Complication Of Multiple Myeloma Research Articles

Intracranial plasmacytoma as an initial presentation of multiple myeloma

Abstract Intra-cranial involvement is an uncommon complication of multiple myeloma. We report a 68-year-old woman hospitalized for acute renal failure, vertigo and headache. Magnetic Resonance Imaging (MRI) revealed two and a half and 3cm length cranial lesion, which proved to be plasmacytoma. After complete staging, we retained the diagnosis of immunoglobulin G lambda-type multiple myeloma with intracranial involvement. Cytogenetic analysis of plasma cells detected no change. Currently, she is a regular hemodialysis patient. She is planned to have both systemic therapy with 40mg dexamethasone and cranial radiotherapy. Involvement of the CNS in multiple myeloma is very rare. Diagnosis of multiple myeloma subsequent to initial intrcranial involvement is confined to exceptional cases. Despite aggressive systemic treatments, including autologous stem cell transplantation and local treatments such as cerebral radiotherapy, the prognosis for patients with CNS myeloma is extremely poor. Our unique case implies that physicians should be alert in case of vertigo or headache in cases with acute renal failure.

Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI).

8135 Background: Treatment-induced peripheral neuropathy (TIPN) is a common, frequently debilitating, therapy-limiting complication in multiple myeloma (MM). Chemotherapies associated with TIPN in MM include thalidomide and bortezomib (BTZ). CFZ, a novel, highly selective PI, is structurally and mechanistically distinct from BTZ. In Ph I-II trials single-agent CFZ is active without dose-limiting PN in pts with relapsed and/or refractory (R/R) MM. Here we compare CFZ and BTZ in a neurotoxicity model and report clinical experience with CFZ in R/R MM. Methods: An in vitro neurotoxicity model established with differentiated SH-SY5Y neuroblastoma cells was used to investigate PI effects on neurite degeneration. A possible mechanism was pursued by bioinformatic and biochemical methods. Data were pooled from 2, ongoing Ph II trials of single-agent CFZ in pts with R/R MM, including neuropathy history, baseline neuropathic symptoms and neurological exam findings, prospective neurological exams, and FACT-GOG/NTx pt survey scores. PN adverse event data were also included. Results: Following 24 hrs of exposure to 10 nM BTZ, SH-SY5Y cells showed 40% reduction in neurite length/cell compared to CFZ- or vehicle-treated cells. Both agents induced equivalent proteasomal inhibition suggesting off-target effects induce neurodegeneration. HtrA2/Omi, a mitochondrial serine protease with a role in neuron survival was identified in databases and confirmed as a target of BTZ (IC50 = 3 nM), but not of CFZ (>10 μ M). At screening, 72% of 135 pts had active Grade (G) 1/2 PN; 81% had a history of TIPN. Pts received a mean of 30.4 CFZ doses (range 2–72) and 17% received >10 mo of therapy. New onset PN or PN worsening from baseline was reported in 16% of pts. There were no reports of G4 PN, missed doses, or treatment discontinuations. Only 1 pt was dose-reduced due to PN. Conclusions: In contrast to BTZ TIPN, CFZ-related PN is uncommon and not dose-limiting. In vitro, BTZ induces neurotoxicity in a proteasome-independent manner and potently inhibits a neuronal cell survival factor, HtrA2. These in vitro and clinical data suggest that severe PN is not a PI class effect. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Bristol-Myers Squibb, Celgene, Facet, Millennium, Novartis, Onyx Onyx Celgene, Johnson & Johnson, Merck, Millennium, Onyx, Ortho, Takeda Bristol-Myers Squibb, Celgene, Facet, Gloucester Pharmaceuticals, Millennium, Novartis, Onyx

