Chapter 136 - Plasma Cell Disorders Flashcards Preview

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Flashcards in Chapter 136 - Plasma Cell Disorders Deck (113):
1

Name the conditions that constitue the plasma cell disorders.

Multiple myeloma, Waldenström macroglobulinemia, primary amyloidosis and heavy chain diseases.

2

Name the synonyms for plasma cell disorders.

Monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias and dysproteinemias.

3

What is the fundamental difference between a normal and a pathological plasma cell?

"Under normal circumstances, maturation to antibody-secreting plasma cells and their proliferation is stimulated by exposure to the antigen for which the surface immunoglobulin is specific; however, in the plasma cell disorders, the control over this process is lost."

4

Which mechanisms explain the clinical manifestations due to plasma cell dyscrasia?

"The clinical manifestations of all the plasma cell disorders relate to ehe xpansion of the neoplastic cells, to the secretion of cell products (immunoglobulin molecules or subunits, lymphokines, and to some extent to the host's response to the tumor."

5

Explain the differences between isotypes, allotypes and idiotypes.

"There are three categories of structural variation among immunoglobulin molecules that form antigenic determinants, and these are used to classifiy immunoglobulins. Isotypes are those determinants that distinguish among the main classes of antibodies of a given species and are the same in all normal individuals of that species. Therefore, isotypic determinants are, by definition, recognized by antibodies from a distinct species (heterologous sera) but not by antibodes from a distinct species (homologous sera). There are five heavy chain isotypes (M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are distinct determinants of the same species in the amino acid sequence of otherwise similar immunoglobulins. These differences are determined by allelic genes; by definition, they are detected by antibodies made in the same species. Idiotypes are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibody-producing cells. Idiotypes are formed by the unique structure of the antigen-binding portion of the molecule."

6

What is the value of normal light chain secretion per day?

Less than 10mg per day.

7

Electrophoretic analysis might identify an M component. Where would you expect to find such a component?

"Electrophoretic analysis permits separation of components of the serum proteins. The immunoglobulins move heterogeneously in an electric field and form a broad peak in the gamma region, which is usually increased in the sera of patients with plasma cell tumors. There is a sharp spike in this region called an M component (M for monoclonal). Less commonly, the M component may appear in the β2 or α2 globulin region."

8

The monoclonal antibody mus be present at a concentration of at least 5g/L to be accurately quantitated by electrophoresis, corresponding to ~10 to the ninth cells producing this antibody.
True or False?

True.

9

What is the different use of electrophoresis versus immunoelectrophoresis?

Immunoelectrophoresis helps one determine the type of immunoglobulin and its monoclonal origin, hence giving a qualitative assessment, while electrophoresis gives one a quantitative assessment of plasma proteins.

10

The M component is not specific enough to be used as a screening test in asymptomatic patients.
True or False?

True.
"the amout of M component in the serum is a reliable measure of the tumor burden, making M component an excellent tumor marker to manage therapy, yet it is not specific enough to be used to screen asymptomatic patients."

11

Name the conditions associated with the differential diagnosis of an M component.

"In addition to plasma cell disorder, M components may be detected in other lymphoid neoplasmas such as chronic lymphocytic leukemia and lymphomas of B- or T- cell origin; nonlymphoid neoplasms such as chronic myeloid leukemia, breast cancer, and colon cancer; a variety of nonneoplastic cponditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher's disease, and pyoderma gangrenosum; and a number of autoimmune conditions, including rheymatoid arthritis, myasthenia gravis, and cold agglutinin disease. Monoclonal proteins are also observed in immunosupressed patients after organ transplant and, rarely, allogeneic transplant. At least two very are skin disease - lichen myxedematous (also knon as papular mucinosis) and necrobiotic xanthogranuloma - are associated with a monoclonal gammopathy."

12

Explain the pathophysiollogy of two rare skin disorders associated with monoclona gammopathy.

"In papular mucinosis[/lichen myxedematous], highly cationic IgG is deposited in the dermis of the patients. This organ specificity may reflect the specificity of the antibody for some antigenic component of the dermis. Necrobiotic xanthogranuloma is a histiocytic infiltration of the skin, usually of the face, that produces red or yellow nodules that can enlarge to plaques. Approximately 10% progress to myeloma."

13

What is the percentage of patients with sensory motor neuropathy with monoclonal paraprotein?

