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Multiple Myeloma
Clonal plasma cell (PC) neoplasms are comprised of a number of interrelated and partially overlapping entities, ranging from benign to fully malignant, which are variously defined and categorized by burden of disease, presence of organ injury, anatomic location, and in some cases, unique constellations of signs, symptoms, and pathologic findings (see box on Rare Disorders Associated With Monoclonal Proteins and/or Plasma Cells , and also Chapter 90, Chapter 93 ). As the majority of neoplastic PCs are functional with respect to secreting clonal immunoglobulins and/or their fragments (i.e., free light or heavy chains), as well as cytokines, growth factors, and other signaling molecules, these abnormal proteins can become relevant both in the pathophysiology of PC disorders, manifesting (e.g., as kidney injury, neuropathy, cardiac impairment, hyperviscosity, etc.) and can also frequently serve as useful biomarkers for evaluating disease burden and response to treatment. This chapter highlights continued advances in both knowledge regarding the underlying pathophysiology of PC neoplasms, and their therapy, with a focus on multiple myeloma (MM) as the prototypical malignant PC disorder. In this context we emphasize minimal residual disease (MRD) testing for risk stratification, disease management, and decision making, and also highlight novel therapies with mechanisms-of-action beyond existing proteasome inhibitors (PIs), immunomodulatory agents, and monoclonal antibodies.
Screening, Epidemiology, and Risk Factors
MM, the dominant malignant PC disorder, accounts for 1.8% of all malignancies and is the second most common hematologic malignancy. It is estimated that in 2016, there were about 138,500 incident cases and 98,500 deaths attributed to MM globally.
Age is a major risk factor for MM as well as its precursor states, smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) (see Chapter 90 ). Generally, MM is a disease affecting a relatively older population with a median age at diagnosis of 69 years ( Fig. 91.1A ), and less than 2% to 5% of patients are younger than 40 years old at diagnosis. Myeloma is more frequent in men than in women, and in African Americans than in White persons in the United States (see Fig. 91.1B ). The incidence of MM in African American men is approximately 15.7 per 100,000 per year as compared with 11.5 per 100,000 per year in African American women; the corresponding incidence rates are 7.7 and 4.5 per 100,000 in White men and women, respectively. In addition, African Americans also generally present with MM earlier in life than Whites. Although there has been an increase in the incidence of MM over time, this can be attributed to better detection and surveillance of the disease, overall aging of the population worldwide, together with increased prevalence attributable to markedly longer median overall survival (OS) of patients in the era of modern therapies, with the current median OS for undifferentiated newly diagnosed MM patients likely longer than 6 years.
In addition to the precursor neoplasms MGUS and SMM (see Chapter 90 ), which are believed to be obligatory precursors to MM, increasing age and certain racial groups are known predisposing conditions. Other risk factors for MM include human immunodeficiency virus (HIV) infection (ameliorated in the era of effective antiviral therapy), obesity, and certain occupations, as well as exposure to specific chemical carcinogens, including Agent Orange (linked to MGUS ). Although clusters of familial MM have been described in the literature, they are rare and are not believed to contribute significantly to the overall epidemiology of MM. Recent genetic studies have identified mutations of LSD1 (KDM1A), DIS3, and Lynch syndrome (deoxyribonucleic acid [DNA] mismatch repair) genes as being associated with familial myeloma. In addition, Gaucher syndrome, a lysosomal storage disorder, is also associated with an elevated risk of developing MM. As malignant PC disorders are rare overall, there are currently no guidelines from national organizations or scientific societies endorsing screening for PC disorders in the asymptomatic general population.
Pathogenesis
The transformative event which initiates the trajectory toward MM occurs in a germinal center B cell that has undergone somatic hypermutation and class-switch recombination (with the exception of rare cases of immunoglobulin M [IgM]-myeloma). Epidemiological and genomic studies have indicated that initial transformation often occurs in the first three decades of life. Years after immortalization of the first plasma cell, when the clonal population has expanded sufficiently, they produce detectable serum monoclonal proteins. Based on clinical features, the condition may be classified as MGUS or SMM. In a minority of patients, clonal plasma cells acquire additional driver, leading to the development of MM and eventually relapsed/refractory disease with a highly aggressive phenotype.
Genomic Landscape of Multiple Myeloma at Presentation
Large-scale studies mapping the driver mutational landscape of MM at presentation have focused on three types of somatic alterations: recurrent translocations involving the immunoglobulin gene loci, copy number alterations (CNAs), and single nucleotide variants (SNVs) ( Fig. 91.2A ) (see Chapter 57 ). Moreover, these early studies focused on alterations detectable by conventional cytogenetics, fluorescence in situ hybridization (FISH), array-based copy number analysis, and whole exome sequencing. More recently, whole-genome sequencing (WGS) studies have added another level of complexity and highlighted areas that remain poorly understood. In one recent WGS study, the median number of SNVs in a tumor was 5377 (range 982 to 15738), with a median of 26 (range 0 to 129) structural variants (SVs), including translocations, inversions, deletions, and tandem duplications, which often combine to form complex SVs. Patients who were highly similar in their recurrent driver profile often displayed striking differences in mutational burden and SV landscape (see Fig. 91.2B ). Extracting the biologically important information from this complex panorama of somatic alterations is a major goal of ongoing research.