PO-48 The influence of paraprotein on bleeding complications in multiple myeloma

PO-48 The influence of paraprotein on bleeding complications in multiple myeloma

Erminio Costa, M.D. (1924–2009)

| | || Erminio (Mimo) Costa, one of the co-founding members of the CINP, died on Saturday, 28 November 2009 from complications of multiple myeloma. Dr Costa is survived by his wife Ingeborg Hanbauer and sons Michael and Max. His son Robert passed away on 1 September 2006. In 1970, when Dr Alessandro Guidotti (Sandro) joined Dr Costa's laboratory at NIMH as a visiting scientist, his intent was to spend 2 years as a research trainee but he found Mimo's take on the various fields of neuroscience so exciting and rewarding, he became his close colleague for the next 40 years. Sandro was one of many who could not fail to be positively affected by Dr Costa's passion for science, by his rigorous approach to the analyses of experimental results, and by the long working hours he spent with each of his pupils in formulating hypotheses, in designing appropriate experiments and in discussing the development of state-of-the-art technologies to implement these studies. Mimo always encouraged and fostered discussion, exchange of ideas, a multidisciplinary approach and top-level scientific interactions … (Email: dgrayson{at}psych.uic.edu) (Email: AGuidotti{at}psych.uic.edu)

Osteomimicry how tumor cells try to deceive the bone

Bone metastases are complications of multiple myeloma and solid tumors, including breast and prostate carcinomas. Several reports have demonstrated that the preference to metastasize to bone by tumor cells is not a casual but an addressed event, which relies on specific interactions among tumor cells, bone marrow microenvironment and bone cells. One of the features that gives tumor cells more chances to survive and proliferate into the bone tissue is osteomimicry, that is the ability to acquire a bone cell phenotype, especially osteoblast-like. As clearly demonstrated, prostate and breast cancer cells try to resemble osteoblasts by expressing bone matrix proteins, the specific marker alkaline phosphatase, and molecules regulating the osteoblast/osteoclast cross-talk. Based on this evidence it is crucial to dissect in more detail the molecular mechanisms underlying the osteomimetic properties of cancer cells and identify new therapeutic targets eventually leading to a better and prolonged life expectation for patients with bone.

“Osteonecrosis of the Jaw: Experience of a Single center”.

Abstract 4935 BackgroundBisphosphonates have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma with a significant improvement of the quality of life. Although these agents are usually well tolerated, osteonecrosis of the jaw (ONJ) has been recently associated with the use of bisphophonates. Nevertheless, the true incidence of this complication is not clearly defined. Therefore, we studied the incidence, characteristics and risk factors for the development of ONJ among patients with multiple myeloma treated with biphosphonates in our institution. Patients and methodsFive-hundred and sixteen patients who received biphosphonates (zoledronic acid, pamidronate, bondronate) and had a minimum exposure of 6 months to the drug were included in this analysis. These patients were asked reterospectivly to fill out a form containing several queries, including sex and age, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2007 to 2009. From this retrospective review thirty-five patients were identified with pain of the jaw. ResultsTwo-hundred of five-hundred and sixteen patients received bondronate, seventy-four patients pamidronate, one-hundred and seventy-four patients zoledronic acid, twenty-three patients oral bisphosphonate and two patients are unable to name the bisphosphonate. Thirty-five patients were identified with pain of the jaw. A total of twenty-five ONJ cases were identified either by histology or estimation of the surgeon among all patients treated and referred to our institute. Five patients had no ONJ, only non-specific pain of the jaw. Five patients have other disease of the jaw (1 patient osteoymelitis; 1 patient cyst of the jaw; 1 patient epulis gigantocellularis, 1 patient granuloma, 1 patient plasmozytoma of the jaw). Ten patients who were diagnosed with ONJ received bondonate, eleven patients pamidonate and thirteen patients zoledronic acid. The majority of the ONJ lesions completely healed in 24 patients. Overall, most of the ONJ lesions were associated with dental procedures and pain was the symptom most frequently reported. ConclusionONJ is a serious complication of bisphosphonate therapy. But with active monitoring for ONJ and early input from dental experts, ONJ has been mild to moderate in severity, had minimal impact on overall quality of life and improved or healed in the majority of patients. These results suggest that with proper management, ONJ is a manageable, infrequent complication that may be associated with a reduced SRE (skeletal-related events) risk and improved overall survival. Length of exposure and the probably the type of biphosphonate used appear to be the most important risk factor for this complication. DisclosuresGoldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau.