5%.

14

In approximately 1% of patients with myeloma, biclonal or triclonal gammopathy is observed.
True or False?

True.

15

What is the percetange of patients with extramedullary or solitatory bone plasmacytomas and no M component?

About one-third.

16

Compare the frequency of ligt and heavy chain myelomas.

"In ~20% of myleomas, only light chains are produced and, in most cases, are secreted in the urine as Bence Jones proteins. The frequency of myelomas of a particular heavy chain class is roughly proportional to the serum concentration, and therefore, IgG meylomas ar emore common than IgA and IgD myelomas."

17

Define multiple myeloma.

"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 and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting anormalities, neurologic symptoms, and manifestations of hyperviscosity."

18

Name the main risk factors currently identified for myleoma.

"The cause of myeloma is not known. Myeloma ocurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myleoma has been seen more commonly than expected among farmers, wood workers, leather workers, and those xposed to petroleum products."

19

Which mutations have been assocaited with multiple myeloma? Is there a common pathway that explain its pathophysiology?

"A variety of chromossomal alterations have been found in patients with myeloma: hyperdiplidy, 13q14 deletions, translocations t(11;14)(q13;q32); t(4;14)(p16;q32), and t(14;16), and 17p13 deletions. Evidence is strong that errors in switch recombination - the genetic mechanism to change antibody heavy chain isotype - participate in the transformation process. However, no common molecular pathogenetic pathway has yet emerged. Genome sequencing studies have failed to identify any recurrent mutations with frequency >20%; N-ras, K-ras, and B-raf mutations are most common and combined occur in over 40% of patients."

20

What is the meaning of the following factors regarding multiple myeloma: (i) additional mutations over time; (ii) IL6; (iii) morphology of plasma cell.

(i) "There is also evidence of complex clusters of subclonal variants at diagnosis that acquire additional mutations over time, indicative of genomic evolution that may drive disease progression."
(ii) "Interleukin (IL) 6 may play a role in driving myeloma cell proliferation."
(iii) "It remains difficult to distniguish benign from malignant plasma cells based on morphologic criteria in all but a few cases."

21

The neoplastic event in myeloma may involve cells earlier in B-cell differentiation than the plasma cell.
True or False?

True.

22

Summarize the epidemiology worldwide of multiple myeloma.

"An estimated 24 050 new cases of myeloma were diagnosed in 2014, and 11 090 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years, it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for 1,3 of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks."
"The incidence of myeloma is highest in African Americans and Pacific Islanders; intermediate in Europeans and North American whites; and lowest in people from developing countries including Asia. The higher incidence in more devloped countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites."

23

Immunoproliferative small-intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area.
True or False?

True.

24

Name the different signaling pathways that lead to the progression of multiple myeloma: (i) growth; (ii) drug resistance; (iii) migration.

(i) Ras/Raf/MAPK
(ii) PI3K/Akt
(iii) Protein kinase C

25

Multiple myeloma cells do not need other cells for growth, drug resistance nor migration.
True or False?

False.
"Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu. These effects are due both to direct MM cell-BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type 1 (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell-derived growth factor (SDF)-1alpha."

26

How frequent is bone pain in multiple myeloma?

Almost 70% of patients are affected.

27

What are the differences between bone pain due to multiple myeloma and metastatic carcinoma?

"Unlike pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipiated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture."

28

Explain the pathophysiology of bone pain in multiple myeloma.

"The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activating factors (OAFs) made by the myeloma cells (....). The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography."

29

How can one measure osteoclast activating factor activity?

"OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NK-kB (RANK) ligand, macrophage inhibitory factor [MIP]-1alpha, and tumor necrosis factor [TNF]"

30

How does one explain hypercalcemia in multiple myeloma?

"The bone lysis resulsts in substancial mobilization of calcium from bone, and serious acute and chronic omplication of hypercalcemia may dominate the clinical picture."

31

Where should one look for palpable bone lesions or their consequences in myeloma?

"Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull, clavicles, and sternum; and the collapse of vertebrae may lead to spinal cord compression."

32

What is the second and third most common clinical problems in multiple myleoma?

First - bone pain (70%).
Second - bacterial infections.
Third - renal involvement (50%) or failure (25%).

33

Name the most common infection in multiple myeloma.

"The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptotoccus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract."

