46 - 116 Plasma Cell Disorders

116 Plasma Cell Disorders

Nikhil C. Munshi, Dan L. Longo,

Kenneth C. Anderson

Plasma Cell Disorders The plasma cell disorders are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the late B-lymphocyte lineage. Multiple myeloma (MM), Waldenström’s macroglobulinemia, primary amyloidosis (Chap. 117), and the heavy chain diseases comprise this group and may be designated by a variety of synonyms such as monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias, and dysproteinemias. Mature B lymphocytes des­ tined to produce IgG bear surface immunoglobulin molecules of both μ and γ heavy chain isotypes with both isotypes having identical idio­ types (variable regions). 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 spe­ cific; however, in the plasma cell disorders, the control over this process is lost. The clinical manifestations of all the plasma cell disorders relate to the expansion 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. Normal development of

B lymphocytes is discussed in Chap. 360 and depicted in Fig. 113-2. Three categories of structural variation are present among immu­ noglobulin molecules that form antigenic determinants, and these are used to classify 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 antibodies from the same 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 that reflect regular small differences between individuals of the same species in the amino acid sequences of otherwise similar immunoglobulins. These differences are determined by allelic genes; by definition, they are detected by antibodies made in the same spe­ cies. Idiotypes are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibodyproducing cells. Idiotypes are formed by the unique structure of the antigen-binding portion of the molecule. Antibody molecules (Fig. 116-1) are composed of two heavy chains (~50,000 molecular weight [mol wt]) and two light chains (~25,000 mol wt). Each chain has a constant portion (limited amino acid sequence variability) and a variable region (extensive sequence variability). The light and heavy chains are linked by disulfide bonds and are aligned so that their variable regions are adjacent to one another. This variable region forms the antigen recognition site of the antibody molecule; its unique structural features form idiotypes that are reliable markers for a particular clone of cells because each antibody is formed and secreted by a single clone. Because of the mechanics of the gene rearrangements necessary to specify the immunoglobulin variable regions (VDJ joining for the heavy chain, VJ joining for the light chain), a particular clone rearranges only one of the two chromosomes to produce an immuno­ globulin molecule of only one light chain isotype and only one allotype (allelic exclusion) (Fig. 116-1). After exposure to antigen, the variable region may become associated with a new heavy chain isotype (class switch). Each clone of cells performs these sequential gene arrange­ ments in a unique way. This results in each clone producing a unique immunoglobulin molecule. In most plasma cells, light chains are syn­ thesized in slight excess, secreted as free light chains, and cleared by the kidney, but <10 mg of such light chains are excreted per day. Electrophoretic analysis permits separation of components of the serum proteins (Fig. 116-2). The immunoglobulins move hetero­ geneously in an electric field and form a broad peak in the gamma region. There is a sharp spike in this region called an M component (M for monoclonal) in the sera of patients with plasma cell tumors.

Less commonly, the M component may appear in the β2 or α2 globulin region. The monoclonal antibody must be present at a concentration of at least 5 g/L (0.5 g/dL) to be accurately quantitated by this method. This corresponds to ~109 antibody producing cells. Confirmation of the type of immunoglobulin and that it is truly monoclonal is deter­ mined by immunoelectrophoresis that reveals a single heavy and/or light chain type. Hence, immunoelectrophoresis and electrophoresis provide qualitative and quantitative assessment of the M component, respectively. The amount of M component in the serum is a reli­ able measure of the tumor burden and an excellent tumor marker to manage therapy, yet it is not specific enough to be used to screen asymptomatic patients. In addition to the plasma cell disorders, M components may be detected in other lymphoid neoplasms such as chronic lymphocytic leukemia (CLL) and lymphomas of B- or T-cell origin; nonlymphoid neoplasms such as chronic myeloid leukemia, breast cancer, and colon cancer; a variety of nonneoplastic conditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease, and pyoderma gangrenosum; and a number of autoimmune conditions, including rheumatoid arthritis, myasthenia gravis, and cold agglutinin disease. Monoclonal proteins are also observed in immunosuppressed patients after organ transplant and, rarely, allogeneic transplant. At least two very rare skin diseases—lichen myxedematosus (also known as papular mucinosis) and necrobiotic xanthogranuloma—are associ­ ated with a monoclonal gammopathy. In papular mucinosis, highly cationic IgG is deposited in the dermis of patients. This organ specific­ ity may reflect the specificity of the antibody for some antigenic com­ ponent 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. Five percent of patients with sensory motor neuropathy also have a monoclonal paraprotein.

CHAPTER 116 Plasma Cell Disorders The nature of the M component is variable in plasma cell disorders. It may be an intact antibody molecule of any heavy chain subclass, or it may be an altered antibody or fragment. Isolated light or heavy chains may be produced. In some plasma cell tumors such as extramedullary or solitary bone plasmacytomas, less than one-third of patients will have an M component. In ~20% of myelomas, 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 myelomas are more common than IgA and IgD myelomas. In ~1% of patients with myeloma, biclonal or triclonal gammopathy is observed. MULTIPLE MYELOMA ■ ■DEFINITION MM 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, hypercal­ cemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity. ■ ■ETIOLOGY The cause of myeloma is not known. Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myeloma has been seen more commonly than expected among farmers, wood workers, leather work­ ers, and those exposed to petroleum products. A variety of recurrent chromosomal alterations have been found in patients with myeloma: hyperdiploidy (trisomies involving one or more of chromosomes 3, 5, 7, 9, 11, 15, 19, or 21) is observed in half of the patients, while the other half have translocations involving the 14q32 chromosome with variable partners including t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16). Other frequent abnormalities include 13q14 deletion, 1q amplification or 1p deletion, and 17p13 deletions. Evidence is strong that errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the early transformation process. However, no single common molecular pathogenetic pathway has yet