Proinflammatory Cytokines Profile in Monoclonal Gammopathies Related to Pathogenesis of Bone Disease.

Abstract 4913Bone disease is one of the most frequent complications in Multiple Myeloma (MM), and as consequence produce irreversible and invaliding lesions. The pathogenesis of bone disease is not completely known. There are several publications about the influence of different cytokines in the bone remodelling, by break the balance between osteoclastic/osteoblastic activities. Aims of the study: to analyze a cytokine panel in a group of consecutive patients diagnosed as Monoclonal Gammopathy according the International Myeloma Working Group, 2003 criteria and to compare the results between MGUS and MM and patients with an without overt bone disease. Patients and methodsBetween June 2008-June 2009, a total of 87 patients were studied (46.0% females) in Miguel Servet University Hospital; mean age: 71.5 (range: 69.1-73.9), distributed in two groups: a) MGUS: 46; mean age: 72.8 (range: 69.7-75.8); b) MM: 41; mean age: 70.2 (range: 66.3-74.0). According subtypes distribution: a) IgG: 18(39.1%); IgA 16(34.8%), IgM: 9 (19.6%), double MC 3 (6.5%). b) Light Chain: 6 (15.0%) IgG: 21 (52.5%); IgA 11(27.5%), double MC 2 (5.0%); In b group the ISS(1: 9, 22.5%, 2: 21 52.5%, 3: 10 25.0%). Four different degrees of bone disease was established: 0: normal (68.5%); 1 osteopenia (9.6%); 2 osteoporosis (2.7%); 3 Lytic lesions (11.0%); 4 fractures (8.2%). The cytokine assay was performed in serum samples stored at -80°C at diagnosis, using Millipore human cytokines Kit according the established protocol by Luminex®100 platform. The profile cytokine panel used were: IL-4, IL6, IL-7, IL-10, IL-13, MIP-1a, MIP-1b, TNF-a. Previously we had compared the cytokine profile with a group of healthy population matched by age and gender. The results of the cytokine panel were compared between groups MGUS/MM, bone disease, immunochemical subtypes and ISS stage, haemoglobine, b2 microglobuline concentration, free light chain ratio in the MM group. Descriptive analysis and non parametric comparative test was performed using STATA SE v.10. ResultsFor the global serie: IL10 concentration showed significant difference between patients with normal vs abnormal bone. The cytokine profile of MGUS vs MM was significant different for IL-4 (p=0.02), MIP-1a(p=0.03) and TNFa(p=0.003). The comparative analysis of profiles according ISS classification showed significant differences for MIP-1a(p=0.04), IL-13(p=0.02) and IL-6(p=0.07) and b2microglobuline vs TNFa (p=0.002). No significant differences were observed for immunochemicals subtypes, free k/l ratio and hemoglobine. CommentsIn our experience Luminex®100 technology is a sensible and accurate technique useful to determine cytokine profile in serum. A different significant cytokine profile was observed in patients with MGUS vs MM and different bone affectation, b2microglobuline and ISS. It is necessary to perform more studies with more patients in order to confirm these results.This work has been partially sponsored by a grant from CIBERER DisclosuresNo relevant conflicts of interest to declare.

Pathogenesis and management of myeloma bone disease

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of increased activity of osteoclasts that is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition, including the RANKL/osteoprotegerin pathway, macrophage inflammatory proteins and the wingless type signaling pathway. These molecules also appear to interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma. Currently, bisphosphonates are the mainstay of treatment for myeloma bone disease, although several novel agents appear promising. This review focuses on recent advances in understanding the biology of bone disease in multiple myeloma, diagnosis and recent progress in treatment options.