34

How does one explain the increased susceptibility for infections in myeloma patients?

"First, patients with myeloma have diffuse hypogammaglobulinemia, if the M component is excluded. The hypogammaglobulinemia is realted to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component resulsts in fractional catabolic rates of 8-16% instead of the normal 2%. These patients have very poor antibody responses, especially to polyssacharide antigens such as those on bacterial cell walls .Most measures of T-cell function in myleoma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probabgly the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used to therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infections, and bortezomib predisposes to herpesvirus reactivation."

35

How frequently is the kidney involved in multiple myeloma patients?

"Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50% of patients."

36

Explain the pathophysiology of renal failure in myeloma.

"Many factors contribute to this. Hyeprcalcemia is the most common cause of renal failure. Glomerualr deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, biphosphonate use, and occasional infiltration of the kidney by myleoma cells all may contribute to renal dysfunction. However, tubular damage assocaited with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes."

37

What is the earlist form of renal failure in myeloma?

Adult Fanconi's syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine."

38

Proteinuria in myeloma is usually associated with hyperetnsion.
True or False?

False.

39

The anion gap is elevated in myeloma.
True or False?

False.
"Patients with myleoma also have a decrased anion gap [i.e., Na+ - (Cl- + HCO3-)] because the M component is cationic, resulting in retention of chloride."

40

What might the explanation for hyponatremia in myeloma?

"[The decreased anion gap] is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water a result of the increased protein."

41

Renal dysfunction due to light chain deposition disease, light chain cast nephopathy, and amyloidosis is partially reversible with effective therapy.
True or False?

True.

42

Dehydration might lead to acute renal failure most commonly in myeloma patients than in the normal population.
True or False?

True.

43

Name the type of anemia most frequently associated with myeloma.

"Normocytic and normochromic anemia occurs in ~80% of myeloma patients."

44

Explain the pathophysiology of anemia in myeloma patients.

"[Anemia] is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoieses by factors made by the tumor, to reduceted production of erythropoietin by the kidney, and to the ffects of long-term therapy. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency."

45

Granulocytopenia and thrombocytopenia are rare in myeloma except when therapy-induced.
True or False?

True.

46

How does one explain the clotting abnormalities in myeloma?

"Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly; the interactio of the M component with clotting factors I, II, V, VII or VIII; antibody to clotting factors; or amyloid damage of endothelium. Deep venous thrombis is also observed with use of thalidomide, lenalidomide, or pomalidomide in combination with dexamethasone."

47

How does Raynaud's phenomenon and hyperviscosity syndrome relates to myeloma?

"Raynaud«s phenomenon and impaired ciruclation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M compoenent (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined based on the relative serum as compared with water. Normal relative serum viscosity is 1,8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level grear than 4 centripoise (cP), which is usually reached at paraprotein concentrations of ~40g/L (4g/dL) for IgM, 50g/L (5g/dL) for IgG3, and 70g/L (7g/dL) for IgA; however, depending on chemical and physical properties of the paraprotein molecule, it can occasionally be observed at lower levels."

48

Explain the neurologic symptoms that might be observed in myeloma patients.

"Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, smnolence, and coma. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) and myeloma is more frequently sensory than motor neuropathy and is associated with IgM more than other isotypes. In >50% of patients with neuropathy, the IgM monoclonal protein is directed against myelin-associated globulina (MAG). Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy."

49

Myeloma cells usually develop within the bone as well as the spleen, lymph nodes, and gut-associated lympathic tissue.
True or False?

False.
For unknown reasons, myeloma cells rarely involve organs other than the bone.

50

Give examples of medical emergencies in myleoma patients.

Cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia.

51

Compare multiple myeloma to Monoclonal Gammopathy of Undetermined Significance (MGUS).

"MGUS is vastly more common than myeloma, ocurring in 1% of the population older than 50 years and in up to 10% f individuals older than 75 years. Although ~1% of patients per year with MGUS go on to develop myeloma, all myeloma is preceded by MGUS."

MGUS criteria:
- M protein in serum

52

Which features of Monoclonal Gammopathy of Undetermined Significance (MGUS) are indicative of a higher risk for myeloma progression?

"Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15g/L (1,5g/dL) are associated with higher incide of progression of MGUS to myeloma. Absence of all three features predicts a 5% chance of progression, wheare higher risk MGUS with the presence of all three features predicts a 60% chance of progression over 20 years."

