PLASMA CELL DISORDERS
The hallmark of plasma cell disorders is the production of immunoglobulin molecules or fragments from abnormal plasma cells. The intact immunoglobulin molecule, or the heavy chain or light chain produced by the abnormal plasma cell clone, is detectable in the serum and/or urine and is called the M (for monoclonal) component. The amount of the M component in any given pt reflects the tumor burden in that pt. In some, the presence of a clonal light chain in the urine (Bence Jones protein) is the only tumor product that is detectable. M components may be seen in pts with other lymphoid tumors, nonlymphoid cancers, and noncancerous conditions such as cirrhosis, sarcoidosis, parasitic infestations, and autoimmune diseases.
A malignant proliferation of plasma cells in the bone marrow (notably not in lymph nodes). Nearly 31,000 new cases are diagnosed each year. Disease manifestations result from tumor expansion, local and remote actions of tumor products, and the host response to the tumor. About 70% of pts have bone pain, usually involving the back and ribs, precipitated by movement. Bone lesions are multiple, lytic, and rarely accompanied by an osteoblastic response. Thus, bone scans are less useful than radiographs. The production of osteoclast-activating cytokines by tumor cells leads to substantial calcium mobilization, hypercalcemia, and symptoms related to it. Decreased synthesis and increased catabolism of normal immunoglobulins lead to hypogammaglobulinemia, and a poorly defined tumor product inhibits granulocyte migration. These changes create a susceptibility to bacterial infections, especially the pneumococcus, Klebsiella pneumoniae, and Staphylococcus aureus affecting the lung and Escherichia coli and other gram-negative pathogens affecting the urinary tract. Infections affect at least 75% of pts at some time in their course. Renal failure may affect 25% of pts; its pathogenesis is multifactorial—hypercalcemia, infection, toxic effects of light chains, urate nephropathy, and dehydration. Neurologic symptoms may result from hyperviscosity, cryoglobulins, and rarely amyloid deposition in nerves. Anemia occurs in 80% related to myelophthisis and inhibition of erythropoiesis by tumor products. Clotting abnormalities may produce bleeding.
Marrow plasmacytosis >10%, lytic bone lesions, and a serum and/or urine M component are the classic triad. Monoclonal gammopathy of uncertain significance (MGUS) is much more common than myeloma, affecting about 6% of people aged >70 years; in general, MGUS is associated with a level of M component <20 g/L, low serum β2-microglobulin, <10% marrow plasma cells, and no bone lesions. Lifetime risk of progression of MGUS to myeloma is about 25%; risk of progression is increased if the paraprotein is IgM, the paraprotein level is >1.5 gm/dL, or the free light chain ratio is <0.26 or >1.65.
Disease stage influences survival (Table 67-5).
|Durie-Salmon staging system|
|STAGE||CRITERIA||ESTIMATED TUMOR BURDEN × 1012 CELLS/m2|
|I||All of the following:||<0.6 (low)|
|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||0.6–1.20 (intermediate)|
|III||One or more of the following:||>1.20 (high)|
|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|
|LEVEL||STAGE||MEDIAN SURVIVAL, MONTHS|
|Subclassification based on serum creatinine levels|
|A <177 µmol/L (<2 mg/dL)||IA||61|
|B >177 µmol/L (>2 mg/dL)||IIA, B||55|
|International staging system|
|β2M <3.5, alb ≥3.5||I (28%)||62|
|β2M <3.5, alb <3.5 or β2M = 3.5–5.5||II (39%)||44|
|β2M >5.5||III (33%)||29|
Treatment: Multiple Myeloma
About 10% of pts have very slowly progressive disease (the so-called smoldering myeloma) and do not require treatment until the paraprotein levels rise above 50 g/L or progressive bone disease occurs. Pts with solitary plasmacytoma and extramedullary plasmacytoma are usually cured with localized radiation therapy. Supportive care includes early treatment of infections; control of hypercalcemia with glucocorticoids, hydration, and natriuresis; chronic administration of bisphosphonates to antagonize skeletal destruction; and prophylaxis against urate nephropathy and dehydration. Therapy aimed at the tumor is usually palliative. Initial therapy is usually one of several approaches, based on whether the pt is a candidate for high-dose therapy and autologous stem cell transplant. Transplant eligible (avoid alkylating agents): lenalidomide, 5−25 mg/d PO for 21 days every 28 days, plus dexamethasone, 40 mg/d on days 1–4 each month, with bortezomib 1.3 mg/m2 IV or SC days 1, 8, and 15, produces responses in nearly 100% of pts and one-third of them are complete. Maintenance therapy with lenalidomide appears to improve survival. Thromboprophylaxis is used with lenalidomide. Transplant ineligible: the same regimens can be used but alkylating agents may also be palliative, e.g., melphalan, 8 mg/m2 orally for 4–7 days every 4–6 weeks, plus prednisone. About 60% of pts have significant symptomatic improvement plus a 75% decline in the M component. Bortezomib also appears to improve response rates to melphalan. Experimental approaches using sequential high-dose pulses of melphalan plus two successive autologous stem cell transplants have produced complete responses in about 50% of pts <65 years. Long-term follow-up is required to see whether survival is enhanced. New proteasome inhibitors like carfilzomib and ixazomib, immune modulators like pomalidomide, monoclonal antibodies like daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7), and histone deacetylase inhibitors like panobinostat are being tested in various combinations. Entering pts on clinical trials will provide a basis for decision making. Palliatively treated pts generally follow a chronic course and median overall survival is now 8+ years.