In the following sections we summarize the main pillars and recent advances in MM genomics, focusing on overall principles and potential genomic biomarkers. We have taken a chronological perspective, starting with the earliest events which led to initiation of monoclonal gammopathy, followed by the key mutational processes and genomic alterations which appear to drive the evolution to overt MM and beyond.
Rare Disorders Associated with Monoclonal Proteins And/Or Plasma Cells
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POEMS : polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes. Typically presents with osteosclerotic rather than frankly lytic bone lesions, and may also co-occur with Castleman disease. POEMS is associated with elevated vascular endothelial growth factor (VEGF) levels, which are helpful in diagnosis and assessing therapy response. Assessing for endocrinopathy at diagnostic evaluation and co-management with an expert endocrinologist may be helpful. POEMS carries a better prognosis than conventional multiple myeloma.
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TEMPI : telangiectasias, erythrocytosis, monoclonal protein, perinephric fluid collections, intrapulmonary shunt. A rare disorder which can be efficaciously treated with bortezomib and daratumumab. Autologous transplant is rarely required.
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AESOP : adenopathy and extensive skin patch overlying a plasmacytoma. This is considered a paraneoplastic syndrome which can co-occur with POEMS, Castleman disease, plasma cell disorders as well as lymphoplasmacytic lymphoma.
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Schnitzler syndrome : an autoinflammatory and rheumatologic disorder associated with M-protein, which may also be associated with splenomegaly, lymphadenopathy, and chronic urticaria. Managed primarily with the IL-1 receptor antagonist anakinra rather than anti-neoplastic therapy per se.
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Cryoglobulinemia type I : monoclonal IgG, IgM, IgA, or free light chains which can be associated with hyperviscosity syndrome and vasculitis.
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Heavy chain diseases: a rare assortment of B lymphoproliferative disorders, typically associated with indolent lymphomas, which produce heavy chains (generally α, γ, μ) which are deposited in tissues, without intact light chains. Variable clinical course. Managed with observation, supportive care (e.g., antibiotics for infections), and anti-lymphoma or anti-myeloma therapy.
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Primary amyloidosis—see Chapter 93 on AL amyloidosis.
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Chronic neutrophilic leukemia associated with plasma cell dyscrasias (see Chapter 72 ).
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Monoclonal gammopathy of renal significance13: these disorders are characterized by low-level clonal plasmacytosis and paraproteinemia causing renal injury. Although they may not meet criteria for MM, therapy may be considered.
Primary Genomic Driver Events
Traditionally, MM has been divided into molecular subgroups based on the presumed initiating driver event. Forty percent of patients have a translocation involving the immunoglobulin heavy chain ( IGH ) locus on chromosome 14 and one of seven canonical partner oncogenes: CCND1 (t11;14), CCND2 (t12;14), CCND3 (t6;14), MMSET (t4;14), MAF (t14;16), MAFA (t8;14), and MAFB (t14;20). These events drive disease development by placing key oncogenes under the transcriptional control of the IGH enhancers, a phenomenon known as super-enhancer hijacking. Sequencing analysis of the IGH locus in primary translocations most commonly reveals a breakpoint in the class-switch recombination regions, consistent with DNA double-strand breaks introduced by activation-induced cytidine deaminase (AID) in the germinal center. Sixty percent of patients have a hyperdiploid genome (HRD), defined by three or more trisomies of odd-numbered chromosomes. Chromosomes 9, 15, 19, and 21 are usually acquired first, which may be followed by gain of additional copies of the same or different chromosomes, typically 3, 5, and 7. Although not considered part of hyperdiploidy, gain of chromosome 1q may occur in the same early time-window and play a role in disease initiation. The etiology of whole chromosome gains in MM remains unknown. Approximately 5% of patients have both HRD and a canonical IGH translocation and <10% of patients have neither. Some patients may be driven by other rare genomic rearrangements, including translocations involving IGH and rare partners such as the B-cell master regulator PAX5 or the co-stimulatory molecule CD40 . Gene expression profiling (GEP) studies have confirmed the importance of primary IGH -translocations and HRD as drivers of MM biology, while providing additional refinement. Clinically, IGH translocations involving MMSET , MAF , and MAFB have been associated with poor prognosis. However, the penetrance of this “high-risk” genotype at the individual patient level is variable, with many of these patients achieving long-term disease control using modern highly effective therapies. Furthermore, the prognostic impact of primary driver events is most likely modulated by the combination of secondary drivers present in each individual patient, although these higher-order interactions are thus far poorly understood.