53

Name the criteria for Smoldering Multiple Myeloma (SMM) as well as the features associated with a higher risk of progression to Multiple Myeloma (MM).

SMM criteria:
- M protein in serum ≥30g/L and/or
- Bone marrow clonal plasma cells ≥10%
- Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)

"The features responsible for higher risk of porgression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30g/L (3g/dL). Patients with only one of these three features have a 25% chance of progression to MM in 5 years, whereas patients with high-risk SMM with all three features have a 76% chance of progression."

54

Describe and compare solitary bone plasmacytoma to soltary extramedullary plasmacytoma.

"These lesions are associated with an M component in less than 30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesions without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or pgroess."

55

Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia in myeloma patients.
True or False?

True.

56

Immunoelectrophoresis is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis.
True or False?

True.

57

A 24-h urine specimen is necessary to quantitate Bence Jones protein excretion.
True or False?

True.

58

How many patients have plasma cell leukemia with >2000 plasma cells/uL?

~1%.
"This may be be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas."

59

What is the frequency of IgG, IgA and IgD myelomas? How many of these have only light chains in serum and urine?

53%, 25%, 1% and 20%, respectively.

60

Which tests might be used to detected Bence Jones protein? How reliable are they? How many patients have this so called Bence Jones protein?

"Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free ligh chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M componenets also have urinary light chains."

61

Compare the survival regarding the type of light chain present in the urine. Why is there such a difference?

"Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Wheter this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains is unclear."

62

Compare the frequency of hyperviscosity syndrome regarding the different types of immunoglobulin.

IgD: half of patients affected.
IgA and IgG: 2-4% patients affected.

63

Is there any use of β2-microglobulin as a prognostic factor in myeloma?

Yes.
"Serum β2-microglobulin is the single most powerful predictor of survival and can substitute for staging. β2-microglobulin is a protein of 11 000 mol wt with homologies to the constant region of immunoglobulins that is the light chain of the class I major histocompability antigens (HLA-A, -B, -C) on the surface of every cell. Patients with β2-microglobulin levels 0,004g/L have a survival of only 12 months. Combination of serum β2-microglobulin and albumin levels forms the basis for a three-stage Internationl Staging System (ISS) that predicts survival."

64

The Durie-Salmon staging system is unable to predict outcome since high-dose therapy and newer agents are used. Therefore, it is no longer used to stage myeloma.
True or False?

True.

65

Besides β2-microglobulin and albumin, which other factors are of prognostic value in myeloma?

"Other factors that may influence prognosis are the presence of cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent in situ hybridization (FISH) - identified chromosome 17p deletion, and translocations t(4;14, (14;16), and t(14;20). Chromosome 13q deletions, previously thought to predict poor outcome, is not a predictor following the use of newer agents. Microarray profiling and comparative genomic hybridization have formed the basis for RNA- and DNA- based prognostic staging systems, respectively. The ISS system, along with cytogenetic changes, is the most widely used method for assessing prognosis."
t(11;14) and t(6;14) are translocations associated with a better prognosis.

66

How should we treat Monoclonal Gammopathy of Undetermined Significance (MGUS)? Summarize the different interventions regarding low-risk, high-risk and neuropathic patients.

"No specific intervention is indicated for patients with MGUS. Follow-up once a year or less frequently is adequate except in higher risk MGUS, where serum protein electrophoresis, complete blood count, creatinine, and calcium should be repeated every 6 months. A patient with MGUs and severe polyneuropathy is considered for therapeutic intervention if a causal relationship can be assumed, especially in absence of any other potential causes for neuropathy. Therapy can include plasmapheresis and occasionally rituximab in patients with IgM MGUS or myeloma-like therapy in those with IgG or IgA disease."

67

When is it that intervention is indicated in patients with Smoldering Multiple Myeloma (SMM)?

"About 10% of patients with myeloma are asymptomatic (SMM) and will have an indolent course demonstrating only very slow progression of disease over many years. For these patients, no specific therapeutic intervention is indicated, although early intervention with lenalidomide and dexamethasone may prevent progression from high-risk SMM to active MM. At present, patients with SMM only require antitumor therapy when the disease becomes symptomatic with development of anemia, hypercalcemia, progressive lytic bone lesions, renal dysfunction, or recurrent infections."