λ Light-chain locus L1 Vλ1 L2 Vλ2 Jλ1 Jλ2 Jλ4 L Vλ–30 Cλ1 Cλ2 Cλ4 κ Light-chain locus L1 Vκ1 L2 Vκ2 L3 Vκ3 Jκ1–5 L Vκ–36 Cκ Heavy-chain locus L1 VH1 L2 VH2 L3 VH3 JH 1–6 Cµ LH VH–40 DH1–23 Light chain Heavy chain L V J C L V J D Germline DNA PART 4 Oncology and Hematology Somatic recombination DNA RNA Protein D–J rearranged DNA joined Somatic recombination L V J C V–J or V–DJ joined rearranged DNA Transcription L V J C Primary transcript RNA AAA Splicing L V J C mRNA AAA Translation VL CL Polypeptide chain FIGURE 116-1  Immunoglobulin genetics and the relationship of gene segments to the antibody protein. The top portion of the figure is a schematic of the organization of the immunoglobulin genes, λ on chromosome 22, κ on chromosome 2, and the heavy chain locus on chromosome 14. The heavy chain locus is >2 megabases, and some of the D region gene segments are only a few bases long, so the figure depicts the schematic relationship among the segments, not their actual size. The bottom portion of the figure outlines the steps in going from the noncontiguous germline gene segments to an intact antibody molecule. Two recombination events juxtapose the V-D-J (or V-J for light chains) segments. The rearranged gene is transcribed, and RNA splicing cuts out intervening sequences to produce an mRNA, which is then translated into an antibody light or heavy chain. The sites on the antibody that bind to antigen (the so-called CDR3 regions) are encoded by D and J segments for heavy chains and the J segments for light chains. (Adapted from Janeway’s Immunobiology, 8th ed by Kenneth Murphy. Copyright © 2012 by Garland Science, Taylor & Francis Group, LLC. Used by permission of W. W. Norton & Company, Inc.) emerged. Genome sequencing efforts have allowed for characterization of critical genes, pathways, and clonal heterogeneity in myeloma. The median number of mutations per transcribed genome in myeloma is ~58, and within the whole genome, it is >7000. A very heterogeneous mutational landscape with no unifying mutation has been observed. The most frequently mutated genes are KRAS and NRAS (~20% each), followed by TP53, DIS3, FAM46C, and BRAF, all mutated in 5–10%

C C L V DJ C L V DJ C L V DJ AAA C L V DJ AAA CH3 CH2 CH1 VH of patients. All other mutations were observed in <5% of the patients. These results are now being applied to develop new targeted personal­ ized therapies in myeloma. Evidence of complex clusters of subclonal variants is present at diagnosis, and additional mutations are acquired over time, indicative of genomic evolution that may drive disease progression. Interleukin (IL) 6 may play a role in driving myeloma cell proliferation. It remains difficult to distinguish benign from malignant

SP G A M Κ λ SP G A M Κ λ SP G A M Κ λ Normal Polyclonal increase Monoclonal IgG lambda FIGURE 116-2  Representative patterns of serum electrophoresis and immunofixation. The upper panels represent agarose gel, middle panels are the densitometric tracing of the gel, and lower panels are immunofixation patterns. The panel on the left illustrates the normal pattern of serum protein on electrophoresis. Because there are many different immunoglobulins in the serum, their differing mobilities in an electric field produce a broad peak. In conditions associated with increases in polyclonal immunoglobulin, the broad peak is more prominent (middle panel). In monoclonal gammopathies, the predominance of a product of a single cell produces a “church spire” sharp peak, usually in the γ globulin region (right panel). The immunofixation (lower panel) identifies the type of immunoglobulin. For example, normal and polyclonal increases in immunoglobulins produce no distinct bands; however, the right panel shows distinct bands in IgG and lambda protein lanes, confirming the presence of IgG lambda monoclonal protein. (Courtesy of Dr. Neal I. Lindeman.) plasma cells based on morphologic criteria in all but a few cases (Fig. 116-3). ■ ■INCIDENCE AND PREVALENCE In 2024 in the United States, 35,780 new cases of myeloma were esti­ mated to be diagnosed, and 12,540 people were estimated to die from the disease. Myeloma increases in incidence with age. The median age at diagnosis is 69 years; it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. In 2021, myeloma accounted for 1.8% of all malignancies, with incidence rates per 100,000 of 8.1 and 5.1 in white and 17.1 and 13.0 in black men and women, respectively. ■ ■GLOBAL CONSIDERATIONS The incidence of myeloma is highest in blacks and Pacific Islanders; intermediate in Europeans and North American whites; and lowest in FIGURE 116-3  Multiple myeloma (marrow). The cells bear characteristic morphologic features of plasma cells: round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen.

CHAPTER 116 Plasma Cell Disorders people from developing countries including Asia. The higher incidence in more developed countries may result from the combination of a lon­ ger life expectancy and more frequent medical surveillance. Incidence of MM 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. Immunopro­ liferative small-intestinal disease (IPSID) with α heavy chain disease is most prevalent in the Mediterranean area. Despite these differences in prevalence, the characteristics, response to therapy, and prognosis of myeloma are similar worldwide. ■ ■PATHOGENESIS AND CLINICAL MANIFESTATIONS MM cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which trig­ gers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu (Fig. 116-4). These effects are due both to direct MM cell–BMSC binding via adhesion molecules and to induction of various cytokines, including IL-6, insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF). Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively. Other cellular elements in the bone marrow microen­ vironment also significantly impact MM cell growth and survival, especially interactions with endothelial cells and osteoclasts. Immune cells such as plasmacytoid dendritic cells (pDC), myeloid-derived sup­ pressor cells (MDSC), and T helper 17 (TH17) cells are increased in number and support myeloma growth, while antimyeloma immune responses, especially T helper and cytotoxic cells, B cells, and natural killer T cells, are suppressed. Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. 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) produced by the myeloma cells (mediated by several cytokines, includ­ ing IL-1, lymphotoxin, VEGF, receptor activator of nuclear factor-κB [RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor

TH17 Osteoclast ↑Proliferation ↑Differentiation ↑Activity IL-17 RANK IL-6 MM cell RANKL IL-6 Cytokine-mediated signaling OPG Adhesion-mediated signaling ↑Differentiation ↑Activity Osteoblast DKK-1 PART 4 Oncology and Hematology Cytokines IL-6 VEGF IGF-1 SDF-1® Endothelial cells ↑Neoangiogenesis NF-κB BMSC FIGURE 116-4  Pathogenesis of multiple myeloma. Multiple myeloma (MM) cells interact with bone marrow stromal cells (BMSCs) and extracellular matrix proteins via adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival, and antiapoptotic effects as well as development of drug resistance. Additional bidirectional interactions lead to inhibition of osteoblast and increase in osteoclast activity, which leads to bone-related issues in myeloma. Similar interactions with immune microenvironment lead to augmentation of tumor-promoting immune responses and suppression of tumor protective immune responses, overall allowing myeloma cell growth. (Adapted from G Bianchi, NC Munshi: Blood 125: 3049, 2015.) necrosis factor [TNF]). The bone lesions are lytic in nature (Fig. 116-5) and are rarely associated with osteoblastic new bone formation due to their suppression by dickkopf-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scan is less useful in diagnosis than is plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Local­ ized bone lesions may cause pathological fracture or the collapse of vertebrae, leading to spinal cord compression. The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelone­ phritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and

Escherichia coli and other gram-negative organisms in the urinary tract. In ~25% of patients, recurrent infections are the presenting features, and >75% of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. The large M component results in fractional catabolic rates of 8–16% instead of the normal 2%. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Various abnormalities in T-cell function are also observed including decreased TH1 response, increase in TH17 cells producing proinflammatory cytokines, and aberrant T regulatory

MDSC pDC Anergic Exhausted Cytotoxic T cell CTLA4 PD-L1 PD-1 Proliferatic p42/44 MAPK Raf MEK BCI-xL Mcl-1 JAK STAT3 Drug resistance antiapoptosis Bad NF-κB Cyclin D PI3-K FKHR Akt p21 Cell cycle Adhesion molecule interactions Migration PKC cell function. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors con­ tribute to the immune deficiency in these patients. Some commonly used therapeutic agents may significantly affect immune function; e.g., dexamethasone suppresses immune responses and increases sus­ ceptibility to bacterial and fungal infection, B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor T (CAR-T) cells and bispecific antibodies can eliminate plasma cells inducing hypogamma­ globulinemia, and bortezomib predisposes to herpesvirus reactivation. Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in >50%. Of many contributing factors, hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occa­ sional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is common. 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. The earliest manifestation of this tubular damage is the 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.

A B FIGURE 116-5  Bony lesions in multiple myeloma (MM). A. The skull demonstrates the typical “punched out” lesions characteristic of MM. The lesion represents a purely osteolytic lesion with little or no osteoblastic activity (above). B. Positron emission tomography/computed tomography showing multiple fluorodeoxyglucose (FDG)-avid lesions in skeleton (left panel) with their resolution on achieving complete response (CR) (right panel). (Part A courtesy of Dr. Geraldine Schechter; with permission. Part B courtesy of Dr. Sundar Jagannath; with permission.) The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal. When the glomeruli are involved, nonselective proteinuria is also observed. Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3 −)] because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal dysfunction due to light chain

deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy. Myeloma patients are sus­ ceptible to developing acute renal failure if they become dehydrated.

Normocytic and normochromic anemia occurs in ~80% of myeloma patients. It is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoiesis by factors produced by the tumor, to reduced production of erythropoietin by the kidney, and to the effects of long-term therapy. In addition, mild hemolysis may contribute to the anemia. A larger than expected frac­ tion of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are rare except when therapy-induced. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly; the interaction of the M component with clotting factors I, II, V, VII, or VIII; antibody to clotting factors; or amyloid damage of endothelium. Deep venous thrombosis is also observed with the use of thalidomide, lenalidomide, or pomalidomide. Raynaud’s phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined based on the relative viscosity of serum as compared with water. Normal relative serum vis­ cosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoises (cP), which is usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA; however, chemico-physical properties of the paraproteins may cause it at lower levels. CHAPTER 116 Plasma Cell Disorders Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weak­ ness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, 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 signifi­ cance (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 globulin (MAG). Sensory neu­ ropathy is also a side effect of therapy, specifically thalidomide and bortezomib. Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue. ■ ■DIAGNOSIS AND STAGING The diagnosis of myeloma requires marrow plasmacytosis (>10%), a serum and/or urine M component, and at least one of the myelomadefining events detailed in Table 116-1. Bone marrow plasma cells are CD138+ and either monoclonal kappa or lambda light chain positive. The most important differential diagnosis in patients with myeloma involves their separation from individuals with MGUS or smolder­ ing multiple myeloma (SMM). MGUS is vastly more common than myeloma, occurring in 1% of the population aged >50 years and in up to 10% of individuals aged >75 years. The diagnostic criteria for MGUS, SMM, and myeloma are described in Table 116-1. Although ~1% of patients per year with MGUS go on to develop myeloma, all cases of myeloma are preceded by MGUS. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. Absence of all three features predicts a 5% chance of progres­ sion, whereas higher-risk MGUS with the presence of all three features predicts a 60% chance of progression over 20 years. The features

PART 4 Oncology and Hematology TABLE 116-1  Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined Significance Monoclonal Gammopathy of Undetermined Significance (MGUS) Serum monoclonal protein (non-IgM type) <30 g/L Clonal bone marrow plasma cells <10%a Absence of myeloma-defining events or amyloidosis that can be attributed to the plasma cell proliferative disorder Smoldering Multiple Myeloma (Asymptomatic Myeloma) Both criteria must be met: • Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60% • Absence of myeloma-defining events or amyloidosis Symptomatic Multiple Myeloma Clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytomaa and any one or more of the following myeloma-defining events: • Evidence of one or more indicators of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) • Renal insufficiency: creatinine clearance <40 mL/minb or serum creatinine >177 μmol/L (>2 mg/dL) • Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc • Any one or more of the following biomarkers of malignancy: • Clonal bone marrow plasma cell percentagea ≥60% • Involved: uninvolved serum free light chain ratiod ≥100 • >1 focal lesion on MRI studiese Nonsecretory Myeloma No M protein in serum and/or urine with immunofixationf Bone marrow clonal plasmacytosis ≥10% or plasmacytomaa Myeloma-related organ or tissue impairment (end-organ damage, as described above) Solitary Plasmacytoma Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cellsa Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder POEMS Syndrome All of the following four criteria must be met:

