**6. Rare paraneoplastic syndromes accompanying myeloma**

Sweet's syndrome is one of the paraneoplastic syndromes that may accompany MM. This is a group of symptoms including granolocytosis, fever and painful erythematous skin changes caused by skin *granulocytic* infiltrations that subside following treatment with corti‐ costeroids [Paydas et al. 1993]. These changes are also found in the mouth, the joints and the internal organs. Sweet's syndrome is extremely rare (0.25% of patients with MM) and is most likely caused by an increased sensitivity to the growth factor. This can be explained by an increased production of interleukin 6 (IL-6) [Bayer-Garner, Cottler-Fox, Smoller 2003].

Bullous epidermal separation (epidermolisis bullosa) may also coexist with MM. This is as‐ sociated with the production of IgG antibodies against the *non-collagenous* domain of type VII collagen. This leads to the formation of subepidermal bubbles and secondary ulcers [Radfar 2006]. Pemphigus has a similar clinical picture. This is a rare complication observed in MM patients and is usually associated with IgA MM. This disease develops extremely rarely and is sometimes also associated with gammopathy of undetermined significance. It has been suggested that treatment should include bortezomib [Adam et al. 2010]. There are many skin symptoms associated with monoclonal gammopathy: leukocytoclastic vasculitis, pyoderma gangrenosum and Schnitzler syndrome. These, however, are rare and discussing them is beyond the scope of this chapter [Harati et al. 2005].

## **7. Family myeloma**

which melphalan was mainly used in combination with prednisone (the treatment duration was 12-24 months), indicate that a response to the treatment was obtained in 40% of patients [Dispenzieri et al. 2003]. Cyclophosphamide allows for remission of the disease in a limited number of patients. This treatment may be used in young patients who are candidates for

The results of high-dose chemotherapy-assisted auto-SCT are promising [Sanada et al. 2006], as a response is obtained in over 90% of patients (Table 4). Transplant related mortality is determined to be approximately 7%. This is higher than in MM patients treated with auto-SCT and lower than in AL patients treated with auto-SCT [Gertz et al. 2002]. High dose che‐ motherapy assisted auto-SCT reduces the symptoms of polyneuropathy. When combined with radiotherapy, this reduction can last months or even years [Ganti et al. 2005]. The clini‐ cal response to the treatment correlates more closely to the VEGF concentration than to the monoclonal protein level [Nakano et al. 2001]. A *complete* haematological remission is not re‐ quired to obtain a clinical improvement. The effectiveness of the most common ways of

> Nakanishi et al. 1984 Orefice et al. 1994

Reitan et al. 1980

Iwashita et al. 1977 Reitan et al. 1980

Ganti et al. 2005 Jaccard et al. 2002

treating patients with POEMS syndrome is shown in Table 4.

**Treatment Response to the treatment References**

Corticosteroids ≥15% Dispenzieri et al. 2003

Treatment with alkylating drugs ≥40% Dispenzieri et al. 2003

Radiation therapy ≥50% Dispenzieri et al. 2003

Auto-SCT ≥90% Sanada et al. 2006

**Table 4.** The effectiveness of the most commonly used treatments in patients with POEMS syndrome.

Auto-SCT (*auto-stem cells transplantation*) – autologous transplantation of the stem cells obtained from peripheral

Apart from the methods of treating POEMS syndrome mentioned above, there are few re‐ ports on the effectiveness of therapy combined with bevacizumab and thalidomide in pa‐ tients diagnosed with a relapse of POEMS syndrome after auto-SCT. The combination of cyclophosphamide, dexamethasone and bevacizumab is another example of a modern com‐ bination therapy, described by Samaras et al., to treat POEMS syndrome relapse after auto-PBSCT [Badros et al. 2005, Straume et al. 2006]. There are also case reports describing the treatment of patients with POEMS syndrome using lenalidomide [Dispenzieri et al. 2007]. Recently, Szturz et al. [2012] reported on the successful application of lenalidomide in Cas‐

auto-SCT.

250 Multiple Myeloma - A Quick Reflection on the Fast Progress

blood.