68

What are the available treatments for solitary plasmacytomas? When should one use systemic therapy?

"Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy at a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually identified because their serum M component falls slowly or disappears initially, only to return after a few months. These patients respond well to systemic therapy."

69

Name the two groups of therapeutic interventions in symptomatic and/or progressive myeloma.

(1) systemic therapy to control the progression of myeloma.
(2) symptomatic supportive care to prevent serious morbidity from the complications of the disease.

70

Give examples of the most used induction regimens for multiple myleoma. Compare the scheduale, efficacy and dosages.

"Thalidomide (200 mg daily), when combined with dexamethasone, achieved responses in two-thirds of newly diagnosed MM patients. Subsequently, lenalidomide (25mg/d on days 1-21 every 4 weeks), an immunomodulatory derivative of thalidomide, and bortezomig (1,3mg/m2 on days 1, 4, 8 and 11 every 3 weeks), a proteasome inhibitor, have each been combined with dexamethasone (40 mg once every week) and otained high response rates (>80%) in newly diagnosed patients with MM. Importantly, their superior toxicity profile with improved efficacy has made them the preferred agents for induction therapy. Efforts to improve the fraction of patients responding an the degree of response have involved adding agents to the treatment regimen. The combination of lenalidomide, bortezomib, and dexamethasone achieves close to a 100% response rate and 30% complete response rate, making it one of the preferred induction regimens in traplsnat-eligible patients. Other similar three-drug combinations (bortezomib, thalidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) also achieve >90% response rate."

71

What are the major adverse effects of the major drug classes used for induction therapy in myeloma patients? Is there any way of preventing them?

"Herpes zoster prophylaxis is indicated if bortezomib is used, and neuropathy attendant to bortezomib can be decreased both by its subcutaneous administration and administration on a weekly schedule. Lenalidomide use requires prophylaxis for deep vein thrombosis (DVT) with either aspirin or warfarin or low-molecular-weight heparin if patiets are at a greater risk of DVT. In patients receiving lenalidomide, stem cells should be collected within 6 months, because the continued use of lenalidomide may compromise the ability to collect adequate number of stem cells. Initial therapy is continued until maximal cytoreduction. In patients who are transplant candidates, alkylating agents such as melphalan should be avoided because they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant."

72

Compare the MP regimen to combinations regimens using MP-agents. What is the rate of response, overall survival and complete response with each regimen?

"In patients who are not transplant cadidates due to physiologic age >70 years, significant cardiopulmonary problems, or other comorbid illnesses, the same two- or three-drug combinations described above are considered standard of care as induction therapy. Previously, therapy consisting of intermittent pulses of melphalan, an alkylating agents, with prednisone (MP; melphalan, 0,25mg/Kg per day, and prednisone, 1mg/Kg per day for 4 days) every 4-6 weeks was used. However, a number of studies have combined novel agents with MP and reported superior response and survival outcomes. In patients >65 years old, combining thalidomide with MP (MPT) obtains higher response rates and overall survival compared with MP alone. Similarly, significantly improved response (71 vs 35%) and overall survival (3-year survival 72 vs 59%) were observed with the combination of bortezomib and MP compared with MP alone. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged progression-free survival combined with MP alone. These combinations of novel agents with MP also achieved high complete response rates (MPT, ~15%; MP plus bortezomib, ~30%; MP plus lenalidomide, ~20%; and MP, ~2-4%)."

73

Although combinations of MP with newer agents are an alternative in these patients, most studies favor continuous therapy with non-MP-contaning regimens due to longer term safety profile and efficacy.
True or False?

True.

74

What is the functional half-life of light chain immunoglobulin?

~6h.

75

Compare standard-dose versus high-dose therapy in myeloma induction therapy.

"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, with up to 25-40% additional complete responses and prolonged progression-free and overall survival; however, few, if any, patients are cured."

76

Two successive high-dose-therapy (tandem transplantations) are more effective than single high-dose therapy.
True or False?

True.
"[although] the benefit is only obseverd in the subset of patients who do not achieve a complete or very good partial response to the first transplantation, which is rare."

77

What are the indications and risks of allogenic transplantation in myeloma patients?

"Allogeneic transplantations may also produce high response rates, but treatment-related mortality may be as high as 40%. Nonmyeloablative allogeneic transplantation can reduce toxicity but is recommended only under the auspices of a clinical trial to exploit an immune grat-versus-myeloma effect while avoiding attendant toxicity."