1. Polyneuropathy
2. Monoclonal plasma cell proliferative disorder
3. Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease; (c) elevated levels of vascular endothelial growth factor (VEGF)
4. Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiag aClonality should be established by showing κ/λ light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. bMeasured or estimated by validated equations. CIf bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. dThese values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The involved free light chain must be ≥100 mg/L. eEach focal lesion must be ≥5 mm in size. fA small M component may sometimes be present. gThese features should have no other attributable causes and have temporal relation with each other. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET-CT, 18F-fluorodeoxyglucose positron emission tomography with computed tomography; POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. responsible for higher risk of progression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/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. Two important variants of myeloma are solitary bone plasmacytoma and solitary extramedullary plasmacy­ toma. These lesions are associated with an M component in <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 lesion 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 com­ ponent 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 progress. ■ ■LABORATORY INVESTIGATION Serum protein electrophoresis and measurement of serum immuno­ globulins and free light chains are useful for detecting and character­ izing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M compo­ nents not detectable by protein electrophoresis. A 24-h urine specimen is necessary to quantitate Bence Jones protein (immunoglobulin light chain) excretion. The serum M component is IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reli­ able 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 compo­ nent; 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 light chain assay. Mass spectrometry has been investigated to accurately

assess M protein. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on disease behavior. Whether 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. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2–4% of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations. A standard workup directed at detecting monoclonal plasma cells and myeloma-defining events as well as prognosis is detailed in Table 116-2. A complete blood count with differential may reveal anemia. Eryth­ rocyte sedimentation rate is elevated. Rare patients (~1%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum β2-microglobulin and albumin (see below). Chest and bone radiographs may reveal lytic lesions or diffuse osteo­ penia. Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root com­ pression in patients with pain syndromes. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomogra­ phy (CT) is a valuable tool to assess bone damage and detect extramed­ ullary sites of the disease (Fig. 116-5). The use of 18F-FDG PET/CT is now considered standard to distinguish between smoldering and active TABLE 116-2  Standard Investigative Workup in Multiple Myeloma (MM) Investigations to Evaluate for Clonal Plasma Cells Bone marrow aspirate and biopsy (fine-needle aspiration of plasmacytoma if indicated) • Histology • Clonality by kappa/lambda immunostaining by flow cytometry or immunohistochemistry Investigations to Evaluate Clonal Paraprotein Serum protein electrophoresis and immunofixation Quantitative serum immunoglobulin levels (IgG, IgA, and IgM) 24-h urine protein electrophoresis and immunofixation Serum free light chain and ratio Immunofixation for IgD or IgE in select cases Investigation to Evaluate End-Organ Damage Hemogram to assess for anemia. Chemistry panel for renal function and calcium Skeletal survey or PET/CT scan to evaluate bone lesions PET/CT or MRI if smoldering MM or solitary plasmacytoma Investigation for Risk Stratification β2-Microglobulin and serum albumin for ISS stage DNA-sequencing or if not available Fluorescent in situ hybridization for hyperdipoidy, del17p, t(4;14); t(11;14), t(14;16), t(14;20), amp1q34, and del1p and p53 mutation on bone marrow sample LDH Specialized Investigation in Selected Cases Abdominal fat pad for amyloid Serum viscosity if IgM component or high IgA levels or serum M component >7 g/dL Myd88 and CXCR4 mutation analysis if IgM component Abbreviations: CT, computed tomography; ISS, International Staging System; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography.

MM and to confirm a suspected diagnosis of solitary plasmacytoma. It is also a valuable tool to evaluate response in patients with oligo- or nonsecretory myeloma.

■ ■PROGNOSIS Serum β2-microglobulin is the single most powerful predictor of sur­ vival and can substitute for staging. β2-Microglobulin is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Combination of serum β2-microglobulin and albumin levels forms the basis for a three-stage International Staging System (ISS) (Table 116-3) that predicts survival. With the use of highdose therapy and the newer agents, the Durie-Salmon staging system is unable to predict outcome and is no longer used. High labeling index, circulating plasma cells, performance status, and high levels of lactate dehydrogenase are also associated with poor prognosis. With low proliferative activity of plasma cells, karyotype is now not recommended in myeloma. Fluorescent in situ hybridization (FISH) has become a standard investigative technique, and the current recom­ mendation suggests switching to DNA sequencing-based methods. Chromosome 17p deletion with 20% clonality or TP53 mutation, and translocations t(4;14), (14;16), or t(14;20) associated with del 1p or amp1q changes along with high β2-microglobulin with normal renal function are considered prognostic for high-risk disease, as described in Table 116-3. Chromosome 13q deletion and t(11;14) are not consid­ ered predictors of high-risk myeloma. CHAPTER 116 TREATMENT Multiple Myeloma Plasma Cell Disorders MGUS, SMM, AND SOLITARY PLASMACYTOMA 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 con­ sidered for therapeutic intervention if a causal relationship can be assumed, especially in the absence of any other potential causes for neuropathy. Therapy can include plasmapheresis and occasionally rituximab in patients with IgM MGUS or myeloma-like therapy TABLE 116-3  Risk Stratification in Myeloma STANDARD RISK (75–80%) (EXPECTED SURVIVAL 8–10+ YEARS) HIGH RISK (20–25%) (EXPECTED SURVIVAL 3–4 YEARS) METHOD DNA sequencing or FISH if sequencing not available t(11;14) del(17p) (20% cutoff) and/ or TP53 mut   del(13) t(4;14)/t(14;16)/t(14;20) with 1q gain and/or 1p del   Hyperdiploidy Del 1p + 1q gain or biallelic del 1p Biochemical assessment   β2M >5.5 with normal creatinine INTERNATIONAL STAGING SYSTEM (ISS) INTERNATIONAL STAGING SYSTEM (ISS) STAGE MEDIAN SURVIVAL, MONTHS β2M <3.5, ALB ≥3.5 I (28%)

II (39%)

β2M <3.5, ALB <3.5 or

β2M <3.5, ALB ≥3.5 or

β2M = 3.5–5.5 III (33%)

β2M >5.5 or β2M <3.5, ALB <3.5 or β2M = 3.5–5.5 aPercentage of patients presenting at each stage. Abbreviations: β2M, serum β2-microglobulin in mg/L; ALB, serum albumin in g/dL; FISH, fluorescent in situ hybridization; LDH, lactate dehydrogenase.

in those with IgG or IgA disease. A subset of patients with MGUS develop renal dysfunction usually based on renal damage from the monoclonal antibody. The damage may affect the glomeruli, tubules, or vessels. No consensus exists on management, but lower­ ing the level of the monoclonal antibody with bortezomib has had some advocates.