Diagnosis and treatment in complication of multiple myeloma

Diagnosis and treatment in complication of multiple myeloma

Management of Complications in Multiple Myeloma

Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease, renal impairment, anemia, and immune dysfunction. Adequate supportive care is considered an essential part of anti-myeloma therapy. The administration of bisphosphonates has been shown to reduce skeletal related events and hypercalcemia. Bisphosphonates are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). Adequate pain control is of crucial importance for the quality of life of MM patients. Local radiotherapy may rapidly ameliorate symptoms of painful MM bone lesions, and vertebroplasty and kyphoplasty are able to control symptoms and restore the original height of vertebral fractures. Symptomatic chemotherapy-induced anemia should preferentially be treated with erythropoietic growth factors, but further studies are required to confirm the long-term safety of this approach. Light-chain-induced renal impairment should be treated without delay with a highly effective anti-myeloma regimen consisting of novel drugs. Prophylaxis of infections should be considered particularly in patients with poorly controlled disease and documented infections should be treated aggressively as they contribute significantly to morbidity and mortality. The concerted action of these supportive therapies can significantly improve the quality of life of MM patients during the different phases of their disease.

Light chain multiple myeloma with cutaneous AL amyloidosis

Cutaneous AL amyloidosis is one complication of multiple myeloma. In our patient, painful sclerotic skin changes on the extremities and macroglossia were the presenting features which led to a more detailed investigation and the diagnosis of multiple myeloma. Histological examination revealed cutaneous deposits of amyloid which were positive with Congo red stain and had an apple green color in polarized light.

Pulmonary embolism in a patient with multiple myeloma receiving thalidomide–dexamethasone therapy

Massive pulmonary embolism is an uncommon complication of multiple myeloma treated with thalidomide-dexamethasone regimen. In 2006, multiple myeloma was diagnosed in a 72-year-old man, who received thalidomide-dexamethasone therapy. In January 2007, echocardiography and computerized tomography identified massive pulmonary embolism in the pulmonary arteries and a deep vein thrombus of the right leg. The patient also had an elevated concentration of B-type natriuretic peptide. After heparinization and warfarin therapy, the patient's condition improved. This is the first report of a patient with a rare complication of pulmonary embolism from thalidomide-treated multiple myeloma.

Rapid Response to High-Dose Steroids of Severe Bortezomib-Related Pulmonary Complication in Multiple Myeloma

Rapid Response to High-Dose Steroids of Severe Bortezomib-Related Pulmonary Complication in Multiple Myeloma

Increased plasma macrophage inflammatory protein (MIP)-1α and MIP-1β levels in type 1 Gaucher disease

Pancytopenia, hepatosplenomegaly and skeletal complications are hallmarks of Gaucher disease. Monitoring of the outcome of therapy on skeletal status of Gaucher patients is problematic since currently available imaging techniques are expensive and not widely accessible. The availability of a blood test that relates to skeletal manifestations would be very valuable. We here report that macrophage inflammatory protein (MIP)-1α and MIP-1β, both implicated in skeletal complications in multiple myeloma (MM), are significantly elevated in plasma of Gaucher patients. Plasma MIP-1α of patients (median 78 pg/ml, range 21–550 pg/ml, n = 48) is elevated (normal median 9 pg/ml, range 0–208 pg/ml, n = 39). Plasma MIP-1β of patients (median 201 pg/ml, range 59–647 pg/ml, n = 49) is even more pronouncedly increased (normal median 17 pg/ml, range 1–41 pg/ml, n = 39; one outlier: 122 pg/ml). The increase in plasma MIP-1β levels of Gaucher patients is associated with skeletal disease. The plasma levels of both chemokines decrease upon effective therapy. Lack of reduction of plasma MIP-1β below 85 pg/ml during 5 years of therapy was observed in patients with ongoing skeletal disease. In conclusion, MIP-1α and MIP-1β are elevated in plasma of Gaucher patients and remaining high levels of MIP-1β during therapy seem associated with ongoing skeletal disease.

Bisphosphonates and Osteonecrosis of the Jaw: Advantages of a New Schedule.

