1 Giorgos Ntetskas2, Nikolaos Karvouniaris2, Stylianos Karatapanis3 Nonsecretory Multiple Myeloma With Hypercalcemic Acute Renal Failure And Lytic Bone LesionsEmmanouil Spanou1, Foteini Lamprianou2, Christos Paliouras2, Konstantinos Roufas2,Giorgos Ntetskas2, Nikolaos Karvouniaris2, Stylianos Karatapanis31Hematology Department, 2Nephrology Department, 31st Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece
2 Introduction: Non secretory multiple myeloma (NSMM) is a rare subtype of multiple myeloma (MM), characterized by absence of monoclonal immunoglobulin (M protein or M component) in the plasma and urine. 1, 2 The lack of M protein in serum and urine may be due to reduced protein synthesis, increased breakdown of abnormal immunoglobulin chains or due to alternation of intracellular transport of the light chains with resulting intermittent excretion of immunoglobulin that evades detection. [2-5] Given the absence of monoclonal light chains in the urine, renal involvement is quite unusual.  Hypercalcemia is also a rare manifestation of NSMM despite the high incidence of osteolytic lesions.  We present a case of NSMM manifesting with hypercalcemic acute renal failure and lytic bone lesions. Case Report: A 42-year-old male patient was admitted to our Hospital due to intense bone pain. Radiography and total body CT scanning revealed multiple osteolytic lesions. Laboratory investigations showed hypocromic microcytic anemia (Hct 30.9%, Hgb 10.1g/dL, MCV 63fL, MCH 20.8pg), acute renal failure (urea 64mg/dL, creatinine 1.55mg/dL) and hypercalcemia (calcium 10.9mg/dL). Serum and urine protein electrophoresis was normal. Bone marrow biopsy revealed infiltration of monoclonal cIgλ+ plasma cells (20%), CD138 and CD56 positive, compatible with early stage of Batl-Frisch classification of plasma cell myeloma. During his hospitalization hypercalcemia and renal function deteriorated (urea 96mg/dL, creatinine 2.69mg/dL, calcium 13.3mg/dL). The patient received a two-round treatment with bortezomib, dexamethasone and cyclophosphamide and he was discharged at the 32nd day of hospitalization with normal renal function and serum calcium levels.
3 Contrarily to MM, in NSMM lytic bone lesions are not accompanied by hypercalcemia. In multiple myeloma as well as NSMM hypercalciemia is to attribute in increased bone resorption as a result of activation of the osteoclast by potent cytokines secreted by the myeloma cells. Discussion: Non secretory myeloma was first described in 1958 by Serre et al as a rare variant of MM with incidence ranging from 1 to 5% of all MM cases. [1, 2]NSMM has been classified in two types, based on the finding of intracytoplasmic immunoglobulin: the “non producer” type, also called “true NSMM” where plasma cells do not produce immunoglobulin, and the “producer” type where immunoglobulin can be found in the plasma cells but not in the serum. [4, 7, 8]Given that MM patients commonly present renal involvement due to secretion of light chains in the urine, kidneys show a reduced capacity to clear excess calcium load, contributing in the elevated serum calcium levels. In case of NSMM, renal function is usually preserved and renal tubular calcium reabsorption and excretion are efficient in maintaining a normal serum calcium concentration. Interestingly our patient showed impaired renal function and hypercalcemia, two clinical features not common in NSMM. It is possible that the underlying pathophysiologic mechanism of hypercalcemia in NSMM is similar to MM. Renal failure could be explained by dehydration and hypercalcemia. Of all NS MM patients, 15% belong to the “non producer” type while the remaining 85% corresponds to the “producer” type. Clinical manifestations may vary, and usually are more intense at the time of diagnosis compared to classic MM, probably because NSMM’s diagnosis is often delayed. Most patients present intense bone pain due to lytic lesions with possible fractures. 
4 Laboratory data usually show normocromic, normocytic anemia and moderate increase in platelets. Our patient presented hypocronic microcytic anemia while platelet count was normal. Hypogammaglobulinemia is also common and indicated defective immunoglobulin production. Serum protein electrophoresis of our patient revealed gamma globulins in the lower normal limit (11%). (Figure 1) Diagnosis can be determined by bone marrow biopsy and cytogenetic evaluation. Bone marrow infiltration ranges between 20 and 75% while no specific chromosomal changes have been associated to NSMM. [3, 12] In this case, bone marrow biopsy revealed a 20% infiltration of CD138 and CD56 positive plasma cells and no chromosomal changes were detected. (Figure 2) Treatment of NSMM is identical to classic MM and includes chemiotherapy, steroids and immunomodulators, obtaining survival rates similar to MM.  Our patient received a two-round treatment with bortezomib sc (2mg/4 days), dexamethasone iv (40mg/4 days) and cyclophosphamide iv (1400mg/15 days) and was discharged on day 32 with normal serum calcium levels and normal renal function. Conclusion: Nonsecretory myeloma should be taken in consideration for differential diagnosis in patients with osteolytic lesions, hypercalciemia and acute renal failure. Diagnosis requires bone marrow aspirate and biopsy. Treatment should include bortezomib and cyclophosphamide.
5 Figure 1. Serum Protein Electrophoresis Fractions % Ref% Albumin 56.7 Alpha 1Beta 1GammaalbuminAlpha 2Beta 2Figure 2 . Genetic evaluation. No chromosomal alternations were detected.Figure 1. Serum Protein ElectrophoresisFractions%Ref%Albumin56.7Alpha 17.1Beta 112.1Beta 27.2Gamma11
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