78

Explain the current evidence that supports the use of maintance therapy in myeloma patients after induction therapy.

"Maintenance therapy prolongs remissions following standard-dose regiments as well as HDT. Two phase 3 studies have demonstrated improved progression-free survival, and one study showed prolonged overall survival in patients receiving lenalidomide compared to placebo as maintenance therapy after HDT. In non-transplant candidates, another phase 3 study showed prolonged progression-free survival with lenalidomide maintenance after MP plus lenalidomide induction therapy. Although there is concern regarding an increased incidence of second primary malignancies in patients receiving lenalidomide maintenance, its benefits far outweigh the risk of progressive disease and death from myeloma. In patients with high-risk cytogenetics, lenalidomide and bortezomib have been combined and show promise as maintenance therapy after transplantation."

79

What are the treatment choices in those patients with relapsed or refractory multiple myeloma (MM)?

"Relapsed myeloma can be treated with a number of agents including lenalidomide and/or bortezomib. These agents in combination with dexamethasone can achieve a partial response rate of up to 60% and a 10-15% complete response rate in patients with relapsed disease. The combination of bortezomib and liposomal doxorubicin is active in relapsed myeloma. Thalidomide, if not used as initial therapy, can achieve responses in refractory cases. The second-generation proteasome inhibitor carfilzomib and immunomodulatory agent pomalidomide have shown efficacy in relapsed and refractory MM, even MM refractory to lenalidomide and bortezomib. High-dose melphalan and stem cell transplantation, if not used earlier, also have activity as salvage therapy in patients with refractory disease."

80

What is the median overall survival of patients with myeloma?

7-8+ years, with subsets of younger patients surviving >10 years.

81

What are the major causes of death in myeloma patients?

"The major causes of death are progressive myeloma, renal failure, sepsis, or therapy-related myelodysplasia. Nearly a quarter of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke - all intercurrent illnesses related more to the age of the patient group than to the tumor."

82

How should one treat hypercalcemia?

"Hypercalcemia generally responds well to biphosphonates, glucocorticoid therapy, hydration, and natriuresis, and rarely requires calcitonin as well. Biphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life, decrease bone-related complications, and may also have antitumor effects."

83

What might be the complications of biphophonates?

"Ostenecrosis of the jaw and renal dysfunction can occur in a minority of patients receiving aminobiphosphonate therapy."

84

Treatments aimed at strenghtnening the skeleton such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested, bur are not of proven efficacy in hypercalcemia.
True or False?

True.

85

How should one prevent renal failure in biphosphonate therapy?

"Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to prevent dehydration and enchance excretion of liight chains and calcium."

86

In the event of acute renal failure, plasmapheresis is ~10 times more effective at clearing light chains than peritoneal dialysis.
True or False?

True.
"however, its role in reversing renal failure remains controversial."

87

Reducing the protein load by effective antitumor therapy with agents such as bortezomib may result in improvement in renal function in over half of the patients.
True or False?

True.

88

Use of lenalidomide is contra-indicated in renal failure.
True or False?

False.
"Use of lenalidomide in renal failure is possible but requires dose modification, because it is renally excreted."

89

What is the treatment of choice for hyperviscosity syndromes?

Plasmapheresis.

90

Which choices does one have to prevent pneumococcus infection in myeloma patients?

"Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococcal polysaccharide vaccines may not elicit an antibody response. Prophylatic administration of intravenous gamma-globulin preparations is used in the setting of recurrent serious infections. Chronic oral antibiotic prophylaxis is not warranted."

91

Myleoma patients might have neurologic symptoms. Which neurologic symptoms might elicit medullary compression syndrome and in that case which therapies should be considered?

"Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency MRI and local radiation therapy and glucocorticoids if cord compression is identified. In patients in whom neurologic deficit is increasing or substantial, emergent surgical decompression may be necessary."

92

Define Waldesntröm's macroglulinemia and its main differences from multiple myeloma.