Genomic Drivers of Progression from Precursor to Myeloma and Beyond
There is currently no single genomic abnormality that separates MM from its precursors, or from advanced relapsed/refractory disease. Instead, there is a gradual increase in genomic complexity over time, characterized by the accumulation of somatic alterations of all types. This evolutionary process follows preferred trajectories, where the early drivers determine which additional hits will confer the greatest advantage and therefore end up being selected (some such common interactions are highlighted by the clusters in Fig. 91.2A ). There are also more general temporal patterns, where oncogene activation tends to occur earlier (e.g., copy number gains, super-enhancer hijacking and gain of function SNVs), while tumor suppressor gene inactivation occurs later (e.g., copy number loss and truncating SNVs).
Key gain-of-function drivers in MM include activation of MYC through a variety of mechanisms including translocation with an immunoglobulin locus (i.e., IGH , IGL , or IGK ), which is particularly enriched in the HRD subgroup, as well as gain of one or more copies of chromosome 1q. MYC is a transcriptional master regulator in MM along with IRF4 , and knock–down of both factors in vitro lead to cell death. Gain of 1q usually involves the whole chromosome arm, but a minimally amplified region on 1q21.3 has led to identification of the putative driver gene CKS1B . Nuclear factor-kappa B (NFκB) pathway activation is a recurrent feature where different types of genomic alterations converge, including recurrent deletions of the NFκB inhibitor (16p.12), while the MAPK pathway genes, NRAS , KRAS , and BRAF , are predominantly affected by SNVs. Given that MAPK mutations in MM are acquired relatively late and most commonly are subclonal, the rationale for targeted therapy using MEK and/or BRAF inhibitor is weaker than in diseases where MAPK inactivation is an early or initiating feature, such as hairy cell leukemia and BRAF -mutant melanoma.
Loss-of-function events in MM tend to converge on established tumor suppressor genes involved in cell cycle regulation, such as TP53 (17p13), RB1 (13q14), and CDKN2C (1p.32). Tumor suppressor genes more specific to MM include FAM46C (1p12), a regulator of messenger RNA (mRNA) polyadenylation, and DIS3 (13q21), encoding the catalytic subunit of the human exosome complex.
Multiple studies have investigated the prognostic impact of secondary genomic drivers, often with conflicting results. Two alterations have been thoroughly established as independent prognostic factors across several studies: bi-allelic inactivation of TP53 and amplification of 1q21. Deletion of 17p has long been considered a marker of poor prognosis, but recent studies including SNV data has shown that this phenotype depends on inactivating mutation of TP53 on the remaining allele. For gains of 1q21, there appears to be a dose response relationship between the number of copies and prognosis, where having four or more copies is associated with particularly poor outcomes.
Recent efforts have begun to reveal the mutational process shaping the evolving genome of MM. We will highlight here three findings of particular clinical importance. First, a hyper-mutator phenotype in MM has been identified in <5% of patients, driven almost entirely by the APOBEC family of cytidine deaminases. High burden of APOBEC-induced mutations is associated with poor prognosis independently from other genomic features, despite many of these patients also having IGH- translocations involving MAF or MAFB . The mechanisms underlying aberrant APOBEC activation in MM and how this might be exploited therapeutically is subject to ongoing investigations. Second, complex SVs termed chromothripsis have been identified as key driver events in up to 24% of patients with MM and are strongly associated with poor prognosis. Chromothripsis is the result of shattering and re-joining of one or more chromosomes, resulting in widespread genomic rearrangements. This is particularly important because it means that a high level of genomic complexity including multiple driver events can be acquired by a single cell at a single point in time, which may contribute to the dramatic changes in clinical behavior that can sometimes be observed in MM. Finally, recent studies have identified mutational signatures specifically associated with prior exposure to melphalan and platinum-containing chemotherapies used as an anti-myeloma therapy. This is perhaps not surprising, since the mechanism of action of these agents is cell-cycle arrest through the introduction of DNA damage. Nonetheless, having identified the specific mutational footprint of these therapies, one can begin to explore their role in development of treatment resistance as well as secondary malignancies. In particular, myelodysplastic syndromes and acute myeloid leukemia (AML) are strongly enriched in MM patients following melphalan therapy. With life expectancies exceeding 10 years for many patients with MM receiving state-of-the-art therapies, long-term toxicity is becoming an increasing concern which may warrant more restrictive use of cytotoxic agents.
In summary, the panorama of genomic drivers in MM is characterized by a limited number of frequent alterations followed by a long tail of rare drivers. Evolution from precursor stages to MM and acquisition of an increasingly aggressive and treatment-refractory phenotype usually results from accumulation of multiple genomic hits over time, converging on pathways responsible for cell proliferation and survival. In some cases, accelerated or “punctuated” evolution may occur as a result of complex SVs introducing multiple drivers in a single genomic event. We anticipate that improved understanding of the processes shaping tumor evolution and how multiple genomic drivers interact to determine tumor biology will lead to the emergence of clinically meaningful MM molecular subgroups.
