The Washington Manual of Oncology, 3 Ed.

Plasma Cell Dyscrasias

Jesse Keller • Ravi Vij

 I. MULTIPLE MYELOMA

1. Subjective. Presenting symptoms of multiple myeloma (MM) may include bone pain, fatigue, and recurrent bacterial infections. Lethargy is a common complaint, occurring in up to one-third of patients at diagnosis and usually attributable to ongoing anemia and metabolic derangements. Symptomatic hypercalcemia is common at diagnosis and may occur in approximately 30% of patients. Weight loss may be an accompanying sign in up to 20% of patients. More uncommon events include neuropathy secondary to the monoclonal paraprotein (M protein), a feature of roughly 5% of newly diagnosed MM patients. Tumor fever is rare, and is a diagnosis of exclusion; febrile MM patients are infected until proven otherwise. One-third of patients have a prior diagnosis of a plasma cell proliferative process preceding the diagnosis of MM.
2. Objective. Physical examination may reveal pallor, bony tenderness, a subcutaneous mass secondary to a plasmacytoma, or focal neurologic signs due to spinal cord compression. Hepatomegaly, splenomegaly, and lymphadenopathy are rare.
3. Workup and staging
4. Laboratory. Anemia is present in three-quarters of patients at diagnosis and is generally normochromic and normocytic. White blood cell (WBC) and platelet counts are usually preserved, although marrow replacement by MM may lead to pancytopenia. Examination of the peripheral smear may reveal rouleaux formation. The erythrocyte sedimentation rate (ESR) is generally elevated in MM. Almost 20% of patients will have a creatinine level of more than 2.0 mg/dL at diagnosis. Hypercalcemia due to extensive bone involvement and hyperuricemia can worsen renal function. Albumin has prognostic significance and is a component of the International Staging System. A serum protein electrophoresis (SPEP) and urinary protein electrophoresis (UPEP) should be performed on patients in whom the diagnosis of MM is suspected. Immunofixation is more sensitive than electrophoresis and is done to confirm the presence and type of a paraprotein (M protein). An M protein is detectable in the serum of more than 90% of patients. The paraprotein is an IgG in approximately half the cases and an IgA in 20% of cases. IgD, IgE, and IgM paraproteins are very rare. IgM paraproteins are almost always associated with Waldenstrom’s macroglobulinemia (WM). Free light chains are present in approximately 15% of patients. Kappa (κ) light chains are more common than lambda (λ) by approximately 2:1. Bence–Jones proteinuria occurs when light chains are freely filtered at the glomerulus and are excreted in the urine. The light chain is rarely detected on SPEP, but will be detected on UPEP. If light chains are detected in the urine, a 24-hour urine specimen should be collected to quantify the protein and monitor response to treatment. The serum-free light chain (SFLC) assay now allows for quantification of light chains in the serum in a direct and efficient manner. Nonsecretory myeloma constitutes less than 5% of patients. These patients have no paraprotein detectable on SPEP, UPEP, and immunofixation. However, a majority will have an abnormal SFLC κ:λ ratio.
5. Radiographic imaging. All patients should have a skeletal survey including the skull, spine, pelvis, femurs, and humeri. Almost 80% of patients have at least one abnormality on radiographs with two-thirds of patients having punched-out lytic lesions. Pathologic fractures, vertebral compression fractures, or osteoporosis are each present in one-fourth of patients. Radionuclide bone scans detect osteoblastic response and are therefore less sensitive than plain radiographs in detecting skeletal involvement by MM. Magnetic resonance imaging (MRI) of the spine is more sensitive than plain radiographs in detecting early lesions, and may be considered in patients with negative skeletal surveys or as clinically indicated for suspicious symptoms. Patients thought to have solitary plasmacytomas should undergo MRI imaging to exclude systemic disease. ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) is now approved for initial workup and follow-up of patients with MM. It is of particular benefit in those with nonsecretory or oligosecretory disease, an increasing problem in refractory and relapsed patients.
6. Bone marrow evaluation. Patients should undergo bone marrow biopsy and aspiration for quantification of bone marrow plasma cells. The malignant plasma cells stain positive for CD138. Monoclonality is established by immunostains that demonstrate κ- or λ-restricted cytoplasmic immunoglobulin staining. Karyotyping is now recommended as a prognostic tool. Conventional cytogenetic analysis in MM is often difficult because of the low-growth fraction and paucity of mitotic cells. However, using a variety of fluorescent in situ hybridization (FISH) probes (del 13q, t[4;14], t[11;14], del 17p, t(14, 16), t(14, 20)) on interphase cells, cytogenetic abnormalities are commonly found in MM. The plasma cell labeling index (PCLI) performed on bone marrow biopsy measures the percentage of MM cells that synthesize DNA; an elevated labeling index implies a more aggressive MM and poor prognosis. Assessment by multiparameter flow cytometry is currently under investigation for the identification of minimal residual disease (MRD). Patients who achieve an MRD negative complete response (CR) may have an improved prognosis as compared with those with persistent disease after treatment.
7. Diagnosis. The historic criteria for the diagnosis of MM have been supplanted by the International Myeloma Working Group (IMWG) criteria for the diagnosis of plasma cell dyscrasias (Table 29-1). End-organ damage is the defining feature that separates MM from a monoclonal gammopathy or smoldering myeloma. Revised criteria have recently been published that update the IMWG criteria (Table 29-2). These criteria add several biomarkers as well as radiographic findings as MM defining events.
8. Staging. In the past, MM was staged according to the Durie–Salmon staging system. In the modern era, this system has been replaced by the International Staging System (Table 29-3), a simplified system that utilizes only the β-2-microglobulin and albumin.
9. Treatment. The initial treatment decision revolves around whether or not a patient is considered a transplant candidate.
10. Transplant eligible. High-dose chemotherapy (HDT) with autologous stem cell transplant is considered standard of care for transplant-eligible patients. Response rates (RRs) to HDT approach 90% with approximately half the number of patients achieving CR.
11. Induction therapy. Patients suitable for transplant usually undergo induction therapy with 4 to 6 months of a two- or three-drug regimen including a proteasome inhibitor, immunomodulatory agent (Thalidomide or Lenalidomide), and corticosteroid.

