Role of urine immunofixation in the complete response assessment of MM patients other than light-chain-only disease.

Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)-negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)-negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serum and urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (<10-6; 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease.

Serum free light chain measurements to reduce 24-h urine monitoring in patients with multiple myeloma with measurable urine monoclonal protein.

Detection of myeloma progression (PD) relies on serial 24-h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24-h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55-312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24-h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24-h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.

Multiple myeloma.

Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.

[Development of an extramedullary plasmacytoma despite disappearing M protein in multiple myeloma by bortezomib treatment].

A 65-year-old male with IgG-kappa multiple myeloma was treated with melphalan-prednisolone (MP) and obtained a minimal response. Five months after the initiation of MP, he developed back pain, renal failure, hypercalcemia and increased plasma cells in the bone marrow. He was treated with bortezomib. After 2 cycles, he developed a peripheral neuropathy, and the dose of bortezomib was decreased to 1.0 mg/m(2). After 5 cycles, serum monoclonal protein was not detected by immunofixation, and the percentage of bone marrow plasma cells decreased to less than 5%. In March 2007, he developed lumbago again, and MRI of the lumbar vertebrae showed a tumor at the para pediculus arcus vertebrae. Immunohistochemistry of the biopsied tumor demonstrated monoclonal plasma cell infiltration. The patient was treated with local radiation therapy. Bortezomib is a new and effective agent for refractory/relapsed multiple myeloma. It has also been reported that bortezomib is effective for solitary extramedullary plasmacytoma (EMP). However, in the patient reported here, although bortezomib induced a complete response with regard to the serum monoclonal protein and the percentage of bone marrow plasma cells, EMP developed in the parapediculus arcus vertebrae. Herein, we document a case of EMP development during successful bortezomib therapy.

Primary systemic amyloidosis associated with multiple myeloma: a case report and review of the literature.

Amyloidosis is a broad and complex class of diseases that comprises several etiologies, many manifestations, and a diversity of outcomes. We discuss a patient with primary systemic amyloidosis associated with multiple myeloma that illustrates many of the typical and atypical features of the disease process. Despite more in-depth assessment and accurate classification, survival for patients with primary systemic disease remains poor.

Wilms tumor gene WT1 peptide-based immunotherapy induced a minimal response in a patient with advanced therapy-resistant multiple myeloma.

The product of the Wilms tumor gene, WT1, is a universal tumor antigen. We performed WT1 peptide-based immunotherapy for a patient with multiple myeloma (MM). This patient was a 57-year-old woman with chemotherapy-resistant MM (Bence Jones kappa type). The patient received weekly intradermal injections of an HLA-A*2402-restricted 9-mer WT1 peptide emulsified with Montanide ISA 51 adjuvant for 12 weeks and achieved a minimal response according to European Group for Blood and Marrow Transplantation criteria without experiencing systemic adverse effects. The proportion of myeloma cells in the bone marrow (BM) decreased from 85% to 25%, and the amount of M protein in the urine decreased from 3.6 to 0.6 g/day after WT1 vaccination. Furthermore, a bone scintigram showed an improvement after the vaccination. As for immunologic parameters, the frequency of WT1 tetramer-positive cells among CD8+ T-cells, which was higher than in healthy donors, temporarily decreased at weeks 4 and 8 but increased at week 12, whereas the frequency of WT1 peptide-responding CD107a/b+ cells among WT1 tetramer-positive T-cells increased from 27.0% to 38.6% after the vaccination. After WT1 vaccination, the frequency of CXCR4+ cells among WT1 tetramer-positive T-cells increased in the BM, where stromal cells expressed the ligand for CXCR4, stromal-derived factor 1 (SDF-1), but decreased in the peripheral blood (PB), implying that WT1-specific cytotoxic T-lymphocytes had migrated from the PB to the BM, a tumor site.

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure.

Salvage therapy of patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this further limits the use of conventional chemotherapy. Thalidomide, both alone and in combination with dexamethasone, has been demonstrated to be useful in patients with advanced MM, as responses could be achieved in 30-60% of the cases. From May 2000 to November 2003, 20 consecutive MM patients (15 males, five females, median age 66.5 yr) with stage III relapsed/refractory MM and renal failure, defined as serum creatinine >130 mmol/L, gave their informed consent to be enrolled in a clinical trial aimed at evaluating the efficacy and the toxic effects of thalidomide. Three patients were undergoing chronic haemodialysis during the time of entry in the study. Eight patients have been treated with thalidomide as a single agent, at a starting dose of 100 mg/d, that was to be increased to 400 mg/d in case of good tolerance. Twelve patients have been treated with thalidomide at the maximum dose of 200 mg/d plus dexamethasone 40 mg/d for four consecutive days every 4 wk. A >50% decrease in serum or urine M component was observed in nine patients (45%), seven of whom have been treated with thalidomide + dexamethasone and three with thalidomide alone. Six additional patients achieved a minor response (>25% paraprotein decrease); the total response rate was thus 75%. Median response duration was 7 months (range 2-24 months). Four patients were refractory to treatment. Recovery of a normal renal function was observed in 12 of 15 responsive patients, two additional patients, in chronic haemodialysis, showed a reduction of serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was comparable with that observed in patients with a normal renal function. In conclusion, our data show that thalidomide can be safely administered in patients with advanced MM and renal failure.

[Monoclonal gammopathies--from MGUS to myeloma]. / Monoklonale Gammopathien--vom MGUS zum Myelom.

Monoclonal gammopathies are characterized by the overproduction of a monoclonal immunoglobulin (M-Protein), which may be detected in serum or urine by protein electrophoresis and immunofixation. The presence of an M-Protein results from the proliferation of a single abnormal clone of differentiated B lymphocytes or plasma cells, and is associated with a variety of clinical conditions, ranging from asymptomatic to malignant disease. Recent years have witnessed considerable advances in the treatment of plasma cell myeloma, the most common malignant disorder of the monoclonal gammopathies. As compared with conventional-dose treatments, high-dose chemotherapy with autologous stem-cell transplantation increases response rates and overall survival of patients with myeloma who are younger than 65 years of age. Progress in supportive therapies and the development of promising new drugs such as proteasome inhibitors and thalidomide analogues may provide further benefits for myeloma patients in the future.

High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: predictors of complete remission.

High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12 Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum

Local and long-range structural effects caused by the removal of the N-terminal polypeptide fragment from immunoglobulin L chain lambda.

The role of the N-terminal polypeptide fragment of the immunoglobulin l-chain in V domain packing stability, and the flexibility of the whole chain was approached by molecular dynamics simulation. The observations were supported by experimental analysis. The N-terminal polypeptide fragment appeared to be the low-stability packing element in the V domain. At moderately elevated temperature it may be replaced at its packing locus by Congo red and then removed by proteolysis. After removal of Congo red by adsorption to (diethylamino)ethyl (DEAE) cellulose, the stability of complete L chain and of L chain devoid of the N-terminal polypeptide fragment were compared. The results indicated that the N-terminal polypeptide fragment plays an essential role in the stability of the V domain. Its removal makes the domain accessible for ANS and Congo red dye binding without heating. The decreased domain stability was registered in particular as increased root mean square (RMS) fluctuation and higher susceptibility to proteolytic attack. The long-range effect was most clearly manifested at 340 K as independent V and C domain fluctuation in the l-chain devoid of the N-terminal polypeptide fragment. This is likely due to the lack of direct connections between the N- and C-termini of the V domain polypeptide. In a complete V domain the connection involves residues 8-12 and 106-110 in particular. Partial or complete disruption of this connection increases the freedom of V domain rotation, while its increased cohesion strengthens the coupling of the V and C domains, making the whole L chain less flexible.

Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma.

Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme-linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0.31 ng/ml and 0.08 ng/ml respectively, P < 0.01; HGF: mean 2.17 ng/ml and 0.45 ng/ml, respectively, P < 0.001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M-protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0.05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0.01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0.01, P < 0.05, P < 0.05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0.01, P = 0.02, respectively, log-rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.

Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas.

Thalidomide is active in patients with refractory myeloma. Seventeen patients (nine men/eight women, median age 73 years) with multiple myeloma (MM) were treated with thalidomide. Fifteen patients had refractory disease and two untested relapse. The median dose of thalidomide was 500 mg (range, 200-800 mg). Nine of the 17 patients (53%) responded. The response rate was significantly higher in patients with no extramedullary disease than in those with soft tissue masses (75% CI: 43-95% versus 0%; P = 0.01)). Of note, no decrease in the size of soft tissue plasmacytomas was observed in all the five patients who had extramedullary involvement. This data suggests that the mechanism of action and effectiveness of thalidomide might depend on the site of the tumour cells.

[Analysis of monoclonal protein in 72 cases of multiple myeloma].

Serum and urinary monoclonal proteins (M protein) were measured in 72 cases of multiple myeloma (MM) using rate nephelometry. In IgG and IgA types of MM, the level of immunoglobulin (Ig) corresponding to the malignant isotype was significantly higher and that of Ig uncorresponding to the malignant isotype lower than the normal level. The light chain corresponding to the malignant isotype in serum was increased and the light chain uncorresponding to that in serum was decreased either kappa-IgG, IgA types or lambda-IgG, IgA types. Either kappa-LC or lambda-LC type of MM, the serum light chain corresponding to the malignant isotype was in the normal range and uncorresponding to that was decreased, and the corresponding light chain in urine was significantly elevated. Kappa/lambda ratio in serum and urine was all significantly abnormal in IgG, IgA, and LC types of MM. Our data suggest that any quota among kappa light chain > 20 g.L-1 or < 5 g.L-1, lambda light chain > 10 g.L-1 or < 2 g.L-1 in serum and kappa/lambda ratio > 5 or < 0.75 in serum and urine has an important value for diagnosing MM.

Thalidomide in the treatment of relapsed multiple myeloma.

OBJECTIVE: To describe the efficacy of therapy with thalidomide, a drug that has antiangiogenic properties, in patients with relapsed multiple myeloma. PATIENTS AND METHODS: We studied 16 patients (median age, 64 years) who received thalidomide for relapsed myeloma at the Mayo Clinic in Rochester, Minn, between November 1998 and August 1999. Treatment consisted of thalidomide given orally at a dose of 200 mg/d for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximal dose of 800 mg/d. RESULTS: The stage of myeloma at treatment was Durie-Salmon IIIA in 9 patients (56%) and IIIB in 7 (44%). The median time from myeloma diagnosis to initiation of thalidomide therapy was 32 months. In 4 patients (25%) prior stem cell transplantation had failed, and 14 (88%) had received 2 or more prior chemotherapeutic regimens before institution of thalidomide. All patients were evaluable for response. Four (25%) achieved a partial response to therapy, with a greater than 50% reduction in the serum or urine M protein level. Responses lasted 2, 4+, 8, and 10+ months. Major adverse effects included constipation, sedation, rash, and peripheral neuropathy. CONCLUSION: Thalidomide is an active agent in the treatment of patients with advanced myeloma.