have been used in the treatment of multiple myeloma. hyperviscosity syndrome. interferon. Thalidomide acts by inhibiting angiogenesis and through its immune-modulatory actions. adhesion molecules and cell proliferation factors. The ability to harvest stem-cells from peripheral blood and the ready availability of hematopoietic growth factors has facilitated of widespread adoption of this procedure. Despite its high cost and significant morbidity ASCT may be considered standard treatment in eligible patient. The initial results of this drug in advanced or refractory patient have been very promising and it is expected to be an important agent for the treatment of this disease in the near future. anemia. These agents inhibit the NfkB induced synthesis of antiapoptotic proteins. Clinical problems like bone pain. These patients are often elderly. which is defined as stable urine and M component level with no other evidence of progression of disease. Bortezomib is a novel agent that belongs to a new class of drugs known as proteasome inhibitors.

Recombinant human erythropoietin has been shown to be effective in correcting the anemia in about 80% of the patients. This therapy has been found to significantly reduce the number of skeletal related events in multiple myeloma.renal failure need special attention. this simple measure has the potential to prevent or delay many complications. Bisophosphonate have been shown to reduce bone pain. Bisphosphonates are a class of compounds that principally act by inhibition of osteoclastic bone resorption. which is the hallmark of myeloma. Palliative irradiation (20-3 Gy in 5-7 fractions over one to two weeks) should be considered only in patient with localized disease not responding to above measures. Severely anemic patient with myeloma should receive packed cell transfusions. Nephrotoxic drugs like intravenous contrast media. Concurrent chemoradiotherapy should be avoided as in can cause . folic acid and cobalamin should be corrected before using erythropoietin. over 3 hours) and zoledronic acid (4 mg once per month over 15 minutes). Anemia is a common complication of multiple myeloma. reduce the frequency of pathologic fractures and prevent or reverse hypercalcemia. The initial best approach for the management of such pain should be simple analgesics along with specific chemotherapy. NSAIDs and aminoglycosides should be used carefully in these patients. All patient should be advised to ensure high daily fluid intake throughout their lives.4 g/kg) have been found to reduce the frequency of life threatening bacterial infections and patients who are deemed to be at high risk serious infections should be considered for such therapy. The commonly used bisophosphonates are pamidronate (90 mg once per month. slow the progression of lytic lesions. Radiotherapy Pain in multiple myeloma can be quite severe. Patients with multiple myeloma are predisposed to infections because of defect in humoral immunity. Chemotherapy and radiotherapy can add to the immune-compromised statae. It is currently recommended that bisophosphonates should be administrated to all patients with skeletal disease and continued indefinitely or until there is such a substantial decline in the patients’ condition that they are unlikely to benefit from continued therapy. Monthly infusions of intravenous immunoglobulins (0. Any coexisting deficiency pf iron.

BIBLIOGRAPHY 1. either alone or in combination.severe myelosuppression and generally an interval of three weeks should be maintained between the two. immune-modulators and proteasome inhibitors have shown great promise. or compressive lesions producing neurological symptoms (e. steroids and some older chemotherapy drugs. Singhal S. Stoppa AM. Intergroupe Francais du myeloma. Alkylating agents.341:1565-71 . Other indications for local radiotherapy include sphenoid or orbital bone involvement causing proptosis. 3. Attal M. or dental or facial abnormalities secondary to myeloma. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Metha J. Patient s who are at a risk of fracture can also be given local radiotherapy to the osseous lesions. cranial nerve palsies. JClin Oncol 1998.g. Desikan R. anti-angiogenic therapy. Harousseau JL. remain the standard initial treatment. 4. N Engl J Med 1996.16:3832-42. Combination chemotherapy versus melphalan and prednisone as treatmentfor multiple myeloma: An overview of 6633 patients from 27 randomized trials. Conclusion multiple myeloma remains an incurable disease. N Engl J 1999. 2.33:91-7. Myeloma trialist collaborative group. Drach J. Antitumor Activity of thalidomide in refractory multiple myeloma. Novel treatments like cytokines. spinal cord compressions). Supportive measures like bisophosphonates have improved the quality of life of these patients and perharps also improved survival. Kaufman H. None of the present day treatment protocols can claim to effect a cure. New insights into the pathophysiology of multiple myeloma. Greater insight into the biology of this plasma cell dyscrasia will likely translate into refinement of the near future.4:557-64. Newer therapeutic approaches are needed and many are being actively researched. et al. Seidi S. Autologous transplantation has improved the outcome and is currently offered to all eligible patients. The importance of common sense measure like avoidance of unnecessary nephrotoxic insults and prompt treatment of infections cannot be overemphasized. Lancet Oncol 2003.

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