Three drug regimens such as Bortezomib (bortezomib), Lenalidomide (Revlimid), and Dexamethasone (VRD) or Bortezomib, Cyclophosphamide, and Dexamethasone (VCD) have shown improved efficacy with increased rates of CR when compared with two-drug regimens. Long-term data for an overall survival (OS) benefit with these regimens are still maturing. Since there are only limited data comparing the available regimens, the therapeutic decisions should be made on the basis of patient characteristics and side-effect profiles. Alkylating agents, such as melphalan, should be avoided prior to stem cell collection in transplant-eligible patients as they are toxic to stem cells.

70. Stem cell collection and transplant. Following induction therapy, patients undergo stem cell collection, consolidative HDT, and transplant. Alternatively, patients may undergo harvest and stem cell storage first, and then proceed with additional conventional therapies, postponing transplant until first relapse. Randomized trials have shown equivalent survival with these two approaches. However, quality-of-life analysis and event-free survival favor early transplant. Conditioning for transplant with single-agent melphalan is the standard of care. Although controlled trials of transplant generally excluded patients older than 65 years, improvements in supportive care have allowed the application of high-dose therapy and autologous transplant to patients older than 70. Medicare approves this procedure for patients up to 78 years of age. Toxicities of high-dose therapy include mucositis and infectious complications. The overall transplant-related mortality is 1% to 2%. Repeated HDT and transplant within 6 months (“tandem transplant”) may provide a survival benefit in patients who have less than a very good partial response (less than 90% reduction in paraprotein) after their first transplant.

MGUS, monoclonal gammopathy of unknown significance; MRI, magnetic resonance imaging.

^aCRAB criteria: include hypercalcemia ≥10.5 mg/dL, renal insufficiency with Cr >2 mg/dL, anemia >2 g/dL below lower limit of normal or <10 g/dL, or bone lesions (lytic lesions or osteoporosis).

^bA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support a classification of myeloma if proven to be myeloma related.

^cA small M-component may sometimes be present.

MGUS, monoclonal gammopathy of unknown significance; MRI, magnetic resonance imaging.

^aCRAB Criteria: includes hypercalcemia ≥11 mg/dL or 1mg/dL > than upper limit of normal, renal insufficiency with CrCl <40mL/min or serum Creatinine >2 mg/dL, anemia >2 g/dL below lower limit of normal or <10 g/dL, or bone lesions (lytic lesions seen on skeletal radiography, CT or PET-CT).

^bClonal bone marrow plasma cell percentage ≥ 60%, Involved: uninvolved serum free light chain ratio of ≥100, >1 focal lesions on MRI studies.

^cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy.

Such dysfunction is sufficient to support a classification of myeloma if proven to be myeloma related.