Background: Bisphosphonates (Bi) have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma (MM) with a significant improvement of the quality of life. The 2002 ASCO guidelines indicate that once initiated intravenous Bi should be continued until an evident substantial decline of performance status. Recently, osteonecrosis of the jaw (ONJ) has been reported as complication of intravenous Bi treatment, with an incidence ranging between 6 and 13% and a greater occurrence in patients (pts) receiving zoledronic acid (Zol) than in those treated with pamidronate (Pam).Aim. In this retrospective study we evaluated the incidence of ONJ and of skeletal related events (SRE) in a cohort of MM pts divided in two groups according to the schedule of administration of Bi; group A: monthly administrations until tolerated (standard), group B: monthly administrations during the first year and then every 3 months (reduced).Methods: One hundred and six MM pts (M: 63, F: 43) were included in this study: 51 pts received a standard treatment (group A) and 55 a reduced schedule (group B). Pam 90 mg i.v. was administered as a three hour infusion and Zol 4 mg i.v. as a 15 minutes infusion. SRE was defined as: pathologic fracture, radiation to bone, spinal cord compression with vertebral fracture, hypercalcemia.Results: No difference was found between the two groups concerning pts characteristics at the onset: age, sex, extension of bone disease, status of the disease (progressive or responsive). Twenty pts received only Pam, 42 only Zol and 44 pts Pam followed by Zol. The distribution of the different type of Bi was not different in the two groups. ONJ occurred in 7 pts (6.6%) with a significant difference between the two groups: 6 pts in standard schedule (11.7%) and 1 in the reduced (1.8%), p=0.01, after a median time of 22.8 months in group A, and 37.8 months in the case of group B. Four of out 7 ONJ occurred during the second year of treatment (12–24 months): that period resulted significantly related (p=0.000) to the occurrence of ONJ with respect to the others (24–38 months, 40–100 months). All ONJ occurred in pts treated with Zol alone (5 pts) or with Zol after Pam (2 pts), whereas no cases were observed in Pam alone pts (p= 0.005). The median number of infusions was 20 with comparable results in the two groups (20 in group A, 19 in group B). SRE was observed in 38 pts (35.8%): 16 pts in group A and 22 pts in group B without statistical difference (p=0.6), after a median time of 9.8 months.Conclusions: These results suggest that the reduced schedule of Bi is associated with a significant lower incidence of ONJ and, although the sample size is limited, the appearance of ONJ seems delayed with respect to the standard treatment. Moreover, the incidence of SRE is similar in the two groups. In conclusion, the reduced schedule, could be applied in order to combine the antiresorptive efficacy of Bi with a higher safety and a better compliance.

Absence of renal lesions in C57BL/KaLwRij mice with advanced myeloma due to 5T2MM cells

Renal failure is one of the main complications in multiple myeloma (MM) and histopathological lesions are due to light chains accumulation in the kidney. The 5T2MM mouse model closely mimics osteolytic lesions observed in clinics. We studied the occurrence of pathological changes in the kidney of mice inoculated with 5T2MM myeloma cells. No renal lesions due to light chain deposition were observed after histological, immunological staining and dosage of creatinine in serum and urine. PTH levels decreased in 5T2MM mice, confirming the absence of secondary hyperparathyroidism. Osteolytic lesions appear to be the unique consequence of 5T2MM cells inoculation.

Renal pathology and retinol status in multiple myeloma patients

Renal dysfunction is a common and serious complication in multiple myeloma (MM) patients. Renal proximal tubule injury is characteristic in MM, and may result in disturbed renal handling of various vitamins. The abnormal excretion of vitamins in urine may result in their low serum levels. The goal of this study was to investigate the urinary excretion of retinol in MM and its relationship with serum retinol concentration. For this purpose, 24 MM patients and 10 healthy individuals were studied. Serum and urinary retinol and retinol-binding protein (RBP) were measured by the high-performance liquid chromatography method and enzyme-linked immunosorbent assay, respectively. The study showed that 58% of MM patients excreted retinol in urine, while only 29% had elevated serum creatinine (P<0.05). There was a strong and highly significant correlation between urinary retinol and RBP (r=0.973, P<0.006). Patients with normal and mildly elevated serum creatinine who excreted retinol in urine had a marked decrease in serum retinol (P<0.007). On the other hand, serum retinol was not decreased in patients with moderate or severe renal failure, despite its urinary loss. Our data indicate that (i) urinary retinol is a more frequent marker of renal dysfunction than elevated serum creatinine in MM patients, (ii) serum retinol is decreased in MM with normal or mildly elevated serum creatinine, but not in patients with moderate/severe renal failure, and (iii) urinary retinol may serve as a diagnostic marker of renal proximal tubule dysfunction in MM patients.

