Nonsecretory multiple myeloma.

ABSTRACT: Nonsecretory multiple myeloma (NSMM) is a rare variant of the classic form of multiple myeloma (MM) and accounts for 1% to 5% of all cases of MM. The clinical presentation and radiographic findings of NSMM and MM are the same. The diagnosis of MM requires the detection of a monoclonal gammopathy in the serum or urine. In NSMM, however, no such gammopathy can be demonstrated, making the diagnosis more difficult. We describe a 43-year-old African American woman who initially had back pain and pathologic vertebral compression fractures that were thought to be due to osteoporosis. Five months later, hypercalcemia developed and NSMM was diagnosed. No monoclonal gammopathy was found in the serum or urine, but skeletal survey showed diffuse osteolytic lesions, and bone marrow biopsy revealed marked plasmacytosis. The immunohistochemical techniques and chromosomal analysis methods that are currently available are discussed.

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MULTIPLE MYELOMA (MM) is a neoplasm of B cell lineage characterized by excessive proliferation of abnormal plasma cells. These malignant plasma cells secrete an abnormal immunoglobulin causing a monoclonal gammopathy that can be identified in the serum and/or urine by electrophoresis. Patients with MM can present with anemia, hypercalcemia, lytic lesions in bone, and renal failure. If a monoclonal spike is not found but the patient has clinical and radio-logic findings similar to those found in MM, then that patient may have a rare variant of myeloma known as the nonsecretory type. In nonsecretory multiple myeloma (NSMM), the plasma cells presumably fail to secrete an immunoglobulin. The first case of this variant was described in 1958, and the reported incidence has ranged from 1% to 5% of all cases of MM. (1) We present a case of delayed diagnosis of NSMM because of its illusive nature.

CASE REPORT

A 43-year-old African American woman was admitted to the hospital with a 2-week history of nausea and vomiting. Five months earlier, she had gone to her primary care physician because of back pain and was found to have multiple thoracic and lumbar vertebral fractures that were thought to be due to osteoporosis. A DEXA scan had revealed osteopenia, more than 1.5 standard deviations below the mean, and the patient was treated with alendronate, vitamin D, calcium supplements, and ibuprofen pm. When the nausea and vomiting began 2 weeks before admission, alendronate and ibuprofen were discontinued, and she was given cimetidine, without improvement. Her medical history included iron deficiency anemia, for which she was taking iron supplementation. She had no history of alcohol, tobacco, or drug use. Her mother had died of multiple myeloma 1 year earlier at age 69.

On physical examination, temperature was 36.9[degrees] (98.4[degrees]F), blood pressure 122/71 mm Hg, pulse rate 117/mm, and respiratory rate 16/mm. The patient was in no apparent distress. Examination of the head, neck, breasts, heart, lungs, abdomen, and extremities was unremarkable except for an obese abdomen, but there was no evidence of hepatosplenomegaly. The cranial nerves were intact, and the patient denied thoracic or lumbar spinal tenderness. No neurologic deficit was found.

Laboratory values were blood urea nitrogen (BUN) 35 mg/dL, creatinine 4.8 mg/dL, hematocrit 29.6%, mean corpuscular volume 84 [micro]m(3) calcium 13.1 mg/dL, total protein 6.6 g/dL, albumin 3.7 g/dL, and phosphate 1.8 mg/dL. Peripheral blood smear showed no evidence of rouleaux. Chest x-ray film showed no abnormalities. Laboratory workup 1 month before admission had shown a BUN value of 13 mg/dL, creatinine value 0.6 mg/dL, hematocrit value 30.6%, and calcium level 10.8 mg/dL.

The patient was admitted to the medical service for treatment of multiple medical problems, in particular hypercalcemia and acute renal failure causing nausea and vomiting. Aggressive hydration was initially started, without significant change in the calcium level. Calcitonin was then given but led to worsening nausea. After a dose of intravenous pamidronate, the hypercalcemia gradually resolved. Evaluation of the acute renal failure revealed a bland urine sediment with a fractional excretion of sodium of less than one. The renal failure may have been prerenal due to the hypercalcemia as well as dehydration induced by the vomiting. Skeletal survey showed diffuse osteolytic lesions and several spinal compression fractures. [[beta].sub.2]-Microglobulin was elevated at 4,600 [micro]g/L (normal, 600 to 2,000 [micro]g/L). Serum and urine protein electrophoresis were both negative for monoclonal gammopathy. Immunofixation of the serum and urine using monoclonal antisera against IgG, IgA, IgM, K, and [lambda] was al so negative. Quantitative immunoglobulin studies revealed hypogammaglobulinemia with a serum IgG value of 456 mg/dL (normal, 700 to 1,700 mg/dL), IgA of 15 mg/dL (normal, 70 to 350 mg/dL), and 1gM of 19 mg/dL (normal, 50 to 300 mg/dL). Bone marrow biopsy showed marked plasmacytosis with 50% to 70% infiltration and osteoclastic invasion of bone. Immunoperoxidase staining of the bone marrow aspirate was positive for intracytoplasmic K light chain consistent with NSMM. Chromosomal analysis of the bone marrow aspirate revealed a loss of one X chromosome. Chemotherapy with vincristine/adriamycin/dexamethasone (VAD) was initiated. The patient tolerated chemotherapy well. The calcium level decreased to 7.8 mg/dL, and the acute renal failure improved with BUN and creatinine levels of 7 and 1.4 mg/dL, respectively, by the time of discharge.