2. Transplant ineligible. Newly diagnosed patients ineligible for transplant constitute the majority of cases. The goals of therapy are to gain quick control of disease and limit complications. Numerous regimens exist for management of these patients. Historically, Melphalan and Prednisone (MP) had been the mainstay of therapy. With the advent of novel agents, randomized trials noted superior results for therapies combining MP with newer agents. The addition of Thalidomide (MPT) conferred a survival benefit compared with MP. Likewise, MP plus Lenalidomide (MPR) showed a superior RR and Progression Free Survival (PFS) when compared with MP alone. Bortezomib in combination with MP (VMP) has additionally shown improvements in RRs, time to progression, and OS as compared with MP. While triple-drug Melphalan-based regimens improved results for transplant-ineligible patients, recent data suggest that two-drug novel regimens such as Lenalidomide and Dexamethasone may be as good as triple-drug Melphalan-based therapies.
3. Maintenance therapy. In a CALGB study, Lenalidomide maintenance in the posttransplant setting was associated with a benefit in both PFS and OS. In a similar French IFM study, however, the benefit from Lenalidomide maintenance was restricted to PFS. Although Thalidomide has been shown in some studies to have an OS benefit in the posttransplant setting, it is also associated with increased toxicity, particularly with neuropathy and thromboembolism. Likewise, bortezomib maintenance has been shown to confer a PFS and OS benefit when utilized in patients undergoing induction therapy with a bortezomib-based regimen. Even in transplant-ineligible patients, Lenalidomide and Dexamethasone given until progression was associated with an OS advantage compared with fixed duration therapy with MPT.
4. Relapsed or refractory disease. Relapse is nearly universal, and refractory disease is frequently encountered in MM patients. Progressive disease (PD) is defined by otherwise unexplained hypercalcemia (≥11.5 mg/dL), new or progressive plasmacytomas, or a predefined absolute rise or 25% increase from best response in a set of markers including the following:

• Serum M-protein (absolute rise of ≥0.5 g/dL)
• Urine monoclonal protein (absolute rise of 200 mg/24 hours)
• Percentage of plasma cells in the bone marrow (10% increase if no M-protein)
• Difference in κ- and λ-FLC studies (must be >10 mg/dL with abnormal K/L ratio)

There is currently no standard of care for relapsed or refractory disease. For eligible candidates who have not previously undergone stem cell transplant, HDT/autologous stem cell transplant is an option. For those who have previously been transplanted, repeat HDT or further conventional chemotherapy may be tried. If prior response was significant and relapse delayed, repeat trials of previous regimens may be considered. Several agents are approved specifically in the relapsed or refractory setting:

1. Carfilzomib. This is a second-generation proteasome inhibitor approved by the FDA for patients who have been treated with at least two prior therapies, including a proteasome inhibitor and immunomodulatory drug, and have shown progression within 60 days of therapy.
2. Pomalidomide. This is a Thalidomide analog that has demonstrated activity in MM. The combination of Pomalidomide and Dexamethasone is FDA approved for patients who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease has progressed within 60 days of last treatment.
3. Other regimens. Combinations of conventional chemotherapeutic agents are still utilized frequently after failure of proteasome inhibitor and immunomodulatory drug therapy. These include a variety of combinations including C-VAD (Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone), D-CEP (Dexamethasone, cyclophosphamide, etoposide, and cisplatin), DT-PACE (Dexamethasone, Thalidomide, cisplatin, Doxorubicin, cyclophosphamide, and etoposide), and M2 (vincristine, carmustine, cyclophosphamide, and melphalan).
4. Allogeneic transplant. Myeloablative allogeneic transplant in MM is associated with a modest rate of potential cure, whereas high upfront treatment-related mortality (TRM) limits its use. Recently, several trials have evaluated tandem autologous transplant compared with autologous transplant followed by nonmyeloablative allogeneic transplant. Although some trials with long-term follow-up have suggested improvement in OS with a tandem autologous and nonmyeloablative allogeneic transplant approach, the majority of trials have not shown a benefit from this strategy, and longer-term follow-up is awaited. Additional trials evaluating the role of autologous transplant followed by allogeneic transplant for relapsed/refractory disease or as initial therapy in high-risk patients are needed.