About 10% of patients have SMM and will have an indolent course demonstrating only slow progression of disease over many years. For patients with SMM, no specific therapeutic intervention is indicated in general. But early intervention with lenalidomide alone or in combination with dexamethasone has been shown to prevent progression from high-risk SMM to active MM. At present, patients with SMM only require antitumor therapy when myelomadefining events are identified. 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 ~40 Gy. Occult marrow involvement may occur at low incidence in patients with TABLE 116-4  Standard Therapeutic Agents in Myeloma CLASS AGENT STANDARD DOSAGE AND ADMINISTRATION COMBINATION MYELOMA INDICATION Immunomodulatory drugs (IMiD) Thalidomide (T) Oral 50–200 mg qd TD, VTD Newly diagnosed and relapsed PART 4 Oncology and Hematology Lenalidomide (R) Oral 5–25 mg daily × 21 days q 4 weeks RD, RVD, DaRD, ERD, KRD, IRD, DaRVD Pomalidomide (P) Oral 2–4 mg daily × 21 days q 4 weeks PD, KPD, DaPD Relapsed Proteasome inhibitors (PI) Bortezomib (V) IV or SC 1.3 mg/m2 days 1, 4, 8, 11 OR days 1, 8, 15 VD, VTD, VRD, DaVD, VCD DaRVD Carfilzomib (K) IV 20–56 mg/m2 days 1, 2, 8, 9, 15, 16 q 4 weeks KD, KRD, KPD, Da KD, Da KRD, IsaKD Ixazomib (I) Oral 4 mg days 1, 8, 15 IRD Relapsed, maintenance Antibodies Daratumumab (Da) IV or SC 16 mg/kg per week for 8 weeks then every 2 weeks for 16 weeks and then every 4 weeks thereafter Elotuzumab (E) IV 10 mg/kg days 1, 8, 15, and 22 for first two cycles, then on days 1 and 15; along with RD Isatuximab (Isa) IV 10 mg/kg weekly for 4 weeks and then every 2 weeks Belantamab mafodotin IV 2.5 mg/kg once every 3 weeks   Relapsed or refractory—4 prior lines of therapy Selective inhibitor of nuclear export (SINE) Selinexor (S) Oral 80 mg on days 1 and 3 of each week SVD Relapsed Histone deacetylase inhibitor Panobinostat (Pa) Oral 20 mg once every other day for 3 doses/week for 2 weeks every 21 days Alkylating agents Melphalan (M) Oral 0.25 mg/kg per day for 4 days (with P) every 4–6 weeks Cyclophosphamide IV—300–500 mg/m2 weekly × 2 q 4 weeks Oral—50 mg qd × 21 days Bendamustine (B) IV 70–90 mg days 1, 2 OR days 1, 8 q 4 weeks BD or BVD Relapsed Melflufen (Me) IV 40 mg day 1 (with D 40 mg on days 1, 8, 15, and 22) q 28 days Glucocorticoid Dexamethasone (D) Prednisone (P) Oral 10–40 mg q week Oral 1 mg/kg Cellular therapy Idecabtagene vicleucel (Ide-cel) IV 450 × 106 cells None At least two prior lines of therapy that includes an PI, IMiD and anti-CD38 antibody Ciltacabtagene autoleucel (Cilta-cel) IV None At least one prior line of therapy, including PI and IMiD and who are refractory to lenalidomide Bispecific antibodies Teclistamab Anti-BCMA–anti-CD3 Step-up doses of 0.06 mg and 0.3 mg per kilogram SC days 1, 4 and 1.5 mg per kilogram of body weight day 8 and q week None Relapsed or refractory—4 prior lines of therapy with prior exposure to PI, IMiD, and anti-CD38 antibody Elranatamab Anti-BCMA–anti-CD3 Step-up doses of 12 and 32 mg on days 1, 4 and 76 mg SC day 8 and then q week for 25 weeks and then q 2 weeks Talquetamab Anti-GPRC5D–anti-CD3 Two step-up doses during first week and then every week or every other week regimen

solitary bone plasmacytoma. Such patients are usually identified because their serum M component falls slowly or disappears ini­ tially after local therapy, only to return after a few months. These patients respond well to systemic therapy. SYMPTOMATIC MM Patients with symptomatic myeloma require therapeutic inter­ vention. In general, such therapy has two purposes: (1) systemic therapy to control myeloma; and (2) supportive care to control symptoms of the disease, its complications, and adverse effects of therapy. Therapy can significantly prolong survival and improve the quality of life for myeloma patients. The therapy of myeloma includes an initial induction regimen followed by consolidation and/or maintenance therapy and, on subsequent progression, management of relapsed disease. All agents available for use at various stages of the therapy and their doses, schedules, and combinations are detailed in Table 116-4. Therapy is partly dictated by the patient’s age and comorbidities, which may Newly diagnosed, maintenance, and relapsed Newly diagnosed and relapsed Newly diagnosed and relapsed Dara, DaRD, DaVD, DaPD, DaKD Newly diagnosed, maintenance, and relapsed ERD, EPD Relapsed IsaPD, IsaKD Relapsed PaVD Relapsed MP, MPT, MPR, MPV, DaMPV, high-dose M Newly diagnosed and relapsed conditioning VCD Newly diagnosed and relapsed MeD Relapsed or refractory—4 prior lines of therapy   All stages None None

