Poems Syndrome, Cryoglobulinemia, and Heavy-Chain Disease

Angela Dispenzieri

David Dingli

Morie A. Gertz

INTRODUCTION

This chapter addresses three types of immunoglobulin-based orphan diseases: the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes), cryoglobulinemia, and immunoglobulin heavy-chain disease (HCD). These diseases are characterized by lymphoproliferative, lymphoplasmacytic proliferative, or plasma cell proliferative disorders and specific serum immunoglobulin findings that serve as markers to define each entity.

POEMS SYNDROME

POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder. The acronym, which was coined by Bardwick in 1980,¹ refers to several, but not all, of the features of the syndrome: polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. There are three important points that relate to this memorable acronym: (1) not all of the features within the acronym are required to make the diagnosis; (2) there are other important features not included in the POEMS acronym, including papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis (P.E.S.T.), elevated vascular endothelial growth factor (VEGF) levels, a predisposition toward thrombosis, and abnormal pulmonary function tests; and (3) there is a Castleman disease variant of POEMS syndrome that may be associated with a clonal plasma cell disorder. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome, Crow-Fukase syndrome, and PEP syndrome.², ³

The disease was initially thought to be more common in patients of Japanese descent, given the most numerous initial reports from Japan.², ³ However, over the years, large series have also been reported from France, the United States, China, and India.⁴, ⁵, ⁶, ⁷, ⁸ A national survey conducted in Japan in 2003 showed a prevalence of approximately 0.3 per 100,000.⁹

ETIOLOGY OF POEMS SYNDROME

The pathogenesis of the syndrome is not understood. Distinctive presenting characteristics of the syndrome that differentiate POEMS syndrome from standard multiple myeloma (MM) include the following: (1) dominant symptoms have little or nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells, or renal failure; (2) dominant symptoms are typically neuropathy, endocrine dysfunction, and volume overload; (3) VEGF levels are high; (4) sclerotic bone lesions are present in the majority of cases; (5) overall survival is typically superior; and (6) λ clones predominate.¹⁰

To date, VEGF is the cytokine that correlates best with disease activity,¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰ although it is likely not the driving force of the disease, based on the mixed results seen with anti-VEGF therapy.²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷ VEGF is known to target endothelial cells, induce a rapid and reversible increase in vascular permeability, and be important in angiogenesis. It is expressed by osteoblasts, in bone tissue, macrophages, malignant plasma cells,²⁸, ²⁹, ³⁰ and megakaryocytes/platelets.³¹ Both IL-1β and IL-6 have been shown to stimulate VEGF production.²⁸ Little is known about the plasma cells in POEMS syndrome except that more than 95% of the time they are λ-light chain restricted with restricted immunoglobulin light chain variable gene usage (IGLV1).³², ³³, ³⁴ Aneuploidy and deletion of chromosome 13 have been described, but hyperdiploidy is not seen.³⁵

DIAGNOSIS OF POEMS SYNDROME

The diagnosis is established based on a composite of clinical and laboratory features. The most notable symptoms include the constellation of neuropathy and any of the following: monoclonal protein (especially λ-light chain), thrombocytosis, anasarca, or papilledema. All the features of the acronym are not required to make the diagnosis. The requirements set forth in Table 101.1 are designed to retain both sensitivity and specificity, potentially erring on the side of specificity. Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones,³⁸ measurement of VEGF,¹³,¹⁷, ²⁰, ³⁹, ⁴⁰ and careful analysis of a bone marrow biopsy⁴¹—can differentiate this syndrome from other conditions like chronic inflammatory polyradiculoneuropathy (CIDP), monoclonal gammopathy of undetermined significance (MGUS) neuropathy, and immunoglobulin light chain amyloid neuropathy.⁴² Figure 101.1 demonstrates several classic findings among patients with POEMS syndrome.

CLINICAL PRESENTATION OF POEMS SYNDROME

Polyradiculoneuropathy

The peripheral neuropathy is the dominant characteristic,², ³, ⁵, ⁷, ³⁶ and it is ascending, symmetrical, and affecting both sensation and motor function.⁴³ In our experience, pain may be a dominant feature in about 10% to 15% of patients, and in one report as many as 76% of patients had painful neuropathy.⁹, ⁴⁴ Nerve conduction studies in patients with POEMS syndrome show slowing of nerve conduction that is more predominant in the intermediate than distal nerve segments as compared to CIDP, and there is more severe attenuation of compound muscle action potentials in the lower than upper limbs.⁹, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸ In contrast to CIDP, conduction block is rare.⁹, ⁴⁶, ⁴⁸ The conduction findings suggest that demyelination is predominant in the nerve trunk rather than the distal nerve terminals, and axonal loss is predominant in the lower limb nerves.⁹ Axonal loss is greater in POEMS syndrome than it is in CIDP.⁴⁸ The nerve biopsy is not specific, but uncompacted myelin lamellae, endothelial cytoplasmic enlargement, opening of the tight junctions between endothelial cells and presence of many pinocytic vesicles adjacent to the cell membranes, and absence of macrophage-associated demyelination have been described.⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁶⁴

TABLE 101.1 CRITERIA FOR THE DIAGNOSIS OF POEMS SYNDROME^a

		% Affected^b
Mandatory major criteria	1. Polyradiculoneuropathy (typically demyelinating)	100
(both required)	2. Monoclonal plasma cell disorder (almost always λ)	100^c
Other major criteria	3. Castleman disease^d	11-25
(one required)	4. Bone lesions, usually sclerotic	27-97
	5. Vascular endothelial growth factor elevation^e
Minor criteria (one required)	6. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)	45-85
	7. Extravascular volume overload (edema, pleural effusion, or ascites)	29-87
	8. Endocrinopathy (adrenal, thyroid^f, pituitary, gonadal, parathyroid, pancreatic^f)	67-84
	9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)	68-89
	10. Papilledema	29-64
	11. Thrombocytosis/polycythemia^g	54-88
Other symptoms and signs	Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B₁₂ values
POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes.
^aThe diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the three other major criteria, and one of the six minor criteria are present. ^bSummary of frequencies of POEMS syndrome features based on largest retrospective series.^{2, 3, 5, 7, 36, 37} ^cTakasuki and Nakanishi series are included even though only 75% of patients had a documented plasma cell disorder. Since these are among the earliest series describing the syndrome, they are included. ^dThere is a Castleman disease variant of POEMS syndrome that occurs without evidence of a clonal plasma cell disorder that is not accounted for in this table. This entity should be considered separately.⁴² ^eA plasma VEGF level of 200 pg/ml is 95%specific and 68%sensitivity for a POEMS syndrome.²⁰ ^fBecause of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion. ^gApproximately 50% of patients will have bone marrow changes that distinguish it from a typical MGUS or myeloma bone marrow.
From Dispenzieri A. How I treat POEMS syndrome. Blood 2012;119(24):5650-5658, with permission.

Organomegaly, Endocrinopathy, Skin Changes, Papilledema, and Extravascular Overload

Depending on the series, 45% to 85% of patients will have any combination of splenomegaly, hepatomegaly, and/or lymphadenopathy. With the exception of lymph node biopsies, the histology of the liver and spleen tends to be nonspecific. Lymph nodes may appear reactive or reveal frank Castleman’s Disease or merely “Castleman’s Disease-like” changes. Historically, it was estimated that between 11% and 30% of POEMS patients with documented clonal plasma cell disorder also have documented Castleman disease or Castleman-like histology.¹, ³, ⁵, ⁷, ³⁶, ⁴² More recent data would suggest that among individuals with POEMS who undergo lymph node biopsy, about 50% show angiofollicular hyperplasia typical of Castleman disease,³, ⁷ and 84% of these are hyaline vascular type.⁷ Only those with peripheral neuropathy AND a plasma cell clone should be classified as standard POEMS syndrome; without both, patients can be classified as Castleman disease variant of POEMS if they have other POEMS features.⁵⁶

Endocrinopathy is a central but poorly understood feature of POEMS. In a recent series,³⁷ approximately 84% of patients had a recognized endocrinopathy, with hypogonadism as the most common endocrine abnormality, followed by thyroid abnormalities, glucose metabolism abnormalities, and lastly by adrenal insufficiency. The majority of patients have evidence of multiple endocrinopathies in the four major endocrine axes (gonadal, thyroid, glucose, and adrenal). Gynecomastia may be present on physical examination.

The characteristic skin changes include hyperpigmentation, a recent outcropping of hemangioma, hypertrichosis, dependent rubor and acrocyanosis, white nails, sclerodermoid changes, facial lipodystrophy, flushing, or clubbing.², ⁴, ⁵, ⁶, ⁷, ⁸, ⁵⁷, ⁵⁸ Rarely, calciphylaxis is also seen.⁵⁹, ⁶⁰ The histologic findings of the dermis have been reported to range from nonspecific to glomeruloid hemangiomata to vascular abnormalities in apparently normal dermis.⁶¹, ⁶², ⁶³, ⁶⁴

Papilledema is present in at least one-third of patients⁶⁵; the majority of these patients do not have specific symptoms relating to this finding but a minority will report blurred vision, diplopia, or ocular pain.

Peripheral edema, ascites, and effusions are the symptoms and signs that cause the next most morbidity after peripheral neuropathy. The manifestations of extravascular overload occur in 29% to 87% of patients with POEMS syndrome and are not typically associated with severe hypoalbuminemia. Severe third spacing can lead to worsening renal function. Serum creatinine levels are normal in most cases, but serum cystatin C, which is a surrogate marker for renal function, is high in 71% of patients.⁶⁶ In our experience, at presentation, fewer than 10% of patients have proteinuria exceeding 0.5 g/24 hours, and only 6% have a serum creatinine greater than or equal to 1.5 mg/dl. Four percent of patients developed renal failure as preterminal events.³⁶ In another series from China, however, 37% of patients had a creatinine clearance (CrCl) of less than 60 ml/minute, 9% had a CrCl of less than 30 ml/minute, and 15% had microhematuria. In POEMS syndrome, the renal histologic findings are diverse, with membranoproliferative features and evidence of endothelial injury being most common.⁶⁷ On both light and electron microscopy, mesangial expansion, narrowing of capillary lumina, basement membrane thickening, subendothelial deposits, widening of the subendothelial space, swelling and vacuolization of endothelial cells, and mesangiolysis predominate.⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴ Standard immunofluorescence is negative,⁶⁹, ⁷⁵ which differentiates it from primary membranoproliferative glomerulitis.⁶⁷ Rarely, infiltration by plasma cell nests or Castleman-like lymphoma have been described.⁷⁴

FIGURE 101.1. Classic findings of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndromes. A: Massive ascites and lipodystrophy. B: Chest radiograph and pulmonary function test results demonstrating reduced lung volumes due to neuromuscular weakness, small effusions, and reduced diffusing capacity of carbon monoxide. C: Improved chest radiograph and pulmonary function tests 2.5 years after ASCT (same patient as H). D: Fusion CT PET of mixed lytic/sclerotic lesion in right scapula. E: Bone windows of CT of mixed lytic/sclerotic lesion in right scapula. F: Hyperemia of extremities and white nails. G: Outcropping of cherry angiomata at diagnosis. H: Shrinkage and disappearance of cherry angiomata after radiation to solitary osteosclerotic lesion right femur. I: Plasmacytoma right scapula with overlying erythema as well as gynecomastia, muscle wasting, and ascites. Also present but unrelated is florid tinea corporis due to chronic steroid used for the incorrect diagnosis of CIDP. (From Dispenzieri, A. How I treat POEMS syndrome. Blood 2012;119(24):5650-5658, with permission.)

Monoclonal Plasma Cell Disorder, Sclerotic Bone Lesions, and Myeloproliferation

Among patients with POEMS syndrome, the CBC is notable for an absence of cytopenias. In fact, nearly half of patients will have thrombocytosis or erythrocytosis.³⁶ In a recent series from China, 26% of patients had anemia, which the authors attributed to impaired renal function.⁷ Their series was enriched with Castleman disease cases (25%), which may have also contributed to this unprecedentedly high rate of anemia.

The bone marrow biopsy reveals megakaryocyte hyperplasia and megakaryocyte clustering in 54% and 93% of cases, respectively.⁴¹ These megakaryocyte findings are reminiscent of a myeloproliferative disorder, but JAK2 V617F mutation is uniformly absent. One-third of patients do not have clonal plasma cells on their iliac crest biopsy. These are the patients who present with a solitary or “multiple solitary” plasmacytomas. The other two-thirds of patients have clonal plasma cells in their bone marrow, and 91% of these cases are clonal λ. The median percent of plasma cells observed is less than 5%. Immunohistochemical staining is more sensitive than is 6-color flow cytometry, since the former provides information on bone marrow architecture, which is key in making the diagnosis in nearly half of cases. In our study of 67 pretreatment bone marrow biopsies from patients with POEMS syndrome, lymphoid aggregates were found in 49% of cases. Of these, there was plasma cell rimming in all but one, and in 75% and 4% the rimming was clonal λ and κ, respectively. This finding was not seen in bone marrows from normal controls or from patients with MGUS, MM, or amyloidosis. Overall, only 8/67 (12%) of POEMS cases had normal iliac crest bone marrow biopsies, i.e., no detectable clonal plasma cells, no plasma cell rimmed lymphoid aggregates, and no megakaryocyte hyperplasia.

Osteosclerotic lesions occur in approximately 95% of patients and can be confused with benign bone islands, aneurysmal bone cysts, nonossifying fibromas, and fibrous dysplasia.³, ³⁶, ⁷⁶, ⁷⁷ Some lesions are densely sclerotic, while others are lytic with a sclerotic rim, while still others have a mixed soap-bubble appearance. Occasionally patients will have a lytic lesion without any evident sclerosis. Bone windows of CT body images are often very informative, often even more so than FDG-uptake, which can be variable and most useful when there is an obvious lytic component to the bone lesion.

Elevated Vascular Endothelial Growth Factor and Other Cytokines

Plasma and serum levels of VEGF are markedly elevated in patients with POEMS¹¹, ²⁰, ²⁸, ⁷⁸ and correlate with the activity of the disease.¹³, ¹⁷, ²⁰, ²⁸ The principal isoform of VEGF expressed is VEGF165.¹³ VEGF levels are independent of M-protein size.¹³ IL-1β, TNF-α, and IL-6 levels are often also increased. Serum VEGF levels are 10 to 50 times higher than plasma levels of VEGF,⁷⁹ making it unclear which test is preferred. In patients with POEMS, VEGF is found in both plasma cells²⁹, ³⁰ and platelets.⁷⁸ The higher level observed in serum is attributable to the release of VEGF from platelets in vitro during serum processing. Our group has recently demonstrated that a plasma VEGF level of 200 pg/ml had a specificity of 95% with a sensitivity of 68% in support of a diagnosis of POEMS syndrome. Other diseases with high VEGF include connective tissue disease and vasculitis.²⁰

Pulmonary and Coagulation Abnormalities

Respiratory complaints are usually limited, given patients’ neurologic status impairing their ability to induce cardiovascular challenges.⁸⁰ The pulmonary manifestations are protean, including pulmonary hypertension, restrictive lung disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon monoxide, but improve with effective therapy.⁷, ⁸⁰, ⁸¹ Whether the digital clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal disease is yet to be determined. Fingernail clubbing is seen in about 4% to 49% of cases.³, ⁸⁰

Patients are at increased risk for arterial and/or venous thromboses during their course, with nearly 20% of patients experiencing one of these complications.¹⁰, ⁸² Ten percent of patients present with a cerebrovascular event, most commonly embolic or vessel dissection and stenosis.⁸³ Thrombocytosis and increased bone marrow infiltration are associated with risk for cerebrovascular accidents.⁸³ Aberrations in the coagulation cascade have been implicated in POEMS syndrome, but are not usually clinically apparent.⁵⁵

TREATMENT OF POEMS SYNDROME

Despite the relationship between disease response and dropping levels of VEGF, the most experience with successful outcomes has been associated with directing therapy at the underlying clonal plasma cell disorder rather than solely targeting VEGF with anti-VEGF antibodies. The treatment algorithm is based on the extent of the plasma cell infiltration (Fig. 101.2). The approach to therapy differs based on whether there is bone marrow involvement as determined by blind iliac crest sampling.⁸⁴

The course of POEMS syndrome is usually chronic, with modern estimated median survivals of nearly 14 years.³⁶, ⁸⁰ Only fingernail clubbing, extravascular volume overload—i.e., effusions, edema, and ascites³⁶—and respiratory symptoms⁸⁰ have been associated with a significantly shorter overall survival. The number of POEMS features does not affect survival.⁵, ¹⁰ In our experience and in a recent report from China, patients with coexisting Castleman disease may have an inferior overall survival as compared to patients without.⁷ In a series of 11 patients, lower VEGF levels predicted for better response to therapy, with resolution of the skin changes, improvement of the neuropathic disturbances, and improvement of all of the features assumed to be related to increased permeability, like papilledema and organomegaly.¹⁷

Management of POEMS Syndrome without Disseminated Bone Marrow Involvement

In the case of patients with an isolated bone lesion without clonal plasma cells found on iliac crest biopsy, radiation is the recommended therapy, as it is in the case of a more straightforward solitary plasmacytoma of bone. Not only does radiation to an isolated (or even two or three isolated) lesion(s) improve the symptoms of POEMS syndrome over the course of 3 to 36 months, but it can be curative.

FIGURE 101.2. Algorithm for the treatment of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome. (From Dispenzieri, A., How I treat POEMS syndrome. Blood 2012;119(24):5650-5658, with permission.)

Management of POEMS Syndrome with Disseminated Bone Marrow Involvement

Once there is disseminated bone marrow involvement, albeit even with a low plasma cell percentage, radiation is not expected to be curative. Typically, once there is disseminated disease identified, systemic therapy is recommended with the caveat that large bony lesions with a significant lytic component may require adjuvant radiation therapy.⁸⁴ Decisions about adjuvant radiation should be made on a case by case basis, and typically not until a minimum of 6 months after completing chemotherapy. It is important to remember that there is a lag between completion of successful therapy and neurologic response, often with no discernible improvement until 6 months after completion of therapy. Maximal response is not seen until 2 to 3 years hence. Other features like anasarca, papilledema, and even skin changes may improve sooner. Optimal FDG-PET response may also lag by 6 to 12 months.

Since there are no randomized clinical trials among patients with POEMS syndrome, treatment recommendations are based on case series and anecdote. The treatment armamentarium is borrowed from other plasma cell disorders, most notably MM and light chain amyloidosis. Table 101.2 summarizes regimens and observed outcomes. Corticosteroids may provide symptomatic improvement, but response duration is limited. The most experience has been with alkylator-based therapy, either low-dose or high-dose, with peripheral blood stem cell transplant. The first prospective clinical trial to treat POEMS syndrome was reported from China.⁸⁹ They treated 31 patients with 12 cycles of melphalan and dexamethasone and found that 81% of patients had hematologic response, 100% had VEGF response, and 100% had at least some improvement in neurologic status. A limitation of this study is that follow-up was only 21 months, so long-term outcomes are not yet available. Personal experience and retrospective reports of the use of cyclophosphamide-based therapy are also promising.⁸⁴

TABLE 101.2 ACTIVITY OF THERAPY FOR THE TREATMENT OF POEMS SYNDROME

Regimen	Outcome
Radiation^{36, 85}, ⁸⁶, ⁸⁷, ⁸⁸	≥50% of patients have significant clinical improvement
Mel-Dex⁸⁹	81% hematologic response rate; 100% with some neurologic improvement
Corticosteroids⁵⁶	≥15% of patients have significant clinical improvement
ASCT⁵⁶	100% of surviving patients have significant clinical improvement
Thal after MP⁹⁰	No hematologic response but improved ascites; stabilized PN, splenomegaly, pulmonary hypertension
Thal + Dex after CAD⁹¹	CD/POEMS: improved ascites, effusions, pulmonary hypertension, PN, renal function, IL-6 level
Thal + Dex⁹²	Nine patients. VEGF improved in all; PN improved in 66%; stable in 33%; improved edema; no HCR
Thal after VAD, CTX, Bev²⁵	Improved cardiopulmonary status, but no improved PN and rising VEGF
Len + Dex⁹³	Improved ascites, PS, PN, VEGF, testosterone, pulmonary function tests
Len + Dex⁹⁴	Nine patients. All had hematologic response; clinical responses in all evaluable patients including PS, neurologic syndrome, edema, and VEGF
Len ± Dex⁹⁵	Ten patients. All had prior therapy a median of 4 mo (range 1-36 mo) prior to starting len. For 7, only Pred and IVIG were used as prior therapy, making it improbable that the salutatory effect was related to anything other than len. After a median of 7.5 cycles of len, all had clinical improvement despite the fact that only half achieved CR. Five were consolidated with ASCT
Len + CTX + Dex⁹⁶	After 4 cycles of therapy, patient was able to walk without support, and after 6 cycles, papilledema and IgA disappeared. 1 y after 9 cycles, she remains in remission
Bortez+AD after VAD, CTX, Mel-Pred, + AD⁹⁷	Improved M-protein, VEGF, paresthesias, splenomegaly, effusions, muscle strength, gynecomastia, and skin changes
Bortez + Dex⁹⁸	Improved M-protein, polyneuropathy, hepatomegaly, testosterone; no change in electromyelography
Bortez × 5 cycles + Thali added at cycle 6 (prior Dex and Mel-Pred)⁹⁹	Improvement of anasarca, PN, VEGF, and PET scan with Bortez alone, but thali added because of persistent edema, M-protein, PN, and barely elevated VEGF. With thali, disappearance of pleural effusion, ascites, and M-protein and normalization of VEGF
Bortez Dex^a¹⁰⁰	Improvement by 3 cycles, but continued for 6. Complete remission 4 y after completing therapy. Improvement in adenopathy, pleural effusion and ascites, hepatosplenomegaly, and IL-6
Bortez, CTX, Dex¹⁰¹	Clinical response of anasarca within 6 wk and tolerated therapy for 18 mo achieving a near complete response and a VEGF response. PN, hyperpigmentation, pulmonary hypertension improved significantly
Bev alone²¹	Death within 6 wk
Bev + mycophenolate + Dex¹⁰²	One month after starting therapy, patient deteriorated further with worsening ascites and shortness of breath. Bev and Dex were discontinued. Mel and Pred were begun. Patient died 1 mo later
Bev alone²² Worsening PN, anasarca, multiorgan failure; died of pneumonia 5 wk after therapy
Bev alone²³	Improved pain, breathing, and walking
Bev + Mel-Dex²⁴	Improved effusions/ascites
Prior VAD/CTX²⁵	Improved edema, pain, weakness, and VEGF
Bev + CTX-Dex²⁶ Initial worsening; repeat with Bev → improved pulmonary HTN, anasarca, skin changes
Bev + CTX-CS²⁷	Initial improvement, but multiorgan failure and death
Bev + CTX-radiation¹⁰³	Two patients. First patient treated with radiation and CTX and then Bev. Clinical improvement started before Bev. At radiologic relapse, Bev no use, so lenalidomide plus Dex used with benefit. Second patient treated with same sequence, but course complicated by sepsis. Biochemical and early neurologic response before Bev started
Bev +CTX²⁰	Clinical and biochemical relapse. No response to CTX, so bevacizumab added. Death
Bev, bevacizumab; Bortez, bortezomib; CS, corticosteroids; CTX, cyclophosphamide; Dex, dexamethasone; HCR, hematologic complete response; HTN, hypertension; Len, lenalidomide; Mel, melphalan; PN, polyneuropathy; POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes; Pred, prednisone; PS, performance status; Thali, thalidomide; VAD, vincristine, doxorubicin, dexamethasone; VEGF, vascular endothelial growth factor.
^aCastleman’s variant of POEMS syndrome.

High-dose chemotherapy with peripheral blood stem cell transplant can also be quite effective, but selection bias may confound these reports. Case series suggest 100% of patients achieve at least some neurologic improvement.¹⁸, ⁵⁷, ⁶⁷, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³, ¹²⁴, ¹²⁵ Doses of melphalan ranging from 140 mg/m² to 200 mg/m² have been used, with the lower doses used for sicker patients. In addition, tandem transplant has been applied in one patient, but again, no information is available regarding any added value of the second transplant.¹²⁶ Anecdotally, responses are durable, but relapses have been reported.²⁷, ¹²⁷ Of the 59 patients with POEMS syndrome treated at the Mayo Clinic Rochester, progression-free survival was 98%, 94%, and 75% at 1, 2, and 5 years, respectively.¹²⁸ Symptomatic progressions were rare, whereas radiographic and VEGF progressions were most common. Treatment-related morbidity and mortality can be minimized by recognizing and treating an engraftment-type syndrome characterized by fevers, rash, diarrhea, weight gain, and respiratory symptoms and signs that occur anytime between days 7 and 15 post-stem cell infusion.¹¹³

Other promising treatments include lenalidomide, thalidomide, and bortezomib, all of which can have anti-VEGF and anti-TNF effects. Enthusiasm for the latter two therapies should be tempered by the high rate of peripheral neuropathy induced by these drugs. We have observed dramatic improvements in one patient
treated with lenalidomide.⁹³ In France, nine patients, one of whom was newly diagnosed, were treated with lenalidomide and dexamethasone.⁹⁴ Serious side effects were noted in three patients, with two hematologic toxicities and a cutaneous allergy. All patients evaluable for hematologic response had at least a partial hematologic response. Clinical responses, including improvement in performance status and neurologic symptoms, were documented among the 8 who had sufficient follow-up. One patient relapsed 5 months after discontinuing therapy, but responded to reintroduction of the drug. Bortezomib use has been reported in three patients.⁹⁷, ⁹⁸, ¹⁰¹ The first report is difficult to interpret, since the patient had a number of chemotherapies prior to receiving a bortezomib, doxorubicin, and dexamethasone combination. There was early evidence of improvement even before starting the bortezomib regimen. The second and third reports are more convincing: in the first, 7 cycles of bortezomib and dexamethasone resulted in patient improvement; and in the second, 18 months of cyclophosphamide, bortezomib, and dexamethasone resulted in dramatic improvements in a patient with refractory paracentesisdependent ascites. Although an anti-VEGF strategy is appealing, the results with bevacizumab have been mixed.²², ²³, ²⁴, ²⁵, ²⁶, ²⁷ Five patients who had also received either radiation or alkylator during and/or predating the bevacizumab had benefit,²⁴, ²⁵, ²⁶, ¹⁰³ including three who had improvement but were then consolidated with high-dose chemotherapy and autologous stem cell transplant.²⁵, ¹⁰³ Three patients receiving bevacizumab died.²¹, ²², ²⁷

Both our experience and the literature would support that single-agent IV IG or plasmapheresis is not helpful. Other treatments like interferon (IFN)-α, tamoxifen, transretinoic acid, ticlopidine, argatroban, and strontium-89 have been reported as having activity, mostly as single case reports.¹⁰

Managing Symptoms of Disease

Attention to supportive care is imperative. Orthotics, physical therapy, and CPAP all play an important role in patients’ recovery. Ankle foot orthotics can increase mobility and reduce falls. Physical therapy reduces the risk of permanent contractures and leads to improved function both in the long and short term. For those with severe neuromuscular weakness, CPAP and/or BiPAP provides better oxygenation and potentially reduces the risk of complications associated with hypoventilation like pulmonary infection and pulmonary hypertension.

Monitoring Response

Patients must be followed carefully on a quarterly basis, tracking the status of deficits and comparing these to baseline.¹²⁸ VEGF responses may occur as soon as 3 months,¹²⁴ but they can be delayed. VEGF is an imperfect marker since discordances between disease activity and response have been reported,¹³⁷ so trends rather than absolute values should direct therapeutic decisions. Serum M-protein responses by protein electrophoresis, immunofixation electrophoresis, or serum immunoglobulin free light chains also pose a challenge. The size of the M-protein is typically small, making standard MM response criteria inapplicable in most cases. In addition, patients can derive very significant clinical benefit in the absence of an M-protein response.⁸⁹, ¹¹³ Finally, despite the fact that the immunoglobulin free light chains are elevated in 90% of POEMS patients, the ratio is normal in all but 18%,⁶⁶ making the test of limited value for patients with POEMS syndrome.

Recommendations about how to approach organ response have recently been suggested for the purposes of clinical trials, since there are more than two dozen parameters that can be assessed in a given patient with POEMS syndrome, given the multisystem nature of the disease.¹²⁸, ¹³⁸ Alternatively, response criteria for POEMS syndrome could be abridged as follows: (1) hematologic response using modified amyloid response criteria; (2) VEGF response; and (3) a simplified organ response, which is limited to those systems causing the most morbidity, like peripheral neuropathy assessment, pulmonary function testing (diffusion capacity of carbon monoxide), and extravascular overload (grading ascites and pleural effusion as absent, mild, moderate, or severe).

CRYOGLOBULINEMIA

In 1933, Wintrobe and Buell¹³⁹ originally reported observing cryoglobulins in a serum sample from a patient with MM. These cold precipitable immunoglobulins were observed in some patients with vasculitis, viral infection, or lymphoproliferative disorders, and were found to be byproducts of lymphoid dysfunction—unchecked and misdirected stimulation and proliferation that cause dysfunction and pathologic changes. An understanding of cryoglobulins and the cells that produce them, along with their interaction with tissue matrix, systemic cytokines, and the remainder of the immune system, may provide insight into basic control pathways and the earliest steps of malignant transformation.

The term “cryoglobulin” was coined by Lerner and Watson¹⁴⁰ in 1947. Precipitation of cryoglobulins is dependent on temperature, pH, cryoglobulin concentration, and weak noncovalent factors.¹⁴¹ Meltzer and others delineated a distinct syndrome of purpura, arthralgias, asthenia, renal disease, and neuropathy—often occurring with immune complex deposition or vasculitis, or both.¹²⁹, ¹⁴² Brouet et al.¹²⁰ popularized a system of classifying cryoglobulinemia on the basis of the components of the cryoprecipitate: type I, isolated monoclonal immunoglobulins; type II, a monoclonal component, usually IgM, that binds to the Fc component of polyclonal IgG (i.e., has rheumatoid factor activity); and type III, polyclonal immunoglobulins of more than one isotype.¹²⁰ This classification provided a framework by which clinical correlations could be made. Associated conditions, such as lymphoproliferative disorders, connective tissue disorders, infection, and liver disease were observed in some patients¹²¹, ¹⁴³ (Table 101.3). Since early studies failed to identify an associated underlying condition in 34% to 71% of cryoglobulinemia cases, the majority of patients were thought to have essential or primary cryoglobulinemia¹²⁰, ¹²¹, ¹⁴⁴; however, with the discovery of hepatitis C virus (HCV) came the recognition that the majority of these cases were actually related to HCV.¹⁴⁵, ¹⁴⁶ (Fig. 101.3). Essential cryoglobulinemia now accounts for fewer than 10% of cases of cryoglobulinemia.¹³⁴