5. Adjunct treatments
6. Bisphosphonates. Bisphosphonates inhibit osteoclast-mediated bone resorption and are an integral part of the management of skeletal lesions in MM. They have been shown to decrease skeletal-related events, improve pain control, and limit hypercalcemia. Intravenous pamidronate or zoledronic acid has been approved by the FDA for this indication and is administered on a monthly schedule. Current recommendations suggest 2 years of continued therapy for patients who remain in remission. Bisphosphonates may be continued longer for PD or active bone disease. Key toxicities to monitor include osteonecrosis of the jaw and renal failure. The MRC IX trial revealed an OS advantage for zoledronic acid compared with cladronate independent of the effect on skeletal-related events.
7. Erythropoietin. Anemia is a common complication of MM. Erythropoietin decreases transfusion requirements in MM patients, including those with refractory disease.
8. Radiation. MM is a radiosensitive tumor. External-beam radiation (RT) can effectively palliate discrete areas of bone pain or areas of mass effect such as spinal cord compression.
9. Surgery. Radiographs of long bones done for staging or to evaluate pain may reveal lytic lesions concerning for impending fracture. Orthopedic surgery consultation and prophylactic surgical pinning may prevent some of the morbidity of a fracture. Patients who undergo pinning generally undergo RT to the area postoperatively.
10. Hemodialysis. Renal failure may occur early in the course of disease. Renal impairment may be reversible if the MM responds to treatment, and support with hemodialysis is appropriate. The value of plasmapheresis to reduce the paraprotein level in this situation is debatable.
11. Infection prophylaxis. MM patients have a deficit in humoral immunity due to decreased levels of normal immunoglobulins. The risk of infection is further increased both by direct marrow suppression from chemotherapy as well as immunosuppression associated with long-term, high-dose corticosteroids. All MM patients should be vaccinated against Streptococcus pneumonia. For those undergoing treatment with proteasome inhibitors, Zoster prophylaxis is recommended. Additionally, some patients may benefit from IVIg therapy to supplement chronically low IgG levels.
12. Venous thromboembolism prophylaxis. DVT prophylaxis is recommended for patients receiving immunomodulatory drug combinations with high-dose steroids and chemotherapy. Low-dose aspirin is thought to be sufficient for most patients. Patients at high risk for thromboembolism should receive full anticoagulation.
13. Follow-up. Close follow-up of serial monoclonal protein levels in the serum and/or urine allows for routine monitoring of disease status. Evaluation of quantitative SFLC should be used as an additional tool to evaluate response in the appropriate patient. In patients who have undergone multiple lines of therapy and have relapsed or refractory disease, malignant plasma cells may de-differentiate and cease secretion of a monoclonal protein or light chain. PET scans may be useful in the follow-up of these patients. Skeletal survey and bone marrow biopsy are usually repeated at the time of suspected disease progression.
14.  Natural history
15. Survival. Historically, MP was the first regimen to show an OS benefit from a median of 6 months to 3 years. The advent of high-dose therapy with autologous transplant provided additional survival benefit, increasing median OS to 5 years or more. With the advent of bortezomib and the immunomodulatory agents, data support an additional 18 months to 2 years improvement in OS. The recent approval of Pomalidomide and Carfilzomib is expected to further improve on rates of OS. In addition, novel agents in development show promise to extend this benefit even further.
16. Prognostic factors. Several factors may be evaluated in the initial workup to assist with prognosis. Serum β-2-microglobulin levels correlate with tumor burden and renal function; elevated levels are an important marker of decreased response to treatment and worse OS. Other poor prognostic factors include high lactate dehydrogenase (LDH), high PCLI, low albumin, plasmablastic features in the bone marrow, and circulating plasma cells. More recently, karyotype has emerged as the most powerful predictor of outcomes. The Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) criteria divide patients into standard-, intermediate-, and high-risk groups. The mSMART criteria are detailed below:

• High risk. Del 17p, t(14;16), t(14;20), or high-risk gene expression profiling (GEP)
• Intermediate risk. Del 13 or hypodiploidy, t(4;14), PCLI ≥3%
• Standard risk. All other abnormalities

1. Background
2. Epidemiology. Based on SEER data, the incidence of MM is roughly 6 per 100,000/year. It represents 1.3% of all new cancer diagnoses and 1.8% of all cancer deaths. Overall, incidence and prevalence appear to be growing as the population ages and treatment improves. Notably, among African Americans the risk of MM is double that in the white population, and men are more frequently affected than women. It is a disease of the elderly, with the median age at diagnosis being 69 years. The etiology of MM is unknown. Certain environmental factors, such as benzene and radiation exposure, appear to be predisposing.
3. Pathophysiology. Cytokines provide autocrine and paracrine growth signals to myeloma cells. IL-6, insulin-like growth factor-1, stromal cell-derived factor-1, and vascular endothelial growth factor have all been shown to be important in myeloma cell survival and growth. The interaction between MM cells and stromal cells involving adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1) is thought to provide critical survival signals. Clinical symptoms result from the infiltration of end organs by malignant cells, or deposition of excess light chains. Lytic bone lesions, a hallmark of MM, appear to be mediated by increased expression of receptor activator of nuclear factor κB ligand (RANKL) and decreased expression of Osteoprotegrin (OPG). Tumor-derived osteoclast activating factors including increased IL-3, IL-6, and macrophage inflammatory protein-1 α (MIP-1 α) levels, as well as osteoblast inhibition through MM-derived dickkopf-1 (DKK-1) are also thought to play a key role in the development of bony lesions. Osteoblast inhibition and osteoclast activation lead directly to bone breakdown and often result in clinical hypercalcemia associated with MM. Renal dysfunction is usually a result of excess light chains, but heavy chains may be involved. Anemia is a result of bone marrow invasion by malignant cells and subsequent alterations in the marrow microenvironment.
4. Molecular biology. The malignant cell in MM is thought to arise from transformation of a postgerminal center plasma cell. The pathogenesis remains unknown, but in almost all cases, initial genetic insults lead to the establishment of a monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma cell disorder. Most of the karyotypic abnormalities characteristic of multiple myeloma are detectable in patients with MGUS. It is thought that subsequent additional genetic changes in the plasma cell and alterations in the microenvironment lead to overt MM. Activating mutations of Ras, Myc dysregulation, inactivation of Rb, and loss or mutation of p53 are thought to be critical late events in pathogenesis. Large-scale genomic sequencing has shown an average mutational burden of 35 amino acid changing mutations and 21 chromosomal rearrangements in protein-coding regions. Statistically significant protein-coding region mutations include: NRAS, KRAS, FAM46C, DIS3, TP53, HLA-A, MAGED1, CCND1, FAM46C, PNRC1, and ALOXI2B. Additional mutations are often found in BRAF, NF-κB pathway genes, and histone modifying enzymes, including regulators of HOXA9.
5. Research frontiers. The number of agents with activity in MM continues to expand. Monoclonal antibodies targeting CS-1 and CD38 are likely to enter the therapeutic armamentarium in the future. Novel oral proteasome inhibitors are being investigated. In addition, a variety of compounds, including signal transduction and cell cycle check point inhibitors, are in clinical trials.
6. OTHER PLASMA CELL DISORDERS
7. Monoclonal gammopathy of undetermined significance. MGUS is defined by the absence of end-organ dysfunction in the setting of a monoclonal protein <3 g/dL and <10% infiltrating plasma cells in the bone marrow. Prevalence varies according to race and age. In a large study of Caucasian patients, the prevalence of MGUS for patients >50 years of age was 3.2%. The African American population and men tend to have higher rates of MGUS. MGUS is often diagnosed incidentally on workup for an increased total serum protein, neuropathy, or in the workup of anemia or renal failure in the setting of other causative factors. MGUS patients should be monitored with SPEP every 6 to 12 months. One percent of patients with MGUS progress to a more clinically significant plasma cell dyscrasia each year. A risk stratification model based on three factors can be used to predict risk of progression over 20 years. These include the following: serum monoclonal protein level ≥1.5 g/dL, non-IgG MGUS, or an abnormal SFLC ratio. The risk of progression for patients with 3, 2, 1, or 0 of these factors is 58%, 37%, 21%, and 5%, respectively.
8. Smoldering myeloma. Smoldering multiple myeloma (SMM) is an intermediate stage between MGUS and MM. It is defined by a monoclonal protein of >3 g/dL and/or BM infiltration of ≥10% plasma cells, in the absence of evidence of end-organ damage. The presence of both defining features in the setting of a FLC ratio outside of the reference range of 0.125 to 8 describes a subset of patients with particularly poor risk for progression to overt MM. At 5 years of follow-up, patients with 3, 2, or 1 of these three features had cumulative risk of progression of 76%, 51%, and 25%, respectively. There is great interest in defining a group of SMM that may benefit from therapy.
9. Plasma cell leukemia. Plasma cell leukemia occurs when high levels of circulating plasma cells are present (greater than 2 × 10⁹/L or greater than 20% in the differential WBC count). The disease is aggressive and survival is worse than MM. In cases arising without an antecedent plasma cell disorder, median survival is 6 to 11 months. When plasma cell leukemia occurs as a late event in a patient with known MM, the median survival is 2 to 6 months. Patients with these disorders usually harbor poor risk cytogenetic abnormalities including p53 deletions at high rates. Aggressive multiagent therapy is employed in treatment for these patients.
10. Solitary plasmacytomas of bone. These patients present with a single bony lesion without signs of systemic disease. An MRI of the spine and pelvis and a PET scan (Table 29-2) should be performed to rule out occult lesions. Radiation provides excellent local control, with 90% of patients free from local recurrence. At this time, there is no evidence that chemotherapy or bisphosphonates during or after radiation provide a benefit to patients with solitary plasmacytoma. Patients with lesions larger than 5 cm have the greatest risk of recurrence after radiotherapy. The median OS is roughly 10 years. Up to 50% to 60% of patients may develop overt MM following radiation therapy.
11. Extramedullary plasmacytomas. Extramedullary plasmacytomas are clonal proliferations of plasma cells that arise outside of the bone marrow (Table 29-1). Lesions occur most frequently in the head and neck, but may occur in virtually any organ. The initial workup and evaluation is similar to patients with solitary plasmacytoma, and care must be taken to exclude additional disease. Lesions are sensitive to radiation therapy, and chemotherapy does not provide additional benefit. Five-year OS ranges from 40% to 85%, and 30% to 50% of patients will develop MM at a median of 1.5 to 2.5 years.

β2M, β-2-microglobulin.

^aThere are two categories for stage II: serum β-2-microglobulin <3.5 mg/L but serum albumin <3.5 g/dL; or serum β-2-microglobulin 3.5 mg/L to <5.5 mg/L irrespective of the serum albumin level.