Clinical Implications of Clonal Heterogeneity and Evolution
In any given patient with MM, a number of distinct subclones of disease are present which differentially populate the bone marrow and soft tissue lesions inside and outside of the skeleton. Tumor phylogenies reconstructed from multiple biopsies at presentation indicate early seeding from a common disease site followed by local expansion. Presence of high-risk features in a single lesion conferred the same adverse prognosis as if every site shared the same high-risk profile. At the extreme end, in multi-regional biopsies obtained at autopsy, there is evidence of accelerated seeding where tumor sites throughout the body have been re-populated by descendants of a single cell which survived intensive therapy. Although the number of patients analyzed with high spatiotemporal resolution remains low, the current evidence indicates that high-risk subclones determine the final outcome of disease but may take years and multiple lines of therapy before emerging as dominant. This time lag may reflect the need of tumor subclones to acquire multiple cooperating driver lesions to achieve their full malignant potential and the gradual increase of immunosuppression resulting from both chronic disease and multiple lines of therapy.
Immune and Bone Marrow Microenvironment
In addition to cell-intrinsic genomic changes and other aberrancies within neoplastic PCs, MM also exhibits a strong dependence on the microenvironment as a feature of disease pathogenesis. Neoplastic PCs both rely on, and in turn promote, an abnormal bone marrow and immune microenvironment as a key feature of oncogenesis ( Fig. 91.3 ). The complex interplay between malignant PCs and their heterogeneous microenvironment, which includes endothelium, osteoblasts, osteoclasts, and a variety of other mesenchymal and stromal cell types, as well as myeloid and lymphoid hematopoietic and immune cell subsets, soluble molecules including growth factors, cytokines, and secreted receptor molecules, as well as diverse extracellular matrix components including collagen and other structural proteins, explains in part some of the clinical features of PC disorders, and has also been increasingly targeted, directly or indirectly, in therapy of these disorders.
The effect of PCs within their environment can reflect disease evolution. For example, in precursor states prior to the development of frank MM, the PETHEMA and Scandinavian groups have shown that biomarkers such as the ratio of abnormal to total plasma cells in the marrow, which reflects in part the paracrine suppression of normal B cell to plasma cell maturation and function, as well as the reciprocal suppression of uninvolved immunoglobulins (termed “immunoparesis” [e.g., low IgA and IgM] in a case of IgG plasma cell neoplasm) can risk-stratify patients for risk of progression to MM, with immunoparesis and high ratios of abnormal to total plasma cells associated with increased risk. With respect to MM and anemia as a defining criterion, this is in large part also believed to be mediated via paracrine effects of malignant PCs suppressing erythropoiesis. Finally, imbalanced osteoblastic vs. osteoclastic activity with resultant bone lesions and hypercalcemia are arguably the sine qua non features of MM. Finally, although not considered a myeloma-defining criterion, impaired cellular and humoral immunity in patients with PC disorders, with resultant infectious complications, arguably also reflects the deleterious effects of neoplastic PCs on the immune microenvironment. Given this, dysregulated B and plasma cell maturation and function, disordered erythropoiesis, and imbalanced osteoblastic versus osteoclastic activity represent some commonly observed clinical examples of neoplastic PCs acting to create an abnormal marrow microenvironment. In turn, MM is a disease most stereotypically confined to the bone marrow (“medullary disease”), with extramedullary manifestations or circulating disease in the blood, sometimes representing progression as a late phenomenon, reflecting the strong dependence of both normal and neoplastic PCs on the marrow microenvironment and its many complex cell-cell interactions and paracrine signaling molecules, for their survival.
With respect to therapy, many current and investigational therapies for MM target the microenvironment, directly or indirectly. Although the many United States Food & Drug Administration (FDA)-approved agents discussed below have direct, cell-autonomous effects on neoplastic PCs, these drugs can also render the microenvironment less hospitable to PC growth. The relative importance of microenvironmental vs. direct anti-neoplastic effects of many commonly used agents are difficult to investigate in preclinical models due to the difficulty of modeling the microenvironment, and this remains an area of interest for investigators.
For example, the immunomodulatory drugs (e.g., thalidomide, lenalidomide) have a particularly complex mechanism of action: in addition to acting directly on PCs to induce apoptosis by mediating the degradation of the essential transcription factors IZKF1 and IZKF3 by coopting the endogenous ubiquitin ligase machinery to degrade these proteins as neo-substrates, lenalidomide also decreases the generation and activity of osteoclasts necessary for myeloma survival, decreases the expression of cell adhesion molecules expressed by other marrow stromal cells which ordinarily promote PC survival, and stimulates T- and natural killer (NK)-cell anti-tumor activity by increasing immune synapse formation, increasing direct NK-mediated killing and CD8 + T-cell effector function. Likewise, thalidomide is known to have anti-angiogenesis and anti-VEGF signaling properties which also likely account in part for its therapeutic efficacy. The other major class of novel agents is the PIs with bortezomib as the prototype agent. Again, the mechanism of action of this drug class is complex: in addition to direct anti-PC activity by inhibition of the proteasome and thus indirect downregulation of NFκB signaling, among a plethora of other cell-autonomous mechanisms, bortezomib also modulates the bone marrow microenvironment, inducing endothelial cell and osteoclast apoptosis, and inhibiting the secretion of PC growth-promoting molecules by the microenvironment, such as IL-6, vascular endothelial growth factor (VEGF), and IGF-1. Similar effects on the balance between osteoblasts vs. osteoclasts has been observed with the irreversible proteasome inhibitor carfilzomib. The newest class of FDA approved agents, the monoclonal antibodies elotuzumab (targeting signaling lymphocytic activation molecule F7 [SLAMF7], aka CS1 or CD319) and daratumumab and isatuximab (targeting CD38) also have both direct anti-neoplastic effects as well as indirect effects by modulating the immune microenvironment. For example, while elotuzumab binding to PCs mediates cell killing, its ligation of SLAMF7 on NK cells may activate NK cells, leading to improved NK-directed killing of PCs. Daratumumab not only inhibits the ectoenzymatic activity of CD38 and induces antibody-dependent cellular cytotoxicity (ADCC) of tumor cells, but has also been suggested to deplete CD38 + regulatory B and T cells and myeloid-derived suppressor cells, thereby favorably altering the tumor immune microenvironment and biasing it toward effective anti-tumor immunity. Finally, daratumumab is also believed to result in immune activation by targeting CD38 + NK cells. The more recently approved anti-CD38 antibody isatuximab is also believed to have similar immune-activating effects. Finally, modulation of osteoclast activity, via bisphosphonates or inhibiting the RANK/RANKL axis with denosumab, also inhibit osteoclast activity and osteoclastogenesis, and additionally also have been suggested to mediate an anti-angiogenic and thereby anti-PC effect.
With respect to other investigational agents, interactions between stromal cells which express the co-stimulatory ligands B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) and malignant PCs which express the cognate receptor B-cell maturation antigen (BCMA) are believed to be important for the survival of normal and neoplastic PCs, thus representing selection pressure for expression of BCMA. This requirement has been exploited with chimeric antigen receptor T cell (CAR-T cells ) as well as monoclonal antibody-drug conjugate-based therapies targeting BCMA (e.g., belantamab mafodotin ), many of which have shown promising efficacy in multiply relapsed MM patients. Other investigational efforts targeting paracrine IL-6 signaling, aberrant VEGF signaling, and secreted or cell surface molecules which mediate interactions between neoplastic PCs and the marrow microenvironment are ongoing and represent additional promising therapeutic venues.
Clinical Manifestations
Patients with MM may present with signs and symptoms that are most commonly related to either marrow infiltration by plasma cells and paracrine disruption of physiologic hematopoiesis, or end-organ damage manifested by renal dysfunction, bone lesions, hypercalcemia, and/or immune dysfunction. However, in a minority of patients, MM may present asymptomatically or even without frank end-organ damage at all, with this group of patients diagnosed on the basis of laboratory or radiologic abnormalities, with investigations generally prompted by initial abnormalities in routine studies performed for other indications. In some patients, signs and symptoms may also be related either to deposition of paraproteins in various organs, such as the heart, kidneys, or neural tissue, as either light chain, amyloid, or very rarely, heavy chain deposits or secondary to the humoral effects of cytokines or other secreted molecules such as IL-6 or VEGF produced by the myeloma cells and/or the bone marrow microenvironment (see box on Rare Disorders Associated With Monoclonal Proteins and/or Plasma Cells ). Various clinical features of myeloma are summarized in Table 91.1 .
Table 91.1
Clinical Features of Multiple Myeloma
| Bone Destruction |
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| Hypercalcemia |
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| Renal Failure |
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| Amyloidosis |
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| Marrow Infiltration |
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| Reduced Immunoglobulins |
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| Cryoglobulins |
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| Hyperviscosity |
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Bone Disease
Almost two-thirds of patients with MM present with bone pain and/or destructive, generally lytic bone lesions as a major symptom. Arguably, bony injury and the resulting pain and functional limitations from skeletal injury are the cardinal symptoms of myeloma which affects quality of life. As discussed above, bone disease is believed to primarily represent unbalanced hyperactivity of osteoclasts and suppression of osteoblastic activity, although direct infiltration of bone by myeloma cells also causes bone destruction. Bone modifying agents including bisphosphonates and RANKL inhibitors can reduce the number of skeletal-related events (SREs) in MM (see Skeletal Protection, below), although risks of renal injury and complications such as atypical fractures and jaw osteonecrosis must be considered. Previous studies have shown a modest OS benefit for the use of these bone-modifying agents, but they were largely performed in the era when markedly less potent induction regimens were used—the survival benefit for these agents in the modern era of potent induction therapies and relapsed/refractory disease therapies is uncertain at present, with the use of bone resorptive agents primarily viewed as adjunctive therapy by most practitioners.
Skeletal injury of the axial and appendicular skeleton can additionally result in hypercalcemia (discussed below) and may contribute secondarily to renal injury, and the functional limitations and immobility associated with skeletal injury can predispose to additional complications, such as loss of muscle mass (sarcopenia) and decreased overall physiologic reserve, increased infection risk, neurologic injury, or thrombotic events. Management is primarily focused on anti-PC therapy and anti-resorptive therapy, although pain control, physical therapy, and local therapies (e.g., kyphoplasty for vertebral fractures, surgery or radiation for cord compression or impending fractures) must be prioritized as clinically appropriate. Finally, note that healing or recovery of existing bone lesions is variable even with effective anti-PC therapy, and the lack of radiologic resolution of a lytic lesion does not necessarily indicate treatment resistance.
Hypercalcemia
Hypercalcemia is observed in approximately 25% to 30% of patients with MM and is usually a manifestation of higher disease burden. In contrast to solid tumors where hypercalcemia is generally a terminal event late in the disease course, hypercalcemia in MM more commonly occurs early, oftentimes prior to initiating effective therapy, and is eminently reversible in essentially all cases. In a minority of cases, hypercalcemia can be a manifestation of relapsing disease. Its occurrence is related to direct bone involvement by PCs with local bony injury as well as production of various cytokines that lead to increased bone resorption and calcium release at distant sites. Hypercalcemia manifests as mental status changes, lethargy, nausea and vomiting, and constipation, and can also induce renal failure directly by injuring the parenchyma, as well as by causing volume depletion. Symptomatic hypercalcemia should be managed as a hematologic emergency: adequate hydration, the use of calcitonin and steroids can temporize hypercalcemia for several days while definitive therapy, generally in the form of anti-PC therapy and/or bone modifying agents are initiated. The use of bisphosphonates or a RANKL inhibitor (denosumab) (often more appropriate when patients present with concomitant renal failure) requires the careful serial monitoring of serum total and ionized calcium as well as phosphorus levels and appropriate correction, as hypo calcemia after treatment with these agents has been reported. Risks and rewards of using anti-resorptive agents in patients who have not yet had dental clearance must be weighed and cautiously considered.
Renal Failure
Renal insufficiency in the context of PC malignancies is a frequent and serious complication with a frequently multifactorial etiology, with significant implications for therapy. Monoclonal gammopathy of renal significance (MGRS) (see box on Rare Disorders Associated With Monoclonal Proteins and/or Plasma Cells ) may represent a forme fruste of classical MM and therapy may be contemplated for such patients. Up to 20% of newly diagnosed MM patients can present with renal injury, ranging from mild laboratory abnormalities through the need for renal replacement therapy (dialysis). With respect to frank MM, patients with milder renal failure may nonetheless be asymptomatic. Despite this, as renal failure can frequently be partially or fully reversible, and because of the profound implications of kidney dysfunction for both overall outcomes and options for MM disease management, new renal failure, whether at presentation or later in the disease course should be considered a medical emergency and treated promptly and aggressively in consultation with an expert nephrologist.
The most common and reversible cause of renal failure in MM is light chain tubular cast deposition and/or light chain deposition disease, though monoclonal proteins may also be deposited as amyloidosis (often associated with nephrotic syndrome range proteinuria) (see Chapter 93 ). Another common cause is hypercalcemia leading to osmotic diuresis and prerenal dysfunction associated with volume depletion—these are readily managed with intravenous volume repletion. Additional mechanisms of renal failure in MM include renal calcium deposition with interstitial nephritis, overuse of nonsteroidal anti-inflammatory drugs, hyperuricemia, chemotherapy-induced nephrotoxicity, and bisphosphonates.
Renal failure both at disease onset and during its course can significantly complicate management, as two of the three immunomodulatory drugs (lenalidomide, pomalidomide), which form the backbone of most modern therapies, are challenging or impossible to use with severe renal failure or in dialysis patients. Additionally, cytotoxic chemotherapy backbones which use cisplatin and etoposide (such as PACE [Platinol cisplatin, Adriamycin, cyclophosphamide, etoposide] or DCEP [dexamethasone, cyclophosphamide, etoposide, Platinol]) may also require therapeutically meaningful dose reductions with renal injury. Finally, because serum light chains are partially catabolized or cleared renally, in patients with kidney injury, levels of both the involved and un-involved free light chain may be elevated, and these tests must be interpreted with caution.
Anemia
Anemia, typically normocytic, is another presenting feature of myeloma. A small fraction of MM patients may present with solitary but profound anemia in the absence of other end-organ damage, and in such scenarios, a thorough evaluation including bone marrow sampling to exclude other causes of anemia is warranted. With respect to anemia secondary to PC disorders, causes are again multifactorial, including anemia of chronic inflammation, direct marrow replacement by PCs in the setting of high disease burden, paraneoplastic suppression of physiologic erythropoiesis even in patients with low marrow PC burdens, as well as inadequate erythropoietin production in patients with concomitant renal injury. After therapy with cytotoxic chemotherapy or autologous transplant, therapy-related anemia is expected and may persist, although moderate anemia can also result from treatment with novel agents, particularly in combination. Supportive management with transfusions may be initially required in newly diagnosed patients, but in most instances, disease-associated anemia is highly reversible with anti-PC therapy in the modern era and is rarely if ever a limiting toxicity when patients are treated with novel agents. Erythropoietin administration in MM patients should be used sparingly and judiciously and only in patients with renal injury, in consultation with an expert nephrologist, as significant risks are present.
Neurologic Symptoms
Patients with MM may present with a number of neurologic symptoms related either to direct involvement of the nervous system or the impact of cytokines and/or paraproteins. The most common overt abnormality is compression of the spinal cord and/or nerve roots, causing neurologic dysfunction, including paraplegia with bladder and bowel dysfunction. Cord compression is a neurologic emergency requiring urgent intervention: in this setting, spine magnetic resonance imaging (MRI) (with contrast if renal function allows) and high-dose glucocorticoids, followed by urgent radiation and/or neurosurgical intervention is generally warranted.
Peripheral neuropathy is another common manifestation and is also a key manifestation of light-chain (AL) amyloidosis (see Chapter 93 ). It may also develop as a result of use of a number of therapeutic agents, such as the immunomodulatory drugs (IMiDs) (most prominently thalidomide), bortezomib and ixazomib, cisplatin, and the vinca alkaloids. Anti-myelin-associated glycoprotein (MAG) peripheral neuropathy can also occur in rare cases in association with paraproteinemias. Moreover, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; see box on Rare Disorders Associated With Monoclonal Proteins and/or Plasma Cells ) includes a prominent sensory neuropathy associated with sclerotic myeloma. As with other signs and symptoms, polyneuropathy in MM may be multifactorial, including amyloid deposits, infiltrative processes with other protein deposits, metabolic causes related to hypercalcemia and/or hyperviscosity, immune processes, or cytokines effects. Management is generally focused on treating the underlying PC disorder and minimizing further exposure to therapies with the risk of neuropathy.
Finally, although leptomeningeal disease (LMD) has traditionally been considered rare in myeloma, with the advent of novel agents and associated prolonged patient survival, this still-rare complication is nonetheless increasing in prevalence. It is a late complication of disease with no standard of care and carries a grim prognosis if present. Diagnosis can be secured with total brain and spine MRI, with and without contrast together with lumbar puncture for cytology and flow cytometry. Even more rarely, true central nervous system (CNS) intraparenchymal plasmacytomas have been reported in advanced disease – again, with no standard of care.
Hyperviscosity
Hyperviscosity in myeloma is uncommon: in general, an IgG more than 10 g/dL, IgA more than 7 g/dL, and IgM more than 5 g/dL are required to cause symptoms, and disease burdens correlated with such profound paraproteinemias would generally come to attention by manifesting other signs or symptoms. Serum viscosity can be measured to confirm hyperviscosity-associated symptoms. However, although symptomatic patients may demonstrate levels greater than 4 centipoise (cP), symptoms may also occur at lower viscosity levels. These can include headache, visual symptoms, shortness of breath, altered mental status, or an acquired bleeding diathesis associated with decreased effective levels of coagulation factor X. Therapy should be initiated more on the basis of symptomatology than on absolute measured levels of viscosity and can require prompt institution of plasmapheresis in addition to anti-PC therapy. Because of their corresponding volumes of distribution, plasmapheresis is generally more effective at rapidly resolving hyperviscosity from large pentameric IgM molecules, which are confined to the circulation, than hyperviscosity due to smaller monomeric IgG or dimeric IgA molecules.
Immune Deficiency
Infection is one of the most important causes of morbidity and a common cause of mortality in myeloma. Myeloma is associated with significant dysfunction across multiple facets of innate and adaptive immunity, with T-, B-, NK-, and myeloid-cell dysfunction all contributing to the immunodeficiency syndrome which affects both the humoral and cell-mediated immune responses. Patients with MM are at increased risk of bacterial, viral, and fungal infections and in some cases of secondary malignancies, which are a consequence of both immune dysfunction from the plasma cell disorder, as well as cytopenias and immunosuppression and the mutagenizing effects of some MM therapies. Most notably, patients receiving PIs require prophylaxis with acyclovir and valacyclovir against varicella zoster reactivation and use of cytotoxic chemotherapy combinations can be associated with prolonged periods of neutropenia, requiring growth factor support, as well as the use of prophylactic antimicrobials. With respect to steroids, the schedule and dose given in most regimens using novel agents typically does not warrant routine Pneumocystis jirovecii prophylaxis for the majority of patients. However, neutropenia can become a limiting toxicity of many therapeutic regimens; indeed PIs, IMiDs, and anti-CD38 monoclonal antibody therapy as well as a number of agents used late in treatments such as panobinostat and selinexor can all be associated with neutropenia—an individualized approach to antimicrobial prophylaxis may be required. Finally, with effective anti-PC therapy, most patients develop hypogammaglobulinemia. However, routine IVIG administration in the absence of recurrent infections is not a common practice for most practitioners who treat MM.