Multiple complications in multiple myeloma

WE PRESENT the case of a 68-year-old woman with a remote past diagnosis of possible multiple myeloma who presented with renal insufficiency, recent hip fracture, anemia, and a monoclonal protein detected on serum and urine electrophoresis. Monoclonal proteins in patients with multiple myeloma may cause renal disease in different ways, including, but not limited to, light chain cast nephropathy, light chain (AL) amyloid, or monoclonal immunoglobulin deposition disease. Renal biopsy determined an unusual cause of her renal insufficiency.

Cerebral Infarction in IgG Multiple Myeloma with Hyperviscosity

Cerebral infarction is an uncommon complication in multiple myeloma with hyperviscosity. Serum hyperviscosity may cause a variety of clinical manifestations including bleeding from mucosal membranes, congestive heart failure, retinopathy, and various neurologic deficits. These manifestations have been attributed to the presence of large quantities of asymmetrical molecules of high molecular weight in the serum. We recently experienced a case of multiple myeloma with acute cerebral infarction, which caused by hyperviscosity, as an initial manifestation in IgG multiple myeloma, and reviewed the relevant literature of myeloma presenting with the stroke. A 68-yr-old woman abruptly developed hypesthesia and monoplegia in the left leg. The stroke confirmed by the brain MRI and MR angiography, which revealed acute infarction at the right anterior cerebral artery territory. On admission, routine blood tests showed a slight decrease in hemoglobin and a marked increase in erythrocyte sedimentation rate. Peripheral blood smear, serum protein electrophoresis, serum visocity, and bone marrow aspiration showed that she had IgG multiple myeloma with hyperviscosity. She was treated by chemotherapy with cyclophosphamide and discharged with the improved clinical condition.

Podocyte injury associated glomerulopathies induced by pamidronate

Pamidronate has been demonstrated to decrease bone-related complications in multiple myeloma and delay progression of the disease. This has led to its use in supportive and maintenance therapy of myeloma in conjunction with steroids and chemotherapy. It has also been selectively used in patients with breast cancer and other neoplasms. We report on five patients who developed glomerular disease induced by pamidronate. Pamidronate was the only drug common to all patients. Tests for hepatitis B and C and human immunodeficiency virus (HIV) were negative for all patients. The first two patients received a high dose of pamidronate for 8 weeks, whereas the other three patients were on monthly therapy for a prolonged period of time. Sources of data included chart review and pathologic analysis of kidney biopsy. Three patients were female and two were males and all were Caucasian, ranging in age from 58 to 71 years. Renal biopsy findings included minimal change disease in two, focal segmental glomerulosclerosis in two, and collapsing focal segmental glomerulosclerosis in one. Immunofluorescence was essentially negative in all cases. Electron microscopy showed variable podocyte injury and extensive foot process effacement. There was no evidence of multiple myeloma-related renal disease. After the biopsy, pamidronate was discontinued and renal function stabilized in all patients except the one with the collapsing variant of focal segmental glomerulosclerosis who required hemodialysis. Three patients had resolution of proteinuria, one patient continued to have proteinuria without deterioration in renal function. Pamidronate has been mainly associated with collapsing focal segmental glomerulosclerosis. This report expands that relationship and adds other glomerular diseases linked with podocyte injury. Additional studies are needed to define the cause of the variability of renal histology with this agent.