 III. AMYLOIDOSIS

1. Subjective. Patients with AL amyloidosis often present with nonspecific complaints including fatigue, weight loss, and lightheadedness. Orthostasis may be a presenting symptom and can be secondary to several sequelae of amyloidosis, including nephrotic syndrome, intravascular volume depletion, restrictive cardiomyopathy, or autonomic neuropathy. Edema can occur from an amyloid-induced nephrotic syndrome or congestive heart failure. Infiltration of soft tissues can cause capillary fragility and purpuric bruising; periorbital ecchymosis is a classic symptom of AL. Other features include macroglossia, endocrinopathies, neuropathy, and carpal tunnel syndrome.
2. Objective. Physical findings in AL vary depending on which organ systems are affected. Examination may reveal macroglossia, periorbital ecchymosis, hepatomegaly, or edema. Nerve involvement can result in sensory, motor, or autonomic deficits. Laboratory evaluation may reveal renal insufficiency or hypoalbuminemia due to nephrotic syndrome. Low voltages in limb leads on electrocardiogram may be noted in roughly 50% of patients. Amyloid cardiomyopathy may appear on echocardiography as hypertrophy with a restrictive filling pattern or with a “sparkling” appearance of the myocardium. Cardiac MRI may reveal a zebra pattern of enhancement within the myocardium.
3. Workup. The first step in the workup of AL is to suspect the diagnosis. A clue to the possibility of AL is the discovery of a paraprotein in the serum or urine of the patient. A diagnosis of AL amyloidosis by IMWG criteria requires evidence of a monoclonal plasma cell proliferative disorder in addition to end-organ damage and pathologic confirmation of AL amyloid deposition. In the setting of confirmed tissue amyloid, evidence of an M protein in serum or urine, an abnormal SFLC ratio, or a clonal plasma cell population in the bone marrow is sufficient to complete the diagnosis. The paraprotein may be a complete immunoglobulin, although only the light-chain component contributes to amyloid formation. Only a small quantity (less than 1 g/dL) of paraprotein may be present. SFLC assays can be utilized in patients with a negative serum immunofixation. The λ light chains are three times more commonly associated with AL, presumably because these more often possess amyloidogenic characteristics. Under polarized light, amyloid shows apple-green birefringence when stained with Congo red stain. Immunoperoxidase stains on tissue specimens can differentiate between different types of amyloid. Mass spectroscopy is a more sensitive and specific test when compared with immunohistochemistry and is increasingly used to delineate between types of amyloid. An initial biopsy of abdominal fat is often done in an attempt to make a tissue diagnosis while avoiding biopsy of vital organs. The presence of amyloid is 100% specific, but sensitivity varies and can be less than 75%. A bone marrow biopsy will be positive for amyloid deposition in 60% of cases. In most cases of primary AL, clonal plasma cells represent less than 10% of the marrow. In rare cases, no clonal population may be found, and diagnosis should proceed with caution. MM and AL sometimes coexist: 20% of patients with AL are found on workup to have myeloma, and in 10% to 15% of patients with MM, AL will eventually develop. Troponin T and N-terminal probrain natriuretic peptide (NT-proBNP) are both powerful predictors of survival in AL patients.
4. Therapy. As with MM, the initial decision in treatment is to determine whether a patient is a candidate for transplantation. As a general rule, transplant-eligible patients should have a low level of Troponin-T and NT-proBNP and limited levels of organ dysfunction.
5. High-dose therapy/autologous transplant. Retrospective data support the role of autologous transplantation in amyloidosis, showing significant improvements in OS when compared with traditional chemotherapy. A randomized trial comparing conventional chemotherapy with autologous transplantation showed no improvement in OS. However, the patient population in this study had significant end-organ involvement and a high transplant-related mortality and is thought not to be representative of modern transplant-eligible patients. When transplant is chosen, melphalan-based regimens are standard of care.
6. Transplant ineligible. Melphalan and Dexamethasone have been extensively used as therapy for patients who are not transplant candidates. Lately, Bortezomib-containing regimens have shown impressive activity, while immunomodulatory drugs may also have a role in this disease.
7. Future directions. Interest lies in the investigation of novel combination therapies as well as new proteasome inhibitors and immunomodulatory agents.
8. Epidemiology and survival. The estimated incidence is 5.1 to 12.8 new cases per million per year. Prognosis depends on the organs affected, with cardiac and hepatic involvement portending worse outcomes. Median survival is approximately 1 to 2 years in untreated patients, but is less than 6 months in patients with cardiac amyloid. However, in those with limited disease, current therapies may offer an OS surpassing 5 years.
9. Pathophysiology. Amyloidosis is a group of syndromes in which symptoms arise from infiltration of tissue with insoluble misfolded proteins. In primary amyloid (AL), the amyloid is composed of paraprotein light chains secreted by monoclonal plasma cells that deposit into tissues in β-pleated sheet conformation. Alternative sources of amyloid protein include chronic inflammation in secondary (AA) amyloid, β-2-microglobulin in hemodialysis-associated amyloidosis, and transthyretin in familial amyloidosis.