"In 1948, Waldesntröm described a malignancy of lymphoplasmacytoid cells that secreted IgM. In contrast to myeloma, the disease was associated with lymphadenopathy and hepatosplenomegaly, but the major clinical manifestation was hyperviscosity syndrome. The disease resembles the related diseases chronic lymphocytic leukemia, myeloma, and lymphocytic lymphoma. It originates from a post-germinal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-bearing memory B cell. Waldesntröm's macroglobulienmia (WM) and IgM myeloma follow a similar clinical course, but therapeutic options are different. The diagnosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration of CD138+ plasma cells in the bone marrow. Such patients are at greater risk of pathologic fractures than patients with WM."

93

Name the mutations that has been rported in over 90% of patients with Waldesntröm's macroglobulinemia and the majority of those with IgM Monoclonal Gammopathy of Undetermined Significance (MGUS).

MYD88 L265P.

94

What is the use of MYD88 L265P as a diagnostic factor?

"Presence of this mutation is now used as a diagnostic test to discriminate WM from marginal zone lymphomas (MZLs), IgM-secreting myeloma, and chronic lymphocytic leukemia (CLL9 with plasmacytic differentiation."

95

Explain the pathophysiology of MYD88 L265P for the progression of Waldesntröm's macroglobulinemia.

"This mutation also explains the molecular pathogenesis of the disease, with inveolvement of Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling leading to activation of IL-1R-associated kinase (IRAK) 4 and IRAK1 followed by nuclear factor-kB (NF-kB) activation."

96

What is the correlation between Waldesntröm's macroglobulinemia and peripheral neuropathy? Is there any marker regarding this association?

"There have been reports that the IgM in some patients with macroglobulinemia mnay have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a great extent than the better known myelin basic protein in patients with multiple sclerosis. Sometimes patients with macroglobulinemia develop a periphearl neuropathy, and half of these patients are positive for anti-MAG antibody. The neuropathy may precede the appearance of the neoplasm."

97

There has speculation that the whole process begins with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component, such as myelin in Waldesntröm's macroglobulinemia.
True or False?

True.

98

Name the markers of lymphoplasmacytic cells in Waldesntröm's macroglobulinemia.

IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10- and CD23-.

99

Renal involvement in Waldesntröm's macroglobulinemia is as frequent as to what one observes in multiple myeloma.
True or False?

Fasle.
"unlike myeloma, the size of the IgM paraprotein results in little renal excretion, and only ~20% of patients excrete light chains. Therefore, renal disease is not common."

100

What is the frequency of lambda and kappa chains in Waldesntröm's macroglobulinemia?

20% and 80%, respectively.

101

Explain the usual manifestations and physical examination in patients with Waldesntröm's macroglobulinemia. Compare the findings to those in multiple myeloma.

"Patients present with weakness, fatigue, and recurrent infections similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms such as peripheral neuropathy, dizziness, headache, and transiet paresis are much more common in macroglobulinemia. Physical examination reveals adenopathy and hepatosplenomegaly, and ophalmoscopic examination may reveal vascular segmentation and dilation of the retinal veins characteristic of hyperviscosity states. Patients may have a normocytic, normochromic anemia, but rouleaux formation and a positive Coomb's tst are much more cmmon than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10$ of macroglobulins are cryoglobulins."

102

Define cryoglobulins and describe the different features of these in Waldesntröm's macroglobulinemia and auto-immune diseases.

"These [cryoglobulins] are pure M components and are not the mixed cryoglobulins seen in rheumatoid arthritis and other autoimmune diseases. Mixed cryoglobulins are composed of IgM or IgA complexed with IgG, for which they are specific. In both cases, Raynaud's phenomenon and serious vascular symptoms precipitated by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood dran into a warm syring and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin."

103

Summarize the treatment of Waldesntröm's macroglobulnemia.

Control of erious hyperviscosity symptoms such as an altered state of consciousness or paresis can be achieved acutely by plasmapheresis because 80% of the IgM paraprotein is intravascular. The median survival of affected individuals is ~50 months, similar to that of MM. However, many patients with WM have indolent disease that does not require therapy. Pretreatment parameters including older age, male sex, general symptoms, and cytopenias define a high-risk population. Treatment is usually not initiated unless the disease is symptomatic or increasing anemia, hyperviscosity, lymphadenopathy, or hepatosplenomegaly is present. Bortezomib and bendamustine are two agents with significant efficacy in WM. Rituximab (anti-CD20) can produce responses, alone or combined with either of these two agents. Rituximab can produce IgM flare, so its use is initially with-held in patients with high IgM levels. Flubaradine (25mg/m2 per day for 5 days every 4 weeks) and cladribine (0,1 mg/Kg per day for 7 days every 4 weeks) are also highly effective isngle agents. With identification of the MYD88 mutation, BTK and IRAK1/4 inhibitors are being evaluated and show significant responses. Although high-dose therapy plus autologous transplantation is an option, its use has declined due to the availability of other effective agents."