Several months after diagnois, the patient had pneumonia that was treated due with antibiotics and was followed by an infection due to Clostridium difficile, confirming the susceptibility of these patients to infection. She received a total of 6 cycles of VAD. After the first 3 cycles, repeated bone marrow biopsy showed a decrease in plasmacytosis to 10% to 20%. However, after an additional 3 cycles of VAD, the bone marrow still showed about 20% to 30% plasma cell infiltration. The effect of the chemotherapy having reached a plateau, the patient had peripheral blood stem cell harvest followed by high-dose chemotherapy with melphalal (200 mg/[m.sup.2]) and an autologous peripheral blood stein cell transplant. Approximately 3 months after transplantation, the patient was in complete remission. The previously documented hypogammaglobulinemia, anemia, anti renal failure have subsided. The calcium level remained normal, and the [[beta].sub.2]-microglobulin decreased to near normal at 2,600 [micro]g/L. The follow- up bone marrow aspirate and biopsy revealed no evidence of plasmacytosis, and chromosomal analysis showed persistent deletion of an X chromosome, without new chromosomal aberrations.

DISCUSSION

Nonsecretory multiple myeloma is a variant of the classic form of MM and has a similar clinical presentation except for the absence of monoclonal gammopathy. Two types of NSMM have been described. In the first type, the plasma cells produce immunoglobulin but are not able to secrete it out of the cell. This form of NSMM the "producer" type (also called true nonsecretory or nonexcretory myeloma). In the "nonproducer" type, the plasma cells are unable to produce immunoglobulin. Although it is difficult to determine the exact frequency of the two types, more cases of the producer type have been reported. (24)

Several hypotheses have been proposed regarding the pathogenesis of NSMM. The nonproducer type may result from problems with the assembly process of proteins and thereby lead to difficulty with immunoglobulin heavy and light chain synthesis. In the producer type, the protein synthesis mechanism may be functioning, but rapid degradation of the immunoglobulin may follow. There may also be a problem with the secretory process itself--whether through a defective transport of immunoglobulin to the cell membrane or through reduced permeability of the membrane to the immunoglobulin. (4-6) No recent insights have been reported regarding the validity of these hypotheses since the original publications in the 1970s and 1980s.

As more information accumulates regarding the etiology of MM, a better understanding of the pathogenesis of NSMM may be reached. Recent reports have described the role of genotypic, phenotypic, and environmental changes involved in the pathogenesis of MM. The genotypic changes occur at the stage of somatic hypermutation and class switching during plasma cell development. Normally, during class switching, small portions of DNA on the immunoglobulin gene rearrange to change from one class, such as IgM, to another class, such as IgG. However, in MM the switch region binds to a portion of the DNA not involved with the immunoglobulin gene. If this nonimmunoglobulin DNA codes for an oncogene, then an abnormal immunoglobulin is produced with neoplastic characteristics. (7) Similar genetic abnormalities may be involved in the development of NSMM where binding of switch DNA to a nonimmunoglobulin part of the DNA may lead to the formation of abnormal nonimmunoglobulins that have lost the ability to be secreted from the plasma cell. Characteristic phenotypic changes may also eventually be linked to NSMM. Early in the maturation process, normal B-lymphocytes express markers such as CD10, 19, 20, 21, 22, 34, and 38. As they continue to mature, they lose expression of many of these markers and gain expression of CD23 and PCA-1. Early plasma cells express CD10, CD23, and PCA-1 that are lost by the time of terminal plasma cell differentiation. In MM, however, plasma cells continue to express CD1O, CD19, and PCA-1, distinguishing them their normal counterparts. It remains to be determined whether NSMM plasma cells have distinct phenotypic characteristics or not. (8,9) Interactions between the malignant plasma cells and the surrounding stromal cells of the bone marrow have been described in MM leading to an increase in IL-6 secretion that causes both an increase in tumor growth and a decrease in apoptosis. Whether similar interactions occur in NSMM remains unknown. (7)

