IgG Kappa Multiple Myeloma Research Articles

Oral Cavity Avascular Bone Necrosis - a Newly Recognized Complication of Intravenous (IV) Bisphosphonate Therapy in Cancer Patients.

Cancer patients with skeletal complications are frequently treated monthly with intravenous bisphosphonates over an extended period of time. The bisphosphonates have been useful in strengthening the bone, in pain control, and in some cases, decreasing the incidence of further skeletal -related events (SRE's), including the hypercalcemia of malignancy. Although bisphosphonate treatment is remarkably well tolerated, recently, a serious complication has been reported in the dental literature - oral cavity avascular bone necrosis. We report on 2 cases of intraoral osteonecrosis in patients treated for more than 2 years with, initially, pamidronate (Aredia; Novartis) and later zoledronic acid (Zometa; Novartis). Patient JG is a 65 year-old man with a 7-year history of IgG kappa multiple myeloma. The patient was originally treated with vincristine, adriamycin and Decadron (VAD) chemotherapy along with monthly pamidronate infusions followed by high-dose melphalan (HDM) and autologous peripheral stem cell transplantation (PBSCT). At the time of relapse < 1 year after the PBSCT, he was maintained on Thalidomide along with monthly infusions of zoledronic acid at a dose of 4mg. Almost 3 years after starting zoledronic acid therapy, the patient began experiencing severe dental pain. He was repeatedly evaluated by his dentist, treated with antibiotics for recurrent dental abscesses and underwent numerous root-canal procedures. A tooth was extracted, and he was subsequently diagnosed with oral cavity avascular bone necrosis in the molar region. Bisphosphonate infusions were discontinued. He has required repeated courses of antibiotics, root canal, and narcotic pain medications to treat the condition. FC is a 60 year-old woman, also with a 7-year history of IgG kappa multiple myeloma treated initially with VAD along with monthly pamidronate infusions followed by HDM and PBSCT. Additionally, she was subsequently treated for ovarian cancer with 6 ycles of carboplatin and paclitaxel. Following this, she was also treated with thalidomide and zoledronic acid. for 2 years after relapsing 2 years post PBSCT. At the end of this time, she noted a purulent drainage arising from a lesion in the mental region of the jaw. The area was biopsied and revealed only necrotic material. A subsequent CAT scan revealed osteonecrosis of the jaw. She has also required therapy with antibiotics and narcotic pain control. The zoledronic acid has been discontinued. Oral cavity avascular bone necrosis is becoming an increasingly more recognized complication of intravenous bisphosphonate treatment in cancer patients. The etiology is not understood although it has been postulated to be secondary to the antiangiogenic effect of the bisphosphonates on inhibiting osteoclasts. Treatment has included discontinuation of the offending drug, antibiotics, pain control, regional débridement, and bone trimming. Hematologists/oncologists should now be alert to this new complication of intravenous bisphosphonates in cancer patients who complain of dental pain.

Granulocyte Colony Stimulating Factor-Producing Multiple Myeloma Associated with Neutrophilia

We report a case of IgG-kappa multiple myeloma associated with neutrophilia (WBC 31,300/microl, neutrophil 90.5%). Interestingly, the serum level of granulocyte colony stimulating factor (G-CSF) in this patient was elevated to 1,500 pg/ml (normal range: 5.78-27.5). Plasma cells were 35% in the bone marrow and were strongly stained with anti-G-CSF antibody. To directly study the production of G-CSF from plasma cells in this patient, CD138 positive plasma cells were purified from bone marrow of multiple myeloma patients by magnetic sorting. The expression of G-CSF mRNA was observed in CD138 positive plasma cells from this myeloma patient with neutrophilia by RT-PCR. In contrast, the expression of G-CSF mRNA was not detected in CD138 positive plasma cells from the other multiple myeloma patients without neutrophilia and 4 human myeloma cell lines (HS-Sultan, IM9, RPMI8226, U266) by RT-PCR. After the CD138 positive plasma cells were cultured in vitro for 48 h, the production of G-CSF protein was confirmed (71.8 pg/ml) in the supernatant by ELISA. These results indicated plasma cells of this myeloma patient directly produced G-CSF and that this was the primary cause of neutrophilia.

Expression of a free gamma heavy chain in serum following autologous stem cell transplantation for IgG kappa multiple myeloma

A 41-year-old male with IgG kappa multiple myeloma is described. He developed a free gamma heavy chain without an accompanying light chain following high-dose chemotherapy and autologous peripheral blood stem cell transplantation. The free gamma heavy chain was detected in serum and urine specimens 2 months after transplant, and eventually evolved into an IgG kappa monoclonal protein with electrophoretic properties similar to the original myeloma protein. Although the origin of the free gamma heavy chain remains uncertain, it was most likely related to the underlying plasma cell malignancy and, therefore, was an early sign of disease relapse.