Newly diagnosed Smoldering myeloma No therapy except on clinical study or high-risk – Regular follow-up Myeloma-defining events Yes Transplant eligible Transplant ineligible* Induction therapy 4-drug regimen with Dara, R, V or K and d; 3-drug regimen without Dara, or VCd until maximum effect No response Alternate regimen Response HDT with ASCT/ consolidation No response Relapse Relapse Maintenance Treatment of relapsed disease 2–4 line of alternate regimen *Due to age or comorbidities. FIGURE 116-6  Treatment algorithm for multiple myeloma. Alternate regimen indicates combinations including daratumumab, elotuzumab, panobinostat, carfilzomib, ixazomib, pomalidomide, or other agents. ASCT, autologous stem cell transplantation; C, cyclophosphamide; D, dexamethasone; HDT, high-dose therapy; M, melphalan; MDE, myeloma-defining events; P, prednisone; R, lenalidomide; RVD-lite, weekly regimen; V, bortezomib. affect a patient’s ability to undergo high-dose therapy and trans­ plantation (Fig. 116-6). Three important classes of agents approved for treatment of newly diagnosed MM are immunomodulatory agents, proteasome inhibitors, and antibodies targeting CD38. The combination of lenalidomide with a proteasome inhibitor (bortezomib or carfil­ zomib) and dexamethasone achieves close to a 100% response rate and a >50% complete response (CR) rate, making this combina­ tion one of the preferred induction regimens in transplant-eligible patients. Other similar three-drug combinations (bortezomib, tha­ lidomide, and dexamethasone or bortezomib, cyclophosphamide, and dexamethasone) also achieve >90% response rate. Addition of a fourth agent, daratumumab or isatuximab, an anti-CD38 antibody, is providing even deeper responses and such four-drug regimens as induction therapy are becoming standard of care. Usually between four and six cycles of these combination regimens are utilized to achieve initial deep cytoreduction before consideration of highdose therapy with autologous stem cell transplantation. In patients who are not transplant candidates due to physiologic age >70 years, significant cardiopulmonary problems, or other comorbid illnesses, the same three-drug combinations described above are considered standard of care as induction therapy with age- and frailty-guided dose and schedule modifications. Com­ bination of daratumumab with lenalidomide and dexamethasone (DRd) and modified lenalidomide-bortezomib-dexamethasone (RVD lite) combination achieve high overall response rates (93 and 86%, respectively) and CR rates (47 and 32%, respectively). The four-drug combinations used in younger patients are also utilized in healthy older patients with excellent response. In the past, the combination of melphalan with prednisone (MP) alone or with thalidomide or bortezomib has been utilized effectively, but with the availability of newer agents and combinations, MP-based com­ binations are now not utilized.

No If appearance of MDE Induction therapy 4-drug regimen with Dara, R, V or K and d, Dara Rd, RVd-lite, VCd, Vd, Rd, VMP until maximum effect Response CHAPTER 116 Maintenance Treatment of relapsed disease: 5th line and beyond alternate regimen Plasma Cell Disorders HIGH-DOSE THERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANTATION High-dose therapy (HDT) and consolidation/maintenance are stan­ dard practice in the majority of eligible patients. In patients who are transplant candidates and receiving lenalidomide, stem cells should be collected within 6 months because the continued use of lenalidomide may compromise the ability to collect adequate numbers of stem cells. Randomized studies comparing standarddose therapy to high-dose melphalan therapy with hematopoietic stem cell support have shown that HDT can achieve higher overall response rates, with up to 25–40% additional CRs and prolonged progression-free and overall survival; however, few, if any, patients are cured. Although two successive HDTs (tandem transplanta­ tions) are more effective than single HDT, the benefit is only observed in the subset of patients who do not achieve a complete or very good partial response to the first transplantation, which is a rare subset. Moreover, a randomized study failed to show any sig­ nificant difference in overall survival between early transplantation after induction therapy versus delayed transplantation at relapse. These data allow an option to delay transplantation, especially with the availability of newer agents and combinations. Allogeneic transplantations may also produce high response rates, but with significant toxicities. Nonmyeloablative allogeneic transplantation can reduce toxicity but is recommended only under the auspices of a clinical trial to exploit an immune graft-versus-myeloma effect while avoiding attendant toxicity. Due to effective cellular therapies, allogeneic transplantation is very rarely used. Maintenance therapy prolongs remissions following standarddose regimens as well as HDT. Several phase 3 studies have demonstrated improved progression-free survival, and one study showed prolonged overall survival in patients receiving lenalido­ mide compared to placebo as maintenance therapy after HDT. In nontransplant candidates, two phase 3 studies showed prolonged

progression-free survival with lenalidomide maintenance after MP plus lenalidomide or lenalidomide plus dexamethasone induction therapy. Although concern arises regarding an increased incidence of second primary malignancies in patients receiving lenalidomide maintenance, its benefits in reducing the risk of progressive disease and death from myeloma far outweigh the small increased risk of second cancers. In patients with high-risk cytogenetics, lenalido­ mide and bortezomib or an oral proteasome inhibitor, ixazomib, show promise as maintenance combination therapy after trans­ plantation. A phase 3 study has also demonstrated the benefit of maintenance therapy with daratumumab after HDT.

RELAPSED DISEASE Relapsed myeloma can be treated with a number of agents includ­ ing lenalidomide and/or bortezomib, if previously not used. The second-generation proteasome inhibitor carfilzomib and immuno­ modulatory agent pomalidomide have shown efficacy in relapsed and refractory MM, even MM refractory to lenalidomide and bortezomib. An oral proteasome inhibitor, ixazomib, has also been approved in combination with lenalidomide and dexamethasone as an all-oral regimen for relapsed MM. Four antibodies are approved for treatment of relapsed MM. Daratumumab targeting CD38 achieves high response rates and improved progression-free sur­ vival as a single agent with further improvement in response and survival when added to bortezomib and dexamethasone or lenalidomide and dexamethasone. A formulation of daratumumab for subcutaneous administration provides decreased toxicity and improved convenience. Isatuximab, another antibody targeting CD38, achieves high response rates and improved progression-free survival in combination with pomalidomide or carfilzomib and dexamethasone. Elotuzumab, which targets SLAMF7, has shown significant activity in combination with lenalidomide and dexa­ methasone in relapsed/refractory myeloma but not as a single agent. Finally, belantamab mafodotin, an antibody-drug conjugate, targets B-cell maturation antigen (BCMA), which is expressed mainly on normal plasma cells and myeloma cells and delivers auristatin, a microtubule inhibitor, to the tumor cells and achieves responses in relapsed/refractory myeloma. The drug has a unique ophthalmo­ logic toxicity that requires close monitoring. Its efficacy increases significantly when combined with pomalidomide or proteasome inhibitor. PART 4 Oncology and Hematology Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone has been approved for treat­ ment of relapsed/refractory myeloma based on superior response and progression-free survival compared to bortezomib and dexa­ methasone alone. Two additional newer agents have unique mecha­ nisms of action: selinexor is a first-in-class exportin inhibitor that blocks export of proteins from the cell nucleus, and melflufen is an alkylating agent conjugated to a peptide to improve specific delivery to myeloma cells that express aminopeptidase required for cleaving of the peptide to deliver the drug intracellularly in myeloma cells. Both agents have been approved based on their effectiveness in relapsed/refractory myeloma. Immunotherapeutic Approaches  Two cellular therapies, both tar­ geting BCMA, are approved for relapsed myeloma. The anti-BCMA CAR transduced T cell, idecabtagene vicleucel (Ide-cel), is approved after at least two prior lines of therapy that includes an immu­ nomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, whereas ciltacabtagene autoleucel (Cilta-cel) is approved for patients who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodula­ tory agent and who are refractory to lenalidomide. In patients with advanced myeloma with a median of six prior lines of treatment, 81% of patients receiving target dose of Ide-cel responded, and a CR rate of 33% was observed. Cilta-cel in a similar patient population achieved 98% overall response with 82% achieving CR. Cytokine release syndrome and neurotoxicity remain primary toxicities requiring close monitoring and aggressive management.