Nonsecretary MM has been associated with a variety of clinical features. The most common presenting complaint consists of bone pain. Some reports have shown a delay in diagnosis of 1 to 12 months, perhaps due to the lack of physical findings. Laboratory data may show a normochromic, normocytic anemia with a slight leukocytosis, or a moderate decrease in platelets. Patients occasionally show signs of renal failure due to dehydration and hypercalcemia. [[beta].sub.2]-Microglobulin has been used as a prognostic indicator, since high levels tend to be seen in patients with relapse of the disease or high tumor burden. Skeletal radiographic survey always reveals lytic lesions with possible fractures or osteoporosis. Hypogammaglobulinemia has frequently been described and may be a sign of defective immunoglobulin production. Bone marrow infiltration with plasma cells is usually between 20% and 75% (6,10)

Several techniques have been used over the past 60 years to detect and identify a monoclonal gammopathy. The first "M-spike" was identified in 1939 by serum electrophoresis. Immunoelectrophoresis was introduced in 1953, and the first case of NSMM was reported in 1958. (1,11) Currently, immunoelectrophoresis of a peripheral blood sample has been replaced by the more sensitive method of immunofixation, which gives clearer results to interpret. Immunofixation produces bands instead of more subjective arcs to identify the monoclonal gammopathy. (12,13) Immunoperoxidase staining of a bone marrow aspirate sample is more sensitive than immunofluorescence and may be easier to use, since special microscopy is not needed, the stains are permanent, and fresh tissue is not necessary for evaluation (as opposed to tissue treated with formalin for preservation). (14)

Another diagnostic tool that is becoming increasingly useful is cytogenetic evaluation. No particular chromosomal anomaly has been associated with NSMM. With the classic form of MM, numerous structural and numeric changes have been reported. The most common abnormality is the translocation t(11;14) (q13;32). (19) Trisomies or tetrasomies of chromosomes 9, 3, 19, 15, 11, 7, 5, 18, and 21 have been reported in decreasing frequency as well as loss of chromosomes 13, X (in females), 14, 8, and 4 resulting in monosomies or nullosomies. (20) The presence of an 11q13 translocation has recently been found to carry an unfavorable prognosis. The clinical significance of the loss of an X chromosome, as documented in our patient, is yet to be determined. Although karyotyping identifies abnormal chromosomes in 20% to 60% of patients with MM, flow cytometry and fluorescence in situ hybridization (FISH) have recently been able to detect abnormal chromosomes in 80% to 90% of patients with MM. (20,21) Since malignant plasma cells divide slowly, metaphase FISH is not as accurate as interphase FISH, which better identifies the slowly proliferating cells of MM. (22)

At initial presentation, patients with NSMM usually have more advanced disease than those with classic myeloma. Although survival ranges from 6 months to 12 years, (6) it may certainly be affected by a delay in diagnosis. Most published reports suggest that there is no significant difference in survival between NSMM and MM. (2,5,10) Conventional treatment of the two forms of myeloma is the same and may include chemoradiotherapy, steroids, and interferon alfa. In some cases, high-dose chemoradiotherapy and hematopoietic stem cell transplantation have been used with improvement in progression-free survival in a highly selective group of patients with MM. Whether this treatment approach will be as effective in NSMM remains unknown. No data are currently available regarding the role of thalidomide in NSMM, though its use may be appropriate when conventional therapy fails.

CONCLUSION

The diagnosis of NSMM should be considered in patients with signs and symptoms similar to those of MM but no evidence of monoclonal gammopathy by serum or urine protein electrophoresis. Further workup, including bone marrow aspiration and biopsy for immunoperoxidase staining, is necessary to arrive at the diagnosis. Currently, both MM and NSMM are treated in a similar fashion, and their long-term outcomes seem to be identical. Further studies are needed to identify the etiology and pathogenesis of these disorders and to develop effective targeted therapy.

References

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(5.) Turesson I, Grubb A: Non-secretory or low-secretory myeloma with intracellular kappa chains. Acta Med Scand 1978; 204:445-451

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RELATED ARTICLE: KEY POINTS

* Nonsecretory multiple myeloma (NSMM) is a rare variant of the classic multiple myeloma (MM).

* The diagnosis of NSMM should be considered in patients with signs and symptoms similar to those of MM but who have no evidence of monoclonal gammopathy by serum or urine electrophoresis.

* Bone marrow aspirate and biopsy are necessary to arrive at the diagnosis of NSMM.

* Treatment and long-term outcomes of MM and NSMM appear identical.

From the Bone Marrow Transplant Program, George Washington University Medical Center, Washington, DC.

Reprint requests to Iman Abdalla, MD, George Washington University Medical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.