 IV. WALDENSTRÖM’S MACROGLOBULINEMIA. In the World Health Organization (WHO) classification of non-Hodgkin’s lymphoma (NHL), WM is a subset of lymphoplasmacytic lymphoma (LPL), a mature B-cell neoplasm closely related to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

1. Subjective. Patients may present with nonspecific symptoms such as fevers, night sweats, fatigue, weight loss, and peripheral neuropathy. In up to one-third of patients, monoclonal IgM may lead to the development of the hyperviscosity syndrome (HVS), with a classic triad of symptoms including bruising and bleeding, visual changes, and neuropsychiatric symptoms. Deposits of IgM in end organs may lead to purpuric skin lesions and severe diarrhea with steatorrhea. Mucosal bleeding results from paraprotein-mediated interference with coagulation factors and platelet function. Neuropsychiatric symptoms associated with the HVS include transient ischemic attacks (TIAs), paralysis, seizure, dementia, or coma. Occasionally, the IgM paraprotein may act as a cryoglobulin and cause Raynaud’s syndrome and acral cyanosis.
2. Objective. Many patients with WM have no obvious physical findings. On funduscopic examination, patients may have retinal hemorrhages, exudates, or papilledema. Approximately one-third of patients have hepatomegaly, splenomegaly, or lymphadenopathy. IgM can act as an autoantibody against autologous antigens, resulting in autoimmune phenomenon such as demyelinating peripheral neuropathy, cryoglobulinemia, cold agglutinin disease, glomerulonephritis, paraneoplastic pemphigus, or retinitis.
3. Workup and staging. Anemia is the most common laboratory abnormality on initial evaluation. Occasional findings include pseudohyponatremia from elevated protein levels, renal insufficiency, and proteinuria. ESR may be greatly increased or normal. LDH and β-2-microglobulin are often elevated. Diagnosis is based on the presence of an IgM monoclonal protein, bone marrow involvement of >10% by LPL (small lymphocytes exhibiting plasmacytoid or plasma cell differentiation), and expression of a typical immunophenotype by the bone marrow infiltrate. Immunophenotypic analysis should exclude other lymphoproliferative disorders including CLL/SLL. LPL cells express cytoplasmic immunoglobulin, distinguishing them from CLL/SLL cells, which do not. Other immunophenotypic markers are similar to those of CLL, including expression of CD19 and CD20. Initial assessment should also include measurement of serum viscosity. Symptomatic hyperviscosity usually does not occur until the IgM paraprotein is greater than 3 g/dL and the serum viscosity is more than 5 cp (normal is 1.4 to 1.8 cp), although symptoms can occur at lower levels of paraprotein and lower serum viscosities. The International Prognostic Staging System for WM (IPSSWM) utilizes five adverse features (age >65, Hbg ≤11.5 g/dL, platelet count ≤100,000, β-2-microglobulin > 3mg/L, and serum IgM >70 g/L) to stratify patients into low-, intermediate-, and high-risk groups. Low-risk patients are less than 65 with zero or one risk factor, and have an 87% 5-year survival. Intermediate-risk patients are older than 65 or those with two risk factors. High-risk patients have more than two risk factors. Five-year OS for intermediate- and high-risk patients are 68% and 38%, respectively.
4. Therapy. The goal of treatment is to limit symptoms and prevent end-organ damage. Treatment is directed at reducing serum viscosity and treating the underlying lymphoma. Notably, severe neurologic symptoms or intractable bleeding due to hyperviscosity are an oncologic emergency, requiring urgent plasmapheresis and chemotherapy to reduce circulating IgM levels. Treatment regimens vary, but initial therapy is usually pursued with a Rituximab-based combination. Notably, Rituximab may cause an initial IgM flare, and patients with high IgM levels (>5 g/dL) should be cytoreduced with chemotherapy before Rituximab is added to the regimen. Novel agents such as Bortezomib and Thalidomide in combination with Rituximab and Dexamethasone as initial therapy have produced impressive results. Additional agents with activity include Bendamustine, nucleoside analogs (fludarabine, pentostatin, and cladribine), and alkylator-based regimens. Autologous stem cell transplantation is an option for eligible patients who have relapsed and refractory disease.
5. Epidemiology/natural history. WM is an uncommon disease, occurring in 3.4 per million men and 1.7 per million women per year. Median age at diagnosis is 64. Unlike MM, WM occurs much more often in Caucasians than in African Americans. Median survival varies according to IPSSWM score and ranges from over 10 years in low-risk patients to 44 months in high-risk patients. Patients may eventually develop refractory disease or undergo transformation into a higher-grade neoplasm.
6. POEMS SYNDROME (POLYNEUROPATHY, ORGANOMEGALY, ENDOCRINOPATHY, M PROTEIN, AND SKIN CHANGES). POEMS syndrome is a rare disorder with variable symptoms. Patients most often present in the fifth to sixth decade of life with stocking-glove numbness, paresthesias, weakness, fatigue, or other nonspecific symptoms. Diagnosis is based on the Mayo clinic criteria, requiring the presence of a monoclonal protein (virtually always κ restricted) and a polyneuropathy, usually peripheral. In addition to these necessary features, diagnosis depends on the presence of at least one major and one minor criterion. Major criteria include Castleman’s disease, osteosclerotic bone lesions, and elevated serum VEGF levels (3 to 4 times the upper limit of normal). Minor criteria include organomegaly, endocrinopathy, skin changes, papilledema, thrombocytosis, polycythemia, or volume overload. Osteosclerotic bone lesions are the most common major criteria, occurring in 97% of cases, and diagnosis should proceed cautiously in their absence. Diabetes mellitus and gonadal dysfunction are the most frequent endocrinopathies in POEMS syndrome. Skin changes may include hyperpigmentation, hemangiomas, hair changes, or acrocyanosis. Bone marrow biopsy generally demonstrates less than 5% plasma cells. Radiation may be utilized for the treatment of limited disease, while more widespread involvement usually requires systemic treatment with myeloma-like regimens. Peripheral blood stem cell transplant following high-dose therapy has been successfully used and should be reserved for young patients with extensive disease or rapidly progressive neuropathy. The course of POEMS syndrome is extremely indolent, with median survival of almost 14 years.

