1. Aswad H. Al.Obeidy FICMS, FICMS GE&Hep Kirkuk General Hospital
Multiple Myeloma
Aswad H. Al.Obeidy
FICMS, FICMS GE&Hep
Kirkuk General Hospital

2. Definition
Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone
The tumor, its products, and the host response to it result in a number of organ dysfunctions
Symptoms of bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.

3. Etiology The cause of myeloma is not known
Increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency
A variety of chromosomal alterations have been found in patients with myeloma; 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate
Overexpression of myc or ras genes has been noted in some cases
Mutations in p53 and Rb-1 have also been described
More commonly than expected among farmers, wood workers, leather workers, and to petroleum

4. Incidence and Prevalence
Myeloma increases in incidence with age
The median age at diagnosis is 68 years
The yearly incidence is around 4 per 100,000
Males are more commonly affected than females
Blacks have nearly twice the incidence of whites
Accounts for ~1% of all malignancies in whites and 2% in blacks; 13% of all hematologic cancers in whites and 33% in blacks
The incidence of myeloma is highest in African-American and Pacific islanders; intermediate in Europeans and North American Caucasians; and lowest in developing countries including Asia

5. Pathogenesis and Clinical Manifestations
Hypercalcemia, osteoporosis, pathologic fractures, lytic bone lesions, bone pain
Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors

6. Renal failure Hypercalcemia Light chain deposition Amyloidosis
Urate nephropathy
Drug toxicity (nonsteroidal anti-inflammatory agents, bisphosphonates)
Contrast dye

7. Easy fatigue—anemia Bone marrow infiltration
Production of inhibitory factors
Hemolysis
Decreased red cell production
Decreased erythropoietin levels

8. Recurrent infections Hypogammaglobulinemia Low CD4 count
Decreased neutrophil migration

9. Neurologic symptoms Hyperviscosity Cryoglobulinemia Amyloid deposits
Hypercalcemia
Nerve compression
Anti-neuronal antibody
POEMS syndrome
Therapy-related toxicity

10. Bleeding/clotting disorder
Interference with clotting factors
Antibody to clotting factors
Amyloid damage of endothelium
Platelet dysfunction
Antibody coating of platelet
Therapy-related hypercoagulable defects

11. Pathogenesis of multiple myeloma
Multiple myeloma cells interact with bone marrow stromal cells and extracellular matrix proteins via adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival, and anti-apoptotic effects as well as development of drug resistance. HSP, heparin sulfate proteoglycan

12. Clinical Manifestations
Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients
The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections In ~25% of patients,the most common infections are pneumonias and pyelonephritis
Renal failure occurs in nearly 25%
Anemia occurs in ~80% of myeloma patients
Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies
Rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue

13. Diagnosis and Staging
The classic triad of myeloma is marrow plasmacytosis (>10%), lytic bone lesions, and a serum and/or urine M component
Symptomatic multiple myeloma   
M protein in serum and/or urine 
Bone marrow (clonal) plasma cellsb or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)

14. Durie-Salmon Staging System
I All of the following:  
1. Hemoglobin >100 g/L (>10 g/dL)
2. Serum calcium <3 mmol/L (<12 mg/dL)
3. Normal bone x-ray or solitary lesion
4. Low M-component production
a. IgG level <50 g/L (<5 g/dL)
b. IgA level <30 g/L (<3 g/dL)
c. Urine light chain <4 g/24 h
II Fitting neither I nor III
III One or more of the following:  
1. Hemoglobin <85 g/L (<8.5 g/dL)
2. Serum calcium >3 mmol/L (>12 mg/dL)
3. Advanced lytic bone lesions
4. High M-component production
a. IgG level >70 g/L (>7 g/dL)
b. IgA level >50 g/L (>5 g/dL)
c. Urine light chains >12 g/24 h

15. Treatment
About 10% of patients with myeloma will have an indolent course demonstrating only very slow progression of disease over many years
Patients with symptomatic and/or progressive myeloma require therapeutic intervention
In general such therapy is of two sorts: systemic therapy to control the progression of myeloma, and symptomatic supportive care to prevent serious morbidity from the complications of the disease
Therapy can significantly prolong survival and improve the quality of life for myeloma patients

16. In patients who are transplant candidates
Alkylating agents such as melphalan should be avoided since they damage stem cells
High-dose pulsed glucocorticoids have been used either alone (dexamethasone 40 mg for 4 days every 2 weeks) or in combination VAD chemotherapy (vincristine, 0.4 mg/d in a 4-day continuous infusion; doxorubicin, 9 mg/m2 per day in a 4-day continuous infusion; dexamethasone, 40 mg/d for 4 days per week for 3 weeks) for initial cytoreduction

17. In patients who are not transplant candidates
Therapy has consisted of intermittent pulses of an alkylating agent, L-phenylalanine mustard (L-PAM, melphalan) and prednisone administered for 4–7 days every 4–6 weeks
Randomized studies comparing standard-dose therapy to high-dose melphalan therapy (HDT) with hematopoietic stem cell support have shown that HDT can achieve high overall response rates and prolonged progression-free and overall survival; however, few, if any, patients are cured
Although complete responses are rare (<5%) with standard-dose chemotherapy, HDT achieves 25–40% complete responses

18. Treatment
Two successive HDTs (tandem transplants) are more effective than single HDT in the subset of patients who do not achieve a complete or very good partial response to the first transplant.
Allogeneic transplants may also produce high response rates, but treatment-related mortality may be as high as 40%.
Non-myeloablative allogeneic transplantation is now under evaluation to reduce toxicity, while permitting an immune graft-vs.-myeloma effect

19. Treatment
There is no standard maintenance therapy to prolong time to progression
IFN- has allowed modest benefit but has significant side effects
Oral prednisone maintenance therapy was effective in a single trial
Ongoing studies are evaluating maintenance thalidomide and lenalidomide to prolong progression-free survival post-transplant
Relapsed myeloma can be treated with novel agents including lenalidomide and/or bortezomib

20. Supportive care
The hypercalcemia generally responds well to bisphosphonates, glucocorticoid therapy, hydration, and natriuresis
In the event of acute renal failure, plasmapheresis is ~10 times more effective at clearing light chains than peritoneal dialysis
Plasmapheresis may be the treatment of choice for hyperviscosity syndromes
Prophylactic administration of IV globulin preparations is used in the setting of recurrent serious infections
Most bone lesions respond to analgesics and chemotherapy, but certain painful lesions may respond most promptly to localized radiation
The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin).