**1. Introduction**

Multiple myeloma (MM) or plasma cell myeloma, is a haematological disease representing 1-2% of all cancers and about 15% of haematological *malignancies*. The classic form of MM is characterized by generalized neoplastic changes in the bones accompanied by kidney damage, impaired haematopoiesis and susceptibility to infections. In laboratory tests, MM manifests it‐ self by the presence of monoclonal protein, called paraprotein, in serum or urine. This results from the fact that pathological plasma cells produce a complete immunoglobulin (Ig), usually IgG or IgA, or only the kappa or lambda light chains. Solitary myeloma (osseous or extraoss‐ eous), non-secretory myeloma and secretory myeloma are rarer forms of MM. Sometimes, however, the clinical picture of MM is quite different from the classic manifestation described in the textbooks. This can cause diagnostic difficulties, thereby delaying treatment.

The atypical clinical and laboratory manifestations and paraneoplastic syndromes concomi‐ tant with a diagnosis of MM and described below, as are those that appear in the course of the disease, especially in progression. Although they do not represent a significant percent‐ age of cases, knowledge of the rare clinical and laboratory variants of MM may assist in making a differential diagnosis in cases of doubt.

In addition to their low incidence, rare manifestations of MM share the lack of valid relevant scientific knowledge, which leads to difficulties in making firm therapeutic guidelines. In fact, most of the information on these conditions derives from case reports and/or small ser‐ ies studies, making it rather difficult to develop any uniform treatment approaches. As a re‐ sult, several of rare manifestations of MM can well be controlled with standard regimens used for classic MM, like for example non-secretory myeloma. However the satisfactory strategies to control some of those conditions, such as plasma cell leukemia, are still unsatis‐ factory. These issues are best illustrated in the present work in the chapter discussing PO‐ EMS syndrome.

© 2013 Jurczyszyn; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Furthermore, rare manifestations of MM are heterogonous also in their underlying cellu‐ lar and/or molecular mechanisms. These can be either a plasma-cell clone (non-secretory myeloma), paraprotein or cytokines (some of the paraneoplastic disorders). Moreover, paraprotein may exhibit autoantibody activity or aggregate into insoluble depositions. This relates to some other uncommon conditions, including various types of amyloido‐ sis and cryoglobulinemia. In amyloidosis, misfolding of proteins occurs. Otherwise solu‐ ble, misfolded protein molecules tend to aggregate as extracellular amyloid fibrils, leading to the damage of the various tissues and organs. In cryoglobulinemia, parapro‐ teins present in circulating blood can become insoluble in a certain temperature, result‐ ing in a wide spectrum of clinical symptoms depending on paraprotein properties (Merlini, Stone 2006).

**Rare manifestation of MM Major diagnostic criteria**

Non-secretory myeloma Bone marrow cytology and immunohistochemistry: the infiltration of clonal plasma cells.

Myeloma IgD Diagnosis: problematic because routine test does not detect the

Myeloma IgM Diagnosis: the presence of IgM monoclonal protein in serum; it is

Myeloma IgE Frequent presence of plasma cells in peripheral blood, osteoblastic lesions, hepatosplenomegaly and amyloidosis.

Plasma cell leukemia Diagnosis: at least 20% plasma cells in a peripheral blood smear and/or

treatment with corticosteroids.

Family myeloma The exact genetic cause remains unknown but autosomal inheritance with low gene penetrance is most probable.

Supporting references can be found in corresponding sections of the main text. Detailed diagnostic criteria of POEMS

lymphadenopathy.

secondary ulcers.

**Table 2.** Major diagnostic procedures and criteria of rare manifestations of multiple myeloma (MM).

foci.

Rare paraneoplastic syndromes accompanying myeloma

syndrome can be found in Table 3.

normal (non-clonal) immunoglobulins.

The clinical picture: classic osteolytic lesions and a decrease in the level of

Rare Manifestations of Multiple Myeloma http://dx.doi.org/10.5772/53385 243

monoclonal protein peak in 60% of patients, and when it is detected, the concentration is usually smaller than 20 g/l. An overproduction of light

The clinical picture: a variant of the light chain disease. Usually affects younger patients, the disease course is more aggressive and often accompanied by amyloidosis and extramedullary infiltrations. Lymphadenopathy, renal failure and hypercalcemia are common.

necessary to differentiate with Waldenström's macroglobulinemia. The clinical picture: the clonal proliferation of plasma cells in bone marrow aspiration and the presence of hypercalcemia, renal failure and osteolytic

the absolute number of plasma cells in the peripheral blood exceeding 2

The clinical picture: extraosseous infiltrations, often with the involvement of the central nervous system, and accompanied by organomegaly and

Sweet's syndrome: granolocytosis, fever and painful erythematous skin changes caused by skin granulocytic infiltrations that subside following

Bullous epidermal separation or pemphigus: subepidermal bubbles and

An annual immunoelectrophoresis of the urine and serum protein least two cases of MM in first or second-degree relatives are present.

chains (usually lambda) is observed in 90-96% of patients.

Myopathy and carpal tunnel syndrome can be present.

g/l with a concomitant monoclonal gammopathy.

Below, rare manifestations of MM are described in details. Their relative prevalence/inci‐ dence is given in Table 1. Table 2 provides short summary of the diagnostic and clinical characteristics of the rare manifestations of MM, except for POEMS syndrome described in more details in Table 3.


**Table 1.** Rare manifestations of multiple myeloma (MM) and their prevalence/incidence.


Furthermore, rare manifestations of MM are heterogonous also in their underlying cellu‐ lar and/or molecular mechanisms. These can be either a plasma-cell clone (non-secretory myeloma), paraprotein or cytokines (some of the paraneoplastic disorders). Moreover, paraprotein may exhibit autoantibody activity or aggregate into insoluble depositions. This relates to some other uncommon conditions, including various types of amyloido‐ sis and cryoglobulinemia. In amyloidosis, misfolding of proteins occurs. Otherwise solu‐ ble, misfolded protein molecules tend to aggregate as extracellular amyloid fibrils, leading to the damage of the various tissues and organs. In cryoglobulinemia, parapro‐ teins present in circulating blood can become insoluble in a certain temperature, result‐ ing in a wide spectrum of clinical symptoms depending on paraprotein properties

Below, rare manifestations of MM are described in details. Their relative prevalence/inci‐ dence is given in Table 1. Table 2 provides short summary of the diagnostic and clinical characteristics of the rare manifestations of MM, except for POEMS syndrome described in

IgD 2%

IgM 0.2-0.5%

IgE Very rare

Extremely rare

**Rare manifestation of MM Percentage of all MM cases**

Non-secretory myeloma 1-5%

Plasma cell leukemia 0.5-3.0%

POEMS syndrome Very rare

Family myeloma Extremely rare

**Table 1.** Rare manifestations of multiple myeloma (MM) and their prevalence/incidence.

Supporting references can be found in corresponding sections of the main text.

(Merlini, Stone 2006).

242 Multiple Myeloma - A Quick Reflection on the Fast Progress

more details in Table 3.

Myeloma IgD, IgM and IgE

Rare paraneoplastic syndromes accompanying myeloma

> Supporting references can be found in corresponding sections of the main text. Detailed diagnostic criteria of POEMS syndrome can be found in Table 3.

**Table 2.** Major diagnostic procedures and criteria of rare manifestations of multiple myeloma (MM).


secretory myeloma do not differ from those observed in the secretory form [Blade, Kyle 1999]. Both the prognosis and the therapeutic recommendations are the same for patients with non-secretory myeloma and the classic form of the disease, i.e. secretory myeloma. Some studies, however, indicate that the prognosis for patients with non-secretory myeloma treated using autologous transplantation is better than for the patients suffering from the

Rare Manifestations of Multiple Myeloma http://dx.doi.org/10.5772/53385 245

The monoclonal production of immunoglobulin IgD A is a rare laboratory manifestation of MM, observed in approximately 2% of patients with MM. Diagnostic problems arise from the fact that the routine test does not detect the monoclonal protein peak in 60% of patients, and when it is detected, the concentration is usually smaller than 20 g/l. An overproduction of light chains (usually lambda) is observed in 90-96% of patients. This makes the clinical picture a variant of the light chain disease [Blade, Kyle 1999, Kuliszkiewicz-Janus et al. 2005, Shimamoto, 1991, Blades et al. 1994, Jancelewicz et al. 1975]. The clinical picture is also slightly different, although this usually affects younger patients – the disease course is more aggressive and often accompanied by amyloidosis and extramedullary infiltrations. Lym‐ phadenopathy is observed in 10% of patients [Shimamoto, 1991, Blades et al. 1994]. Renal failure is observed in 33% of cases at the moment of diagnosis and hypercalcemia in 20% [Homan et al. 1990]. The disease is often accompanied by neurological symptoms such as myopathy and carpal tunnel syndrome, which is probably associated with the coexistence of amyloidosis. IgD myeloma is often associated with connective tissue diseases. This can hin‐ der diagnosis due to the resulting low concentration of monoclonal protein. Previous analy‐ ses suggest that the mean survival time of patients with IgD MM is 13.7-21 months. This is shorter than for the classic IgG and IgA MM [Blade et al. 1994, Jancelewicz et al. 1975]. More recent analyses, however, indicate that 30% of patients with IgD myeloma live more than 3 years and 20% more than 5 years [Blade et al. 1994]. Shimamoto regards the presence of the lambda chain and leukocytes in excess of 7 g/l as adverse factors responsible for the shorter progression-free time in patients with IgD MM. Depending on the number of prognostic fac‐ tors, patients are classified into three prognostic groups: 0, 1 and 2 [Shimamoto et al. 1991]. Based on a retrospective analysis of 36 patients undergoing ablative chemotherapy, the probability of 3-year survival and progression-free time were 69% and 38% respectively [Sharma et al. 2010]. Some authors indicate that the use of myeloablative chemotherapy re‐ duces the differences between IgD MM and the classic forms of the disease [Sharma et al. 2010, Maisnar et al. 2008], but this remains a matter for discussion [Morris et al. 2010].

MM IgM is even less frequent (0.2-0.5% of patients with MM) [Reece et al. 2010, MacLennan 1992, Avet-Loiseau et al. 2003]. Although the presence of IgM monoclonal protein in serum is one of the clinical features common to the disease and Waldenström's macroglobulinemia (WM), the overall clinical picture is different. The differing prognoses and therapeutic rec‐ ommendations make a correct diagnosis all the more important. The clonal proliferation of plasma cells usually observed in bone marrow aspiration, together with other characteristic

classic form of the disease [Terpos et al. 2003].

**3. Myeloma IgD, IgM and IgE**

**Table 3.** The criteria for diagnosis of POEMS syndrome.

#### **2. Non-secretory myeloma**

Non-secretory myeloma is one of the least frequent forms of MM. The classic diagnostic methods of immunoelectrophoresis and immunofixation do not detect any monoclonal pro‐ tein in either urine or serum. These patients are usually referred to a haematologist as part of a diagnosis for anaemia or bone changes. It is estimated that this form represents 1-5% of all MM cases [Kyle et al. 2003, Blade, Kyle 1999]. The diagnosis is based on a bone marrow examination (cytology and immunohistochemistry). This will confirm the infiltration of clo‐ nal plasma cells, although immunohistochemical tests do not confirm the existence of light kappa or lambda chains in 15% of patients with non-secretory myeloma. The clinical picture reveals classic osteolytic lesions and a decrease in the level of normal (non-clonal) immuno‐ globulins [Kyle et al. 2003, Blade, Kyle 1999] in 92% of patients. Although classic diagnostic tests do not indicate the presence of monoclonal protein, the ratio of free light chains in se‐ rum (FLCr) is abnormal in more than 2/3 of patients. This test is recommended for these pa‐ tients to evaluate the effectiveness of the therapy [Durie 2006, Dispenzieri 2009]. A more detailed analysis of the immunofixation test, together with the results of the test for free light chains, allows the presence of monoclonal protein in serum to be ascertained. The pro‐ portion of patients with "true" non-secretory myeloma is consequently found to be much smaller than 2%. Repeated bone marrow smear tests are the only way to assess the activity of the disease [Durie 2006] in these patients. Cytogenetic abnormalities in patients with nonsecretory myeloma do not differ from those observed in the secretory form [Blade, Kyle 1999]. Both the prognosis and the therapeutic recommendations are the same for patients with non-secretory myeloma and the classic form of the disease, i.e. secretory myeloma. Some studies, however, indicate that the prognosis for patients with non-secretory myeloma treated using autologous transplantation is better than for the patients suffering from the classic form of the disease [Terpos et al. 2003].

## **3. Myeloma IgD, IgM and IgE**

**Disease Definitionof the disease References**

1. The presence of the monoclonal protein (in serum and/or in urine),

Kyle et al. 2009 Dispenzieri

Dispenzieri et al. 2007 Rajkumar et al. 2011

et al. 2003

• the enlargement of the internal organs (liver, spleen, lymph nodes)

• abnormal secretion of the endocrine glands (adrenal glands, thyroid, parathyroid, pancreas, gonads, with the exception of diabetes or

•skin lesions (hyperpigmentation, hypertrichosis, peripheral cyanosis,

Non-secretory myeloma is one of the least frequent forms of MM. The classic diagnostic methods of immunoelectrophoresis and immunofixation do not detect any monoclonal pro‐ tein in either urine or serum. These patients are usually referred to a haematologist as part of a diagnosis for anaemia or bone changes. It is estimated that this form represents 1-5% of all MM cases [Kyle et al. 2003, Blade, Kyle 1999]. The diagnosis is based on a bone marrow examination (cytology and immunohistochemistry). This will confirm the infiltration of clo‐ nal plasma cells, although immunohistochemical tests do not confirm the existence of light kappa or lambda chains in 15% of patients with non-secretory myeloma. The clinical picture reveals classic osteolytic lesions and a decrease in the level of normal (non-clonal) immuno‐ globulins [Kyle et al. 2003, Blade, Kyle 1999] in 92% of patients. Although classic diagnostic tests do not indicate the presence of monoclonal protein, the ratio of free light chains in se‐ rum (FLCr) is abnormal in more than 2/3 of patients. This test is recommended for these pa‐ tients to evaluate the effectiveness of the therapy [Durie 2006, Dispenzieri 2009]. A more detailed analysis of the immunofixation test, together with the results of the test for free light chains, allows the presence of monoclonal protein in serum to be ascertained. The pro‐ portion of patients with "true" non-secretory myeloma is consequently found to be much smaller than 2%. Repeated bone marrow smear tests are the only way to assess the activity of the disease [Durie 2006] in these patients. Cytogenetic abnormalities in patients with non-

All four criteria must be met:

244 Multiple Myeloma - A Quick Reflection on the Fast Progress

especially the light chain type λ. 2. Peripheral polyneuropathy.

• pleural effusion, ascites, oedema

abnormal structure of the nails)

• thrombocythaemia, polycythemia.

• Castleman's disease

hypothyroidism)

• optic disc oedema,

**Table 3.** The criteria for diagnosis of POEMS syndrome.

**2. Non-secretory myeloma**

3. The presence of at least one "great" criterion: • osteosclerotic changes in the skeletal system

• high levels of vascular endothelial growth factor. 4. The presence of at least one "small" criterion:

POEMS syndrome

> The monoclonal production of immunoglobulin IgD A is a rare laboratory manifestation of MM, observed in approximately 2% of patients with MM. Diagnostic problems arise from the fact that the routine test does not detect the monoclonal protein peak in 60% of patients, and when it is detected, the concentration is usually smaller than 20 g/l. An overproduction of light chains (usually lambda) is observed in 90-96% of patients. This makes the clinical picture a variant of the light chain disease [Blade, Kyle 1999, Kuliszkiewicz-Janus et al. 2005, Shimamoto, 1991, Blades et al. 1994, Jancelewicz et al. 1975]. The clinical picture is also slightly different, although this usually affects younger patients – the disease course is more aggressive and often accompanied by amyloidosis and extramedullary infiltrations. Lym‐ phadenopathy is observed in 10% of patients [Shimamoto, 1991, Blades et al. 1994]. Renal failure is observed in 33% of cases at the moment of diagnosis and hypercalcemia in 20% [Homan et al. 1990]. The disease is often accompanied by neurological symptoms such as myopathy and carpal tunnel syndrome, which is probably associated with the coexistence of amyloidosis. IgD myeloma is often associated with connective tissue diseases. This can hin‐ der diagnosis due to the resulting low concentration of monoclonal protein. Previous analy‐ ses suggest that the mean survival time of patients with IgD MM is 13.7-21 months. This is shorter than for the classic IgG and IgA MM [Blade et al. 1994, Jancelewicz et al. 1975]. More recent analyses, however, indicate that 30% of patients with IgD myeloma live more than 3 years and 20% more than 5 years [Blade et al. 1994]. Shimamoto regards the presence of the lambda chain and leukocytes in excess of 7 g/l as adverse factors responsible for the shorter progression-free time in patients with IgD MM. Depending on the number of prognostic fac‐ tors, patients are classified into three prognostic groups: 0, 1 and 2 [Shimamoto et al. 1991]. Based on a retrospective analysis of 36 patients undergoing ablative chemotherapy, the probability of 3-year survival and progression-free time were 69% and 38% respectively [Sharma et al. 2010]. Some authors indicate that the use of myeloablative chemotherapy re‐ duces the differences between IgD MM and the classic forms of the disease [Sharma et al. 2010, Maisnar et al. 2008], but this remains a matter for discussion [Morris et al. 2010].

> MM IgM is even less frequent (0.2-0.5% of patients with MM) [Reece et al. 2010, MacLennan 1992, Avet-Loiseau et al. 2003]. Although the presence of IgM monoclonal protein in serum is one of the clinical features common to the disease and Waldenström's macroglobulinemia (WM), the overall clinical picture is different. The differing prognoses and therapeutic rec‐ ommendations make a correct diagnosis all the more important. The clonal proliferation of plasma cells usually observed in bone marrow aspiration, together with other characteristic

clinical features of multiple myeloma such as hypercalcemia, renal failure and osteolytic fo‐ ci, support a diagnosis of IgM MM much more frequently than a diagnosis of WM. These differential diagnostics may not be easy. Cytogenetic tests are helpful in these situations. Re‐ cent study results indicate that the presence of translocation t(11;14) associated with deregu‐ lation of cyclin D1 is specific for MM, but not for WM [Avet-Loiseau et al. 2003]. Another differentiating feature is that 6q deletion istypical of WM [Schop et al. 2006]. Some authors, however, indicate the limited sensitivity of cytogenetic testing in diagnosing MM IgM and therefore seek other differential diagnostic tests [Schuster et al. 2010]. One would be an in‐ creased expression of interleukin-1b (IL-1b). This substance is responsible for the increased production of interleukin 6 (IL-6) reported in patients with MM [Donovan et al. 2002]. The treatment of patients with IgM MM does not differ substantially from the treatment of pa‐ tients with the classic form of MM. Some studies however, indicate a significantly worse prognosis compared with the classic forms, i.e. a much shorter survival time and progres‐ sion-free time in patients with the rare form of MM [Morris et al. 2010]. Mean survival time is 30 months and myeloablative chemotherapy does not alter this prognosis [Reece et al. 2010, Schuster et al. 2010].

