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1760 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1761

therapies. 601,602 For example, gene-expression profiling of patient tumor majority of cases, in contrast to EMP, where only 50 percent eventu-
samples showed genes upregulated in patients responding to borte- ally develop myeloma. The median survival of 86.4 months and 100.8
zomib compared to patients who did not respond. Hsp27 upregula- months for patients with SOP and EMP, respectively, is similar; how-
tion correlated with intrinsic or acquired bortezomib resistance (Chap. ever, PFS is markedly different, 16 percent for SOP patients versus 71
109). Preclinical studies showed that p38 MAPK inhibition downregulated percent for EMP patients. The persistence of stable monoclonal Ig in the
Hsp27 expression and restored Velcade sensitivity in resistant myeloma serum and/or urine after primary treatment of plasmacytoma does not
603
cell lines and patient samples, providing the basis for a trial combin- necessitate additional therapy, as it does not influence survival or dis-
609
ing these two agents. ease-free survival. In contrast, rising monoclonal Ig levels in a patient
Gene-expression profiling data should have an important impact with a history of either SOP or EMP should trigger a workup for either
on the interpretation of future clinical trials. Validated prognostic recurrent plasmacytoma or myeloma. It has been suggested, as is true
models from gene microarray data are now used for improved prog- for myeloma, that serum β M has prognostic value in patients with SOP.
2
nostication and will ultimately be used to assist in selecting therapy for For example, 17 of 19 patients with elevated serum β M had transfor-
2
individual patients. mation to myeloma and shorter survival (31 months) as compared with
Myeloma is a very complex disease at the genomic level. Parallel those with normal serum β M levels. 612
2
sequencing of paired and normal samples from 203 myeloma patients Local therapy, primarily radiotherapy, with surgery as needed for
were performed and mutations were most frequently observed in KRAS, structural anatomic support is the standard treatment for SOP and
112
NRAS, BRAF, FAM46C, TP53, and DIS3. The tumors demonstrated EMP. 609–611 Patients with soft-tissue solitary plasmacytomas can often
significant heterogeneity. Mutations were often present in subclonal be cured with appropriate local radiation (dose of at least 4.5 Gy). By
populations and multiple mutations within the same pathway were contrast, this local treatment approach fails in the majority of patients
observed within the same patient. Results of whole-exome sequencing, with solitary plasmacytomas of bone. The development of myeloma
613
copy-number profiling, and cytogenetics of myeloma samples, includ- in such patients probably reflects multifocal systemic disease present at
ing serial samples in 15 patients, demonstrated complex clonal evolu- the outset and hitherto not detectable by standard radiographic imaging
614
tion over time. Moreover, clonal and subclonal heterogeneity within but readily by applying MRI and PET-CT. 615
108
the same patient without the predominant clone did not necessarily The benefit of chemotherapy, either alone or in combination with
translate into mRNA. These and other studies demonstrate the com- radiotherapy and surgery, as primary therapy for SOP or EMP has not
plexity of the myeloma genome underscoring a need for rapid identifi- been proven. Moreover, the benefit of adjuvant chemotherapy, given to
cation of possible druggable oncogenic mutations to customize therapy prevent recurrent disease and/or progression to myeloma, is also unde-
for myeloma patients. Genomic analysis technology that can facilitate fined. Disappearance of protein after involved-field radiotherapy pre-
this understanding may prove valuable in the further development of dicts for long-term disease-free survival and possible cure. 613
effective targeted therapies. Future strategies of treatment may include
the combination of targeted therapies with existing proteosome inhib-
itors and IMiDs. In addition, identification of mutations may provide AMYLOID LIGHT-CHAIN AMYLOIDOSIS
important prognostic information. For example, SP140 mutations were When clinical features of congestive heart failure, nephrotic syndrome,
associated with increased risk of relapse suggesting that this gene may malabsorption, coagulopathy, skin rash (oral mucosal rash, “raccoon’s
have prognostic features in myeloma. eyes”) or neuropathy are present, a careful search for primary amyloi-
dosis should be carried out (Chap. 108). LCDD may also have a similar
SPECIAL DISEASE MANIFESTATIONS clinical presentation. The primary difference between AL amyloidosis
and LCDD is the difference in structure of the deposited protein; in AL
IGM MYELOMA amyloidosis it is fibrillar versus granular in LCDD. LCDD is usually
A rare diagnostic dilemma concerns the existence of an IgM myeloma associated with the κ light-chain subtype, whereas AL amyloidosis is
associated with the λ light-chain subtype of myeloma.
entity that is distinct from Waldenström macroglobulinemia (histo- Primary AL amyloidosis and immunoglobulin deposition diseases
pathologic diagnosis, immunocytoma). 604,605 Upon examination, plasma are best characterized functionally as MG with clinical manifestations
cells, rather than the lymphoplasmacytic infiltrate, are seen to domi- because of normal tissue infiltration by these processes, although they
nate the marrow of myeloma, whereas mastocytosis is a hallmark of can also accompany overt myeloma. Further workup following suspicion
immunocytoma. DNA aneuploidy and the presence of lytic bone lesions on clinical presentation depends on the organ of concern. Cardiac amy-
support a diagnosis of myeloma. Myeloma, also of the IgM isotype, is loidosis may be associated with low voltage on an electrocardiogram,
resistant to purine analogues, which are effective in Waldenström arrhythmias, increased interventricular septal thickness greater than 12
macroglobulinemia. 606,607 mm, diastolic dysfunction or speckling on echocardiogram, and eleva-
tion of markers, such as B-type natriuretic peptide, N-terminal pro–B-
SOLITARY PLASMACYTOMA type natriuretic protein, and cardiac troponin T. 616,617 Involvement of the
Plasmacytomas are collections of monoclonal plasma cells originating gastrointestinal tract may present with decreased albumin and preal-
either in bone (solitary osseous plasmacytoma [SOP]) or in soft tissue bumin. Renal involvement may present as nonspecific proteinuria with
(extramedullary plasmacytoma [EMP]). They comprise less than 10 high total protein on 24-hour collection and low monoclonal immuno-
percent of plasma cell dyscrasias. Indications of systemic disease such globulin. Carpal tunnel syndrome and peripheral neuropathy may be
as marrow plasmacytosis, anemia, renal insufficiency, or multiple lytic a manifestation of amyloid, and nerve conduction studies may help in
or soft-tissue lesions must be excluded before the diagnosis of either this diagnosis. Orthostatic hypotension also should alert to the possi-
SOP or EMP can be made. MRI can be useful to show additional mar- bility of systemic amyloidosis as a result of amyloid deposition in vasa
row abnormalities consistent with myeloma. The median age of diag- nervorum of the autonomic nervous system or in adrenal glands result-
608
nosis of either SOP or EMP is approximately 50 years, nearly 10 years ing in hypoadrenalism. Occasionally, primary amyloidosis presents as
younger than that for myeloma. 609–611 Although patients with SOP and tumors either mostly consisting of amyloid or mixed with plasmacy-
EMP can both progress to myeloma, persons with SOP progress in the toma. Typically, MRI signals can distinguish plasmacytomas, which

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