Three bispecific antibodies are also approved for treatment of relapsed and refractory myeloma after four prior lines of thera­ pies. Bispecific antibodies can bind to two different cell surface targets through two distinct binding domains. One domain binds to CD3 on human lymphocytes, while the other domain binds to a cell surface target specific for myeloma cells, bringing the T cells closer and leading to myeloma cell death. Two bispecific antibodies, teclistamab and elranatamab, target BCMA, whereas talquetamab targets a novel cell surface target on myeloma cells, G protein– coupled receptor class C group 5 (GPRC5D). In patients with relapsed refractory myeloma, these antibodies result in a 60–70% response rate, with a quarter of the patients achieving CR. Bispecific antibodies are associated with toxicities including cytokine release syndrome, neurotoxicity, and significant susceptibility to infectious complications. Incorporation of the large number of active agents at various stages of treatment, including in newly diagnosed patients, is improving survival as well as quality of life. THERAPY ENDPOINT Improvement in the serum M component may lag behind the symp­ tomatic improvement due to longer serum half-life (~3 weeks) of the immunoglobulin. The fall in M component depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin. Serum and urine light chains with a functional half-life of ~6 h may fall much quicker within the first week of treatment. Because urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill in patients with renal dysfunc­ tion. Achieving CR, defined as disappearance of serum and urine monoclonal protein with normal bone marrow by light microscopy, has been a standard goal of therapy. However, sequencing or multi­ color flow cytometry–based assessment of minimal residual disease (MRD) in bone marrow to measure the presence of one myeloma cell in a million cells is being considered as an important new end­ point, both in newly diagnosed and relapsed patients. Absence of MRD at this sensitivity predicts for both longer progression-free survival and longer overall survival. Although patients may not achieve complete remission, clinical responses may last for long periods of time in small numbers of patients. The median overall survival of patients with myeloma is 8+ years, with subsets of younger patients surviving >10 years. 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, which are all intercurrent illnesses related more to the age of the patient group than to the tumor. SUPPORTIVE THERAPY Herpes zoster prophylaxis is indicated if bortezomib is used, and neuropathy attendant to bortezomib can be decreased both by its subcutaneous administration and by administration on a weekly schedule. Lenalidomide use requires prophylaxis for deep-vein thrombosis (DVT) with either aspirin or, if patients are at a greater risk of DVT, warfarin, low-molecular-weight heparin, or direct-acting anticoagulants DOACs. Patients receiving anti-BCMA CAR-T cell therapy or bi-specific antibodies may need supplemen­ tation with intravenous γ globulin due to induction of prolonged hypogammaglobulinemia. Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. Hypercalcemia generally responds well to bisphosphonates, glu­ cocorticoid therapy, hydration, and natriuresis and rarely requires calcitonin as well. Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg initially once a month for 12–24 months and later every 2–3 months) reduce osteoclastic bone resorption and pre­ serve performance status and quality of life, decrease bone-related complications, and may also have antitumor effects. Osteonecrosis of the jaw and renal dysfunction can occur in a minority of patients receiving bisphosphonate therapy. Denosumab is an alternative agent administered intravenously at 120 mg monthly and achieves

a similar level of effect as bisphosphonates to prevent bone-related complications in myeloma. Treatments aimed at strengthening the skeleton such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested but are not of proven efficacy. Kyphoplasty or vertebroplasty should be considered in patients with painful collapsed vertebra. Iatrogenic worsening of renal function may be prevented by maintaining a high fluid intake to prevent dehydration and enhance excretion of light chains and calcium. In the event of acute renal failure, plasmapheresis is ~10 times more effective at clearing light chains than peritoneal dialysis; however, its role in reversing renal failure remains controversial. Importantly, 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. Use of lenalidomide in renal failure is pos­ sible but requires dose modification because it is renally excreted. Urinary tract infections should be watched for and treated early. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococcal polysaccharide vaccines may not elicit an antibody response. The pneumococcal conjugate vaccines are more protective. Prophylactic administration of intravenous γ globulin preparations is used in the setting of recurrent serious infections and in patients receiving CAR-T therapy or bispecific antibodies. Routine chronic oral antibiotic prophylaxis is not war­ ranted. Patients receiving bortezomib or CD38-directed therapies receive prophylaxis against herpes zoster. Patients with myeloma and even SMM and MGUS may be at a higher risk of developing COVID-19 and thus are encouraged to have vaccination for preven­ tion and, if positive for infection, to receive antiviral therapy for COVID-19. 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. Most bone lesions respond to analgesics and systemic therapy, but certain pain­ ful lesions may respond more promptly to localized radiation. The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin). The pathogenesis of the anemia should be established and specific therapy instituted, whenever possible. WALDENSTRÖM’S MACROGLOBULINEMIA In 1948, Waldenström described a malignancy of lymphoplasmacy­ toid 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 dis­ ease resembles the related diseases CLL, 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. Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a similar clinical course, but therapeutic options are different. The diag­ nosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells usually with t(11;14) translocation in the bone marrow. Such patients are at greater risk of pathologic fractures than patients with WM. A familial occurrence is common in WM, but its molecular bases are yet unclear. A distinct MYD88 L265P somatic mutation is present in >90% of patients with WM and the majority of IgM MGUS. Other commonly occurring mutations include CXCR4 (30–40%), ARID1A (17%), and CD79B (8–15%). Presence of MYD88 mutation status is now used as a diagnostic test to discriminate WM from marginal zone lymphomas (MZLs), IgM-secreting myeloma, and CLL with plasma­ cytic differentiation. This mutation also explains the molecular patho­ genesis of the disease with involvement 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-κB

(NF-κB) activation. MYD88 mutation also triggers Bruton’s tyrosine kinase (BTK) and hemopoietic cell kinase (HCK)-mediated growth and survival signaling, which are now important therapeutic targets in WM. CXCR4 mutations induce AKT and extracellular regulated kinase 1/2 (ERK1/2) signaling. This pathway can lead to development of drug resistance in the presence of its ligand CXCL12.