104

Describe POEMS syndrome.

"The features of this syndrome are polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS). (...) Patients usually have a severe progressive sensorimotor polyneuropathy associated with sclerotic bone lesions from myeloma. Polyneuropathy associated with sclerotic bone lesions from myeloma. Polyneuropathy occurs in ~1,4% of myelomas, but the POEMS syndrome is only a rare subset of that group. Unlike typical myeloma, hepatomegaly and lymphadenopathy occur in about two-thirds of patients, and splenomegaly is seen in one-third. The lymphadenopathy frequently resembles Castleman's disease histologically, a condition that has been linked to IL-6 overproduction. The endocrine manifestations include amenorrhea in women and impotence and gynecomastia in men. Hyperprolactinemia due to loss of normal inhibitory control by the hypothalamus may be assocaited with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in about one-third of patients. Hypothyroidism and adrenal insufficiency are occasionally noted. Skin changes are diverse: hyperpigmentation, hypertrichosis, skin thickening, and digital clubbing. Other manifestations include peripheral edema, ascites, pleural effusions, fever, and thrombocytosis. Not all the components of POEMS syndrome may be present initially."

105

Sumamrize the treatment of POEMS syndrome.

"Patients are often treated similarly to those with myeloma. Plasmapheresis does not appear to be of benefit in POEMS syndrome. Patients presenting with isolated sclerotic lesions may have resolution of neuropathic symptoms after local therapy for plasmacytoma with radiotherapy. Similar to multiple myeloma, novel agents and high-dose therapy with autologous stem cell transplantation have been pursued in selected patients and have been associated with prolonged progression-free survival."

106

Name the heavy chains associated with heavy chain diseases and those never reported to cause this disease..

"Patients have absence of light chain and secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared."

107

Describe Franklin's disease and its treatment.

"This diseae affects individuals of widely different age groups and countries of origin. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. It is frequently associated with autoimmune diseases, especially rheumatoid arthritis. Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer's ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstration of an anomalous serum M component (often less than 20g/L), that reacts with anti-IgG but not anti-light chain reagents. The M component is typically present in both serum and urine. Most of the paraprotein have been of the ϒ1 subclass, but other subclasses have been seen. The patients may have trombocytopenia, eosinophilia, and nondiagnostic bone marrow that may show increased numbers of lymphocytes or plasma cells that do not stain for light chain. Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy. Therapy is indicated when symptomatic and involves chemotherapeutic combinations used in low-grade lymphoma. Rituximab has also been reported to show efficacy."

108

What is the most common heavy chain disease?

Alpha heavy chain disease.

109

Describe the epidemiology of Seligmann's disease.

"[Alpha heavy chain disease] is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South Africa."

110

What is the correlation between alpha heavy chain disease and the following: (i) hyperviscosity syndrome; (ii) Light chains.

(i) "Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease. Without J chain-facilitated dimerization, viscosity does not increase dramatically."
(ii) Light chains are absent from serum and urine."

111

Explain the therapy used for seligmann's disease.

"Chemotherapy may produce long-term remissions. Rare atients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone."

112

Describe IPSID.

"Immunoproliferative small-intestinal disease (IPSID) is recognized as an infectious pathogen-associated human lymphoma that has association with Campylobacter jejuni. It involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive proteins lacking the light chains as well as the first constant domain. Early-stage IPSID responds to antibiotics (30-70% complete remission). Most untreated IPSID patients progress to lyphoplasmacytic and immunoblastic lymphoma. Patients not responding to antibiotic therapy are considered for treatment with combination chemotherapy used to treat low-grade lymphoma."

113

Describe Mu heavy chain disease.

"The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with chronic lymphocytic leukemia (CLL). The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine. The diagnosis requires ultracentrifugation or gel filtration to confirm the nonreactivity of the paraprotein with the light chain reagents, because some intact macroglobulins fail to interact with these serums. The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm. There is no evidence that such patients should be treated differently from other patients with CLL."