forms of the disease [Fonseca et al. 2004, Chang et al. 2009, Colovic et al. 2008]. Plasma cell leukaemia is the most aggressive clinical form of MM. Patients usually manifest extraoss‐ eous infiltrations, often with the involvement of the central nervous system, and accompa‐ nied by *organomegaly* and lymphadenopathy. The aggressiveness of the disease is also demonstrated by the significantly increased activity of serum lactate dehydrogenase, high levels of β2-microglobulin (in 65% of patients > 6 mg/l) and low serum albumin levels.

Rare Manifestations of Multiple Myeloma http://dx.doi.org/10.5772/53385 247

The prognosis remains poor, especially in the secondary form, where it is a consequence of the progression of the disease and increasing *chemoresistance*. Moreover, resistance very quickly develops in patients with primary leukaemia, despite their initial response to treat‐ ment. The average survival time is 8 months for patients with the primary form and 2 months for those with the secondary form [Garcia-Sanz et al. 1999, Tiedemann et al. 2008]. Because of the low incidence of the disease, there are no randomized controlled trials and thus no therapeutic recommendations. Traditional schemes for treatment of MM are usually ineffective. Even though prolongation of survival time was reported in patients after mye‐ loablative chemotherapy assisted by autotransplantation, this treatment was less effective than it was in patients with the classic form of the disease. Allotransplantation is an alterna‐ tive, especially in the primary disease, which often affects younger people. Due to the limit‐ ed number of patients and lack of randomized studies, the effects of this treatment are difficult to assess, but previous reports indicate moderate effectiveness and high mortality

New drugs, such as proteasome inhibitors and immunomodulatory drugs, are promising, although the effectiveness of this treatment remains unsatisfactory. As thalidomide is of lim‐ ited efficacy and seems to have no significant effect on prolonging survival time in patients with plasma cell leukaemia (reported mean survival time is 3 months) [Petrucci et al. 2007], other authors have been presenting more promising data (survival time up to 14 months) [Johnston, Abdalla 2002]. The use of lenalidomide has enabled a response to be obtained in individual patients, as with resistance to other schemes, but this usually lasts 4-5 months [Musto et al. 2008, Benson and Smith 2007]. The results of bortezomib treatment are slightly more promising. This therapy, especially the combination therapy (VDT-PACE), enables a response to be obtained in more than 90% of patients, including those in whom the disease is initially chemoresistant. Mean survival time is 7-12 months [Albarracin, Fonseca 2011, Musto et al. 2007], although survival times of up to 20 months have also been reported [Sher et al. 2010, Ali et al. 2007]. Bortezomib appears to be able to overcome the adverse effects of cytogenetic abnormalities [Katodritou et al. 2009] – as it does with classic MM – and should

therefore be considered a first-line treatment in patients with plasma cell leukaemia.

The syndrome was first described in 1956 and was originally named the Crow–Fucasi syn‐ drome. Since 1980, it has been known by the acronym POEMS, derived from the symptoms polyneuropathy, enlarged internal organs (organomegaly), endocrine disorders, monoclonal

(the mean survival time is 3 months) [Yeh et al. 1999].

**5. POEMS syndrome**

protein and skin changes.

IgE myeloma is very rarely detected. Several cases of this variant have been described [In‐ vernizzi et al. 1991, Hagihara et al. 2010, Chiu et al. 2010]. It manifests itself by the frequent presence of plasma cells in peripheral blood, osteoblastic lesions, hepatosplenomegaly and amyloidosis. The clinical course of this form of MM is usually aggressive and patients have a shorter survival time than those with the classic forms (16 months on average). This may be a result of a delayed diagnosis [Macro et al. 1999].