About 8500 new cases are diagnosed each year. HD is a tumor of Reed-Sternberg cells, aneuploid cells that usually express CD30 and CD15 but may also express other B or T cell markers. Most tumors are derived from B cells in that immunoglobulin genes are rearranged but not expressed. Most of the cells in an enlarged node are normal lymphoid, plasma cells, monocytes, and eosinophils. The etiology is unknown, but the incidence in both identical twins is 99-fold increased over the expected concordance, suggesting a genetic susceptibility. Distribution of histologic subtypes is 75% nodular sclerosis, 20% mixed cellularity, with lymphocyte predominant and lymphocyte depleted representing about 5%.
Usually presents with asymptomatic lymph node enlargement or with adenopathy associated with fever, night sweats, weight loss, and sometimes pruritus. Mediastinal adenopathy (common in nodular sclerosing HD) may produce cough. Spread of disease tends to be to contiguous lymph node groups. Superior vena cava obstruction or spinal cord compression may be presenting manifestation. Involvement of bone marrow and liver is rare.
- Infection: mononucleosis, viral syndromes, Toxoplasma, Histoplasma, primary tuberculosis
- Other malignancies: especially head and neck cancers
- Sarcoidosis: mediastinal and hilar adenopathy
Immunologic and Hematologic Abnormalities
- Defects in cell-mediated immunity (remains even after successful treatment of lymphoma), cutaneous anergy, diminished antibody production to capsular antigens of Haemophilus and pneumococcus
- Anemia; elevated erythrocyte sedimentation rate, leukemoid reaction, eosinophilia, lymphocytopenia, fibrosis, and granulomas in marrow
The Ann Arbor staging classification is shown in Table 67-6. Disease is staged by performing physical examination, chest x-ray, thoracoabdominal CT, bone marrow biopsy, ultrasound examinations, and lymphangiogram. Staging laparotomy should only be used to evaluate the spleen only if radiation therapy alone is being contemplated as treatment. Pathologic staging is unnecessary if the pt is treated with systemic chemotherapy.
|I||Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring)|
|II||Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is a single site; hilar lymph nodes should be considered “lateralized” and, when involved on both sides, constitute stage II disease)|
|III||Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm|
|III1||Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes|
|III2||Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1|
|IV||Involvement of extranodal site(s) beyond that designated as “E”|
|More than one extranodal deposit at any location|
|Any involvement of liver or bone marrow|
|B||Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation|
|Unexplained, persistent, or recurrent fever with temperatures >38°C (100.5°F) during the previous month|
|Recurrent drenching night sweats during the previous month|
|E||Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow|
Treatment: Hodgkin’s Disease
About 85% of pts are curable. Therapy should be performed by experienced clinicians in centers with appropriate facilities. Most pts are clinically staged and treated with chemotherapy alone or combined-modality therapy. Those with stage II disease often receive either two or four cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) with or without involved-field radiation therapy or Stanford V, a combined-modality program using lower doses of chemotherapy. Those with stage III or IV disease receive six cycles of combination chemotherapy, usually ABVD. Replacing bleomycin with the anti-CD30 immunotoxin, brentuximab vedotin, is equally effective or possibly slightly more effective than ABVD. Pts with any stage disease accompanied by a large mediastinal mass (greater than one-third the greatest chest diameter) should receive combined-modality therapy with mechlorethamine, vincristine, procarbazine, prednisone (MOPP)/ABVD or MOPP-ABV hybrid followed by mantle field radiation therapy. (Radiation plus ABVD is too toxic to the lung.) A persistently positive midtreatment (after two cycles) positron emission tomography scan is associated with a higher risk of relapse and need for additional therapy. About one-half of pts (or more) not cured by their initial chemotherapy regimen may be rescued by high-dose therapy and autologous stem cell transplant. The likelihood of the success of salvage therapy is related to the length of initial remission; pts with initial remissions lasting more than a year are more likely to achieve long-term disease control than those whose initial remission was shorter than a year. Brentuximab vedotin has activity in pts relapsing after transplant.
With long-term follow-up, it has become clear that more pts are dying of late fatal toxicities related to radiation therapy (myocardial infarction, stroke, second cancers) than from HD. Radiation therapy and its late toxicities can be avoided by using combination chemotherapy alone in early-stage disease as well as in advanced-stage disease.