The cause of MM remains unknown [Lynch et al. 2008, Alexander et al. 2007, Morgan, Da‐ vies, Lineta 2002]. It seems that the hereditary cause is negligible, although family cases of this cancer have been observed. It has also been described in connection with gammopathy of undetermined significance [Lynch et al. 2008]. Large population studies also indicate that MM, prostate cancer and malignant melanoma run in families, as do central nervous system neoplasms, although the results of some studies do not confirm this [Eriksson, Hallberg 1992, Camp, Werner, Cannon-Albright, 2008]. The risk of familial MM is small. It is estimat‐ ed that the probability of first-degree relatives developing MM is 3.2 per 1000 cases and women are usually affected. Autosomal inheritance with low gene *penetrance* is believed to be responsible for the onset of the disease. The risk of familial gammopathy of undeter‐ mined significance is slightly higher, although still small. Had there been at least two cases of MM in first or second-degree relatives, an annual immunoelectrophoresis of the urine and serum protein in people 40 years and over would be recommended. If MM had occur‐ red in anyone under 40 years old, the test would be recommended to relatives 35 years and over [Gerkes et al. 2007].

[8] Badros A., Porter N., Zimrin A. *Bevacizumab therapy for POEMS syndrome*. Blood 2005;

Rare Manifestations of Multiple Myeloma http://dx.doi.org/10.5772/53385 253

[9] Bayer-Garner I.B., Cottler-Fox M., Smoller B.R. *Sweet syndrome in multiple myeloma: a*

[10] Benson D.M. Jr., Smith M.K. *Effectiveness of lenalidomide (Revlimid) for the treatment of*

[11] Blade J., Kyle R.A. *Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell*

[12] Blade J., Lust J.A., Kyle R.A. *Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases.* J Clin Oncol 1994; 12: 2398–1404.

[13] Bryce A.H., Ketterling R.P., Gertz M.A. et al. *Cytogenetic analysis using multiple myelo‐ ma targets in POEMS syndrome. Proceedings of American Society of Oncology Meeting*.

[14] Camp N.J., Werner T.L., Cannon-Albright L.A. *Familial myeloma.* N Engl J Med 2008;

[15] Chang H. et al. Genetic aberrations including chromosome 1 abnormalities and clini‐

[16] Chiu W. et al. IgE-type multiple myeloma with the late development of IgA2 kappa

[17] Colovic M. et al. Thirty patients with primary plasma cell leukemia: a single center

[18] Coto V., Auletta M., Oliviero U. et al. *POEMS syndrome: an Italian case with diagnostic*

[19] Dispenzieri A., Kyle R.A., Lacy M.Q. et al. *POEMS syndrome: definitions and long-term*

[20] Dispenzieri A., Klein C.J., Mauermann M.L. *Lenalidomide therapy in a patient with PO‐*

[21] Donovan K.A. et al. IL-1beta expression in IgM monoclonal gammopathy and its re‐

[22] Durie B.G. et al. International uniform response criteria for multiple myeloma. Leu‐

[23] Endo I., Mitsui T., Nishino M. et al. *Diurnal fluctuation of edema synchronized with plas‐ ma VEGF concentration in a patient with POEMS syndrome*. Intern Med 2002; 41: 1196–

[24] Eriksson M., Hallberg B. *Familial occurrence of hematologic malignancies and other diseas‐ es in multiple myeloma: a case-control study.* Cancer Causes Control 1992; 3: 63–67.

*series of six cases.* J Cutan Pathol 2003; 30: 261–264.

*plasma cell leukemia.* Leuk Lymphoma 2007; 48: 1423–1425.

*leukemia.* Hematol Oncol Clin North Am 1999; 13: 1259–1272.

cal features of plasma cell leukemia. Leuk Res 2009; 33: 259–262.

*and therapeutic implications*. Ann Ital Med Interna 1991; 6: 416–419.

lationship to multiple myeloma. Leukemia 2002; 16: 382–385.

and plasma cell leukaemia. Pathology 2010; 42: 82–84.

experience. Med Oncol 2008; 25: 154–160.

*outcome*. Blood 2003; 101: 2496–2506.

kemia 2006; 20: 1467–1473.

1198.

*EMS syndrome*. Blood 2007; 110: 1075–1076.

106: 1135.

Chicago 2007.

359: 1734–1735; author reply 1735.

The described forms of MM are extremely rare. They are an important diagnostic problem because of their atypical clinical manifestation. The course of the disease is usually aggres‐ sive and the prognosis is serious. It is therefore essential that it be quickly and accurately diagnosed. The lack of prospective studies of large groups of patients is an additional prob‐ lem. This makes these atypical clinical forms a therapeutic as well as a diagnostic challenge.