EPIDEMIOLOGY OF CRYOGLOBULINEMIA

It is difficult to determine the prevalence of cryoglobulinemia since the syndrome is clinically heterogenous and it may be difficult to distinguish incidental laboratory findings from the symptomatic disease state. Although only a minority of patients with serum cryoglobulins have symptoms referable to them, cryoglobulins may be found in patients with cirrhosis (up to 45%), alcoholic hepatitis (32%), autoimmune hepatitis (40%), subacute bacterial endocarditis (90%), rheumatoid arthritis (47%), Sjögren syndrome, IgG myeloma (10%), and Waldenström macroglobulinemia (19%).¹²⁰, ¹²¹, ¹²², ¹²³, ¹³⁶, ¹⁴³ The presence of cryoglobulins should alert the physician to the possibility of undiagnosed chronic infections such as subacute bacterial endocarditis, Lyme disease, and Q fever.¹⁴³ Case reports describe cryoglobulinemia associated with hepatitis A virus, hepatitis B virus, Hantavirus, cytomegalovirus, Epstein-Barr virus, human T-cell lymphotropic virus type I, hepatitis G virus, human immunodeficiency virus,

and parvovirus B19.¹¹⁶, ¹⁴³, ¹⁴⁷ The association with HCV was reported in 1990 and 1991,¹⁴⁵, ¹⁴⁶ and the majority (42% to 100%) of patients with mixed cryoglobulinemia were found to be infected with HCV.¹⁴⁶, ¹⁴⁸, ¹⁴⁹, ¹⁵⁰, ¹⁵¹, ¹⁵², ¹⁵³, ¹⁵⁴, ¹⁵⁵

TABLE 101.3 CRYOGLOBULINEMIA: CLINICAL AND EXPERIMENTAL ASSOCIATIONS

Infectious Diseases
	Viral
		Epstein-Barr virus
		Cytomegalovirus
		Hepatitis B virus
		Hepatitis A virus
		Adenovirus
		Hepatitis C virus^{114, 115}
		Human immunodeficiency virus¹¹⁶, ¹¹⁷, ¹¹⁸
	Bacterial
		Subacute bacterial endocarditis (± nephritis)
		Lepromatous leprosy (± erythema nodosum)
		Acute poststreptococcal nephritis
		Syphilis
		Lyme disease (± erythema chronicum migrans)
		After intestinal bypass with arthritis
		Q fever¹¹⁹
	Fungal
		Coccidioidomycosis
	Parasitic
		Kala-azar
		Toxoplasmosis
		Tropical splenomegaly syndrome
		Echinococcosis
		Malaria
		Schistosomiasis
		Trypanosomiasis
Autoimmune Diseases
	Systemic lupus erythematosus
	Nephritis, hypocomplementemia
	Drug-induced lupus (procainamide)
	Rheumatoid arthritis
	Extra-articular disease, Felty syndrome, synovial fluid
	Polyarteritis nodosa (positive or negative for hepatitis B surface antigen)
	Kawasaki syndrome (± macroglobulinemia)
	Sjögren syndrome
	Scleroderma
	Sarcoidosis
	Thyroiditis
	Henoch-Schönlein purpura
	Behçet syndrome
	Polymyositis
	Inflammatory bowel disease
	Celiac disease, ulcerative colitis, regional enteritis
	Endomyocardial fibrosis
	Pulmonary fibrosis
	Cutaneous vasculitis
	Pemphigus vulgaris
	Erythema elevatum diutinum
	Cold-induced urticaria
	Epidermolysis bullosa acquisita
	Erythema multiforme
	POEMS syndrome
	Pyoderma gangrenosum
Lymphoproliferative Disorders
	Macroglobulinemia (primary and secondary)^{120, 121, 122, 123}
	Lymphoma (Hodgkin and non-Hodgkin)^{120, 121, 122, 123}
	Chronic lymphocytic leukemia
	Immunoblastic lymphadenopathy
	Hairy cell leukemia
Renal Disease
	Proliferative glomerulonephritis
Liver Diseases
	Cirrhosis (Laënnec, postnecrotic)
	Biliary cirrhosis
	Chronic hepatitis
Familial (Symptomatic, Asymptomatic)
Essential
	Experimental
	Pneumococcal vaccines
	Streptococcal (A and C) hyperimmunization
	NZB/NZW, MRL/1, BXSB mice
POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes.
From Dispenzieri A, Gorevic PD. Cryoglobulinemia. Hematol Oncol Clin North Am 1999;13(6):1315-1349. By permission of WB Saunders.

FIGURE 101.3. Relationship among underlying diseases, cryoglobulins, and symptoms of cryoglobulinemia. Question marks represent unknown contributing factors. HCV, hepatitis C virus. (Adapted from Dispenzieri A, Gertz MA. Cryoglobulinemia. In: Gertz MA, Greipp PA, eds. Handbook of Multiple Myeloma and Related Cell Disorders (Primary Amyloidosis, AL). Berlin: Springer-Verlag, 2004.)

Results of most studies show that the median age at diagnosis is the early to mid 50s.¹³⁶, ¹⁵⁶, ¹⁵⁷ In some studies, the female predominance for cryoglobulinemia is greater than 2:1 (Table 101.4). No racial preference has been noted, but the incidence is higher
in regions where HCV occurs at higher frequencies (for example, southern Europe).

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