Multiple Myeloma

Aswad H. Al.Obeidy

FICMS, FICMS GE&Hep

Kirkuk General Hospital

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.

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

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

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

Renal failure

Hypercalcemia Light chain deposition Amyloidosis Urate nephropathy Drug toxicity (nonsteroidal anti-

inflammatory agents, bisphosphonates) Contrast dye

Easy fatigue—anemia

Bone marrow infiltration Production of inhibitory factors Hemolysis Decreased red cell production Decreased erythropoietin levels

Recurrent infections

Hypogammaglobulinemia Low CD4 count Decreased neutrophil migration

Neurologic symptoms

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

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

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

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

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)

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

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

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

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

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

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

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).