The disease is similar to myeloma in being slightly more com­ mon in men and occurring with increased incidence with increasing age (median age 64 years). The IgM in some patients with macro­ globulinemia may 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 greater extent than the better-known myelin basic protein in patients with multiple sclerosis. Sometimes patients with macroglobulinemia develop a peripheral neuropathy, and half of these patients are positive for anti-MAG antibody. The neuropathy may precede the appearance of the neoplasm. The whole process may begin with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component. Like myeloma, the disease involves the bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Bone mar­ row shows >10% infiltration with lymphoplasmacytic cells (surface IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and CD23−) with an increase in number of mast cells. Like myeloma, an M component is present in the serum in excess of 30 g/L (3 g/dL), but 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. The light chain isotype is kappa in 80% of the cases. Patients present with weakness, fatigue, and recurrent infec­ tions similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms such as peripheral neuropathy, dizziness, headache, and transient paresis are much more common in macro­ globulinemia. Presence of MYD88 and CXCR4 mutations also affects disease presentation. Presence of CXCR4 mutations is associated with higher bone marrow disease burden and higher incidence of hyper­ viscosity. Patients with wild-type MYD88 show lower bone marrow disease burden. CHAPTER 116 Plasma Cell Disorders Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic 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 Coombs test are much more common than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10% of macroglobulins are cryoglobulins. These are pure M components and are not the mixed cryoglobulins seen in rheuma­ toid 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 cryoglobu­ lins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood drawn into a warm syringe and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin. TREATMENT Waldenström’s Macroglobulinemia A diagnosis of WM requires lymphoplasmacytic infiltrate of any level in the bone marrow and an IgM monoclonal paraprotein of any size. Treatment is usually not initiated unless the disease is symptomatic or increasing anemia, hyperviscosity, lymphadenopa­ thy, or hepatosplenomegaly is present. Control of serious hypervis­ cosity 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. 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. BTK inhibitors (ibruti­ nib), alkylating drugs (bendamustine and cyclophosphamide), and proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), alone or more frequently in combination with rituximab, are con­ sidered as first-line therapy for symptomatic patients with WM. Ibrutinib targets the constitutively activated BTK. In patients with one prior line of therapy, the overall response to ibrutinib was 91%. Best responses to ibrutinib are observed in patients with mutated MYD88 and wild-type CXCR4 status, while delayed and lower response rates to ibrutinib are observed in patients with mutated CXCR4. At first relapse, in patients with an initial durable response, either the previous regimen or another primary therapy regimen can be used. The therapeutic choice is dependent upon the genomic features, drug availability, and the patient’s clinical profile.

Rituximab can produce an IgM flare, so either plasmapher­ esis should be used before rituximab or its use should be initially withheld in patients with high IgM levels. Fludarabine (25 mg/m2

per d for 5 days every 4 weeks) is also an effective single agent. With identification of the MYD88 mutation, novel BTK inhibitors (acalabrutinib, zanubrutinib, and tirabrutinib), inhibitors targeting IRAK1/4, and the BCL2 antagonist venetoclax are being explored for the treatment of WM. HDT plus autologous transplantation has been utilized in the past, but it is now not recommended due to the availability of other effective agents. PART 4 Oncology and Hematology POEMS SYNDROME The features of this syndrome are polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS). Diagnostic criteria are described in Table 116-1. Patients usually have a severe, progressive sensorimotor 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 onethird. 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 associated 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 club­ bing. Other manifestations include peripheral edema, ascites, pleural effusions, fever, and thrombocytosis. Not all the components of POEMS syndrome may be present initially. The pathogenesis of the disease is unclear, but high circulating levels of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have been documented, and levels of the inhibitory cytokine transforming growth factor β are lower than expected. Treatment of the myeloma may result in an improvement in the other disease manifestations. Patients are often treated similarly to those with myeloma. Plas­ mapheresis 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 MM, novel agents and HDT with autologous stem cell transplantation have been pursued in selected patients and have been associated with prolonged progression-free survival. HEAVY CHAIN DISEASES The heavy chain diseases are rare lymphoplasmacytic malignan­ cies. Their clinical manifestations vary with the heavy chain isotype. 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.

Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted. ■ ■GAMMA HEAVY CHAIN DISEASE (FRANKLIN’S DISEASE) This disease 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 involve­ ment of nodes in Waldeyer’s ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstra­ tion of an anomalous serum M component (often <20 g/L [<2 g/dL]) 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 paraproteins have been of the γ1 subclass, but other subclasses have been seen. The patients may have thrombocytopenia, 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 combina­ tions used in low-grade lymphoma. Rituximab has also been reported to show efficacy. ■ ■ALPHA HEAVY CHAIN DISEASE

(SELIGMANN’S DISEASE) This is the most common of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma, a dis­ ease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. 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, viscos­ ity does not increase dramatically. Light chains are absent from serum and urine. The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopa­ thy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may develop diffuse aggressive histologies of malignant lymphoma. Chemotherapy may produce longterm remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimula­ tion, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone. IPSID is recognized as an infectious pathogen–associated human lymphoma associated with Campylobacter jejuni. It involves mainly the proximal small intestine, resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain 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 lymphoplasmacytic and immunoblastic lym­ phoma. Patients not responding to antibiotic therapy are considered for treatment with combination chemotherapy used to treat low-grade lymphoma. ■ ■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 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