Hyperphosphatemia in multiple myeloma

We report three cases of IgG kappa multiple myeloma with pseudohyperphosphatemia. The patients' serum calcium levels were normal, and the hyperphosphatemia was not related to impaired renal function. No hypoparathyroidism was found, and no exogenous phosphate preparation had been given. Since the hyperphosphatemia was of no obvious clinical or physiological significance, as evidenced by normal serum levels of 1,25 dihydroxy vitamin D3, it was diagnosed as spurious and was connected to interference of the paraprotein with the chromogenic assay. In two of the patients major fluctuations in serum phosphate levels were seen, induced by the changes in globulin and paraprotein levels that occurred during therapy and relapse.

Discordant LFA‐1/ICAM‐1 expression in a case of secondary plasma cell leukemia associated with subcutaneous plasmacytoma

We observed a unique case of multiple myeloma that was transformed into plasma cell leukemia presenting with subcutaneous and soft tissue infiltrates. Subcutaneous and minor pelvic soft tissue plasmacytomas and the leukemic transformation were diagnosed in a 72-year-old woman after she had completed 9 months of chemotherapy for IgG kappa multiple myeloma. Immunophenotypic study revealed that leukemic cells in her peripheral blood were positive for ICAM-1 (CD54) but negative for LFA-1 alpha (CD11a) and LFA-1 beta (CD18), whereas infiltrating leukemic cells in the subcutaneous plasmacytoma of the left thigh were positive for LFA-1 alpha and LFA-1 beta but negative for ICAM-1. In addition, intermingling capillary endothelial cells were positive for ICAM-1. Extramedullary soft tissue plasmacytoma is uncommon in association with plasma cell tumors, and the exact mechanism of the development of plasmacytoma is not known. In the present case, however, the discordant expression of LFA-1/ICAM-1 adhesion molecules may have accounted for the distinct patterns of growth and the spread of the subcutaneous plasmacytoma through homing of the LFA-1 alpha+, LFA-1 beta+ leukemic cells to ICAM-1+ endothelial cells.

Cryocrystalglobulinemia: pH-dependent precipitation of a monoclonal IgG-kappa-immunoglobulin

Cryoglobulinemia is seen in a minority of patients with plasma cell dyscrasias and can be of clinical relevance if intravascular gelling or precipitate formation occurs at low temperatures. We observed a patient suffering from IgG-kappa multiple myeloma which was complicated by instability of the immunoglobulin forming crystalline precipitates at low pH and low temperature. Short exposure to extreme cooling initiated an unusual course terminating in disseminated vascular occlusion and fatal outcome which was connected with an adverse effect of blood exchange. Crystal formation was noticed in anticoagulated blood samples even at 37 degrees C. In vitro studies showed a critical pH dependency of solubility of the immunoglobulin close to the physiological pH of the blood. These observations suggest that the fatal outcome was due to a vicious circle of ischemia, metabolic acidosis and intravascular precipitations, initiated not only by low acral temperatures but by cold-induced ischemic tissue acidosis as well. Serum of patients with monoclonal gammopathy and cryoglobulinemia should be tested for pH dependent immunoglobulin insolubility.

Establishment of two new myeloma cell lines from bilateral pleural effusions: evidence for sequential in vivo clonal change

Two new human myeloma cell lines have been established from a 36-year- old woman with refractory IgG kappa multiple myeloma in whom bilateral malignant pleural effusions developed. The malignant plasma cells from each effusion were set up in a liquid culture using an L-15 medium containing catalase, glutathione, selenous acid, ascorbic acid, insulin, transferrin, additional glutamine hydrocortisone, and 2- mercaptoethanol and designated as M-3 medium. Two IgG kappa cell lines, LB -831 and LB-832, were established and proved to be Epstein-Barr virus negative using the internal repeat sequence DNA probe. Characteristic plasma cell morphology was evident by light and electron microscopy. Immunotyping revealed an IgG kappa , B1+, B2-, Ia (HLA- DR)+, CALLA+ phenotype for each cell line as well as for the original pleural fluid and bone marrow myeloma cells. The supernatants also contained IgG kappa, beta 2 microglobulin, and large amounts of osteoclast-activating factor (indicating bone-resorbing activity). Cytogenetic analysis of the LB-831 cell line revealed a nearly triploid highly abnormal karyotype with numerous clonal chromosomal abnormalities involving chromosomes 1, 3, 5, 7, 13, and 15; several structurally abnormal marker chromosomes; and a putative homogeneously staining region on chromosome 7p at band p22. Analysis of the LB-832 cell line revealed several additional clonal abnormalities. These additional cytogenetic changes suggest that in vivo sequential clonal evolution occurred in this patient. Therefore, two new but related cell lines have been established, which should prove useful for further biological studies.

Karyotypic evolution in multiple myeloma

A patient with IgG kappa multiple myeloma was studied cytogenetically prior to therapy and was found to have a clone of 55,XX cells. After treatment leading to a clinical response, the patient relapsed with a clone of 57,XX cells, which were derivatives of the original neoplastic cell line. This is the first case of demonstrated clonal evolution of myeloma in a patient studied prior to chemotherapy.