Coagulation Disorders
Coagulation abnormalities are observed in MM patients and can be a consequence of treatment. A disease-related hypercoagulable state is observed in many patients, secondary to hyperviscosity, acquired activated protein C resistance, lupus-like anticoagulants with thromboembolic complications, acquired protein S deficiency, and a therapy-related hypercoagulability associated specifically with the use of IMiDs. As with other cancers, venous thromboembolic events dominate over arterial clots. Given this, aspirin or direct oral anticoagulant prophylaxis (factor Xa inhibitors) is routine when patients are prescribed IMiD-based therapeutic regimens, and a high index of suspicion is warranted for patients who present with potential clinical signs or symptoms consistent with venous thromboembolism. Although in newly diagnosed patients, thrombocytosis is more frequently associated with myeloma than thrombocytopenia, as a consequence of extensive bone marrow infiltration by myeloma cells, and more commonly repeated cycles of chemotherapy over multiple lines of treatment, patients may become significantly thrombocytopenic during the advanced stages of disease. The dangers of bleeding tendency in combination with weakness and debility and the potential for falls and traumatic injury in advanced patients is particularly worrisome. Furthermore, much like neutropenia, thrombocytopenia can become a dose-limiting toxicity for effective disease-directed therapy, particularly in later lines.
Amyloidosis
Monoclonal proteins, specifically light chains, can be deposited in various organs as an insoluble fibrillar protein, amyloid, affecting organ dysfunction (see Chapter 93 ). Around 5% to 20% of patients with AL amyloidosis also have a concurrent diagnosis of MM, and by definition, all patients with AL amyloid have clonal light-chain production. Although clinically overt amyloidosis is observed less frequently in MM, intense investigation to identify amyloid deposits using fat pad biopsies (for immunohistochemistry, electron microscopy, or mass spectrometry), concurrent staining of bone marrow with Congo Red, and obtaining biopsies of other tissues (such as the GI tract) can identify some level of amyloid deposit in almost one-third of such patients. Identification of cardiac amyloidosis can have implications for treatment planning in MM patients with respect to use of regimens with potential cardiotoxicity, such as carfilzomib, and screening patients with cardiac troponins, B-type natriuretic peptide (BNP), or N-terminal pro-B-type natriuretic peptide (NT-proBNP) is recommended. EKG as well as both echocardiogram and cardiac MRI (to demonstrate an infiltrative cardiomyopathy) may be helpful non-invasive modalities which can suggest cardiac amyloidosis. Patients with both amyloid deposits and MM can present with a number of features primarily related to organ damage, including renal and cardiac dysfunction and neuropathy. Such patients may be challenging to treat, but therapeutic intervention is generally similar to those with MM without amyloidosis, with the necessary concessions to modifications of regimens for cardiomyopathy, renal dysfunction, etc.
Laboratory and Radiologic Studies for the Diagnosis and Monitoring of Multiple Myeloma and Related Entities
A thorough diagnostic evaluation is required to secure the diagnosis of MM and to assess for disease sequelae and organ dysfunction, related to the plasma cell neoplasm or otherwise. The findings can have significant impact on the precise entity diagnosed (e.g., MM vs. solitary plasmacytoma), disease risk stratification and associated selection of appropriate treatment regimens, and of course patient counseling and prognostication. A number of investigations are also useful to assess for treatment response and to restage patients after therapy. For a summary of the workup of new patients, see box on Investigations for Patients Suspected or Confirmed to Have Newly Diagnosed Multiple Myeloma .
Investigations to Detect Clonality
Protein Electrophoresis
Serum protein electrophoresis is performed for screening, and to quantitate the monoclonal proteins present in plasma cell disorders (see box on Investigations for Patients Suspected or Confirmed to Have Newly Diagnosed Multiple Myeloma ). In approximately 70% of the patients, the monoclonal protein is IgG; in 20%, it is IgA; and in 5% to 10% of patients, it is light chains only without an intact immunoglobulin molecule. Less than 1% of patients have a monoclonal protein that is IgD, IgE, or IgM or even more rarely, a true non-secretory myeloma. The identification of the precise paraprotein(s) in both serum and urine currently requires immunofixation ( Fig. 91.4 ), and this test should always be paired with protein electrophoresis studies. Of note, because of the rarity of clonal IgD and IgE disorders, immunofixation studies do not routinely assess for IgE or IgD paraproteins; on initial evaluation for a new patient, measurement of total serum levels of IgE and IgD is recommended.
Investigations For Patients Suspected or Confirmed to Have Newly Diagnosed Multiple Myeloma
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