 VI. LIGHT-CHAIN/HEAVY-CHAIN DEPOSITION DISEASE. Some patients with the clinical features of amyloidosis but without detectable tissue amyloid may have nonamyloid light-chain deposition disease (LCDD). LCDD results from a similar process as AL amyloidosis, but circulating light chains lack the ability to form α-pleated sheets, and thus amyloid is not deposited in end-organ tissues. LCDD tends to present with nephrotic syndrome or renal insufficiency. The mean age of presentation is in the fifties. Unlike AL, φ light chains predominate over κ; LCDD deposits do not take on the amyloid structure or stain with Congo red. Most patients have detectable serum or urinary M protein and may have an associated plasma cell dyscrasia or lymphoproliferative disorder. As with LCDD, patients who have heavy-chain deposition disease (HCDD) have no detectable amyloid, but have evidence of end-organ damage from deposition of monoclonal immunoglobulin heavy chains. Deposits of heavy chains are usually truncated and have no associated light-chain components. Heavy chains most commonly come from IgG and IgA (φ and κ heavy chains). The mean age of presentation is in the fifties. The usual presenting symptoms are renal failure, hypertension, proteinuria, and anemia. The nephrotic syndrome is common. Diagnosis rests on demonstration of heavy chains in end organs. Treatment for both LCDD and HCDD is similar to that described for AL amyloidosis.

 VII. HEAVY-CHAIN DISEASE. Rarely, an M protein is found to be a truncated heavy chain with no associated light chain. Three classes of heavy-chain disease are appreciated, based on the class of heavy chain produced—these include alpha (α), gamma (γ), and Mu (µ) heavy chains. The γ- and µ-heavy-chain paraproteins are rare and are usually associated with NHL. α-HCDD is associated with immunoproliferative small intestinal disease (IPSID), also called Mediterranean lymphoma. IPSID, now considered to be a mucosa-associated lymphoid tissue (MALT) lymphoma, primarily affects young adults in areas of the Mediterranean, North Africa, and the Middle East who suffer from chronic intestinal diseases and malnutrition. Peripheral adenopathy is rare, but retroperitoneal adenopathy may be palpable as an abdominal mass. Diffuse infiltration of the intestine by lymphocytes or plasma cells results in a thickened, hard, pipelike intestine on endoscopy or imaging. The truncated α-heavy chain M protein associated with IPSID is an abnormal IgA molecule that may be detectable by immunofixation on serum, urine, tissue samples, or jejunal secretions sampled by endoscopy. Electrophoresis is less effective at detecting heavy chains, as they migrate as a smear rather than a discrete band. Biopsy of the intestine or mesenteric nodes is necessary for diagnosis. Patients should be evaluated for intestinal pathogens such as Giardia. Similar to Helicobacter pylori–associated gastric MALTomas, early-stage IPSID may respond to antimicrobials directed at any documented intestinal pathogens. More advanced disease may require chemotherapy appropriate for low-grade NHL. IPSID has an indolent course with approximately two-thirds of patients alive at 5 years.

SUGGESTED READINGS

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