Subgroup Of Multiple Myeloma Patients Research Articles

Plasma cell growth fraction using Ki‐67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I

The current most powerful prognostic model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the ISS stage I (high albumin and low b2m) may vary. Ki-67 is a nuclear protein associated with cell proliferation. We retrospectively evaluated the percentage of bone marrow plasma cells expressing Ki-67 antigen (Ki-67 index) in a series of 174 untreated MM patients at diagnosis. Median survival was 51, 41 and 20 months respectively, and median Ki-67 index was 3.0%, 6.1% and 6.5% in ISS stages I, II, and III respectively. Independently of ISS, Ki-67 index > or =4% was highly predictive of adverse prognosis. Ki-67 index correlated with markers of intrinsic malignancy and with markers of tumour burden. Within ISS stage I, median survival was of 31 months (RR of death 2.65) in patients with Ki-67 index > or =4%. Eventually, the combination of Ki-67 with b2m produced an efficient prognostic model, which appeared most effective in our series when compared with b2m and KI-67 with chromosome 13 deletion models. In this series, we demonstrated that a proliferation marker provides clear-cut additional survival prognostic information to b2m into the ISS model.

Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of Multiple Myeloma patients displaying short survival within the ISS stage I

Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of Multiple Myeloma patients displaying short survival within the ISS stage I

Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted?

The natural history of multiple myeloma (MM) was revolutionized by the introduction of haematopoietic stem cell transplantation to the treatment armamentarium of this disease. Defined subgroups of MM patients (such as the elderly or dialysis-dependent) have required an individualized approach in order to minimize the transplant-related mortality. Little, however, is known about the management of 12-30% of MM patients with coexistent AL amyloidosis as the amyloidopathy is often overlooked and when recognized these patients commonly are excluded from clinical trials. While occult amyloidosis appears to have no impact on the toxicity and outcome of MM patients, the presence of symptomatic amyloidopathy clearly worsens their prognosis. Use of induction chemotherapy drugs that can cause further damage to the heart (Adriamycin), nervous system (Vincristine) or kidneys should be avoided as should lengthy delays in proceeding to autograft. Further, refining the transplant eligibility criteria for this subgroup of patients with co-existent amyloidopathy to include the number of organs involved and the degree of cardiac involvement (NYHA class, Troponins and NT-pro-BNP levels) along with melphalan dose-adjustment will minimize the treatment-related toxicity and mortality and possibly allow a reversal of the organ damage induced by the amyloidogenic light chain.

High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients

To identify genetic events underlying the genesis and progression of multiple myeloma (MM), we conducted a high-resolution analysis of recurrent copy number alterations (CNAs) and expression profiles in a collection of MM cell lines and outcome-annotated clinical specimens. Attesting to the molecular heterogeneity of MM, unsupervised classification using nonnegative matrix factorization (NMF) designed for array comparative genomic hybridization (aCGH) analysis uncovered distinct genomic subtypes. Additionally, we defined 87 discrete minimal common regions (MCRs) within recurrent and highly focal CNAs. Further integration with expression data generated a refined list of MM gene candidates residing within these MCRs, thereby providing a genomic framework for dissection of disease pathogenesis, improved clinical management, and initiation of targeted drug discovery for specific MM patients.

Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

Bcl-xl Expression in Multiple Myeloma

In the present study the immunohistochemical expression of Bcl-xl, a downstream target of the IL-6-controlled signal transducer and activator of transcription-3 (Stat3) was studied in 40 multiple myeloma (MM) cases before treatment and 11 MM patients at relapse. Correlation analysis was performed between Bcl-xl expression, C-reactive protein (CRP) level, beta-2-microglobulin (beta2m), microvessel density (MVD), and clinical outcome. Before treatment 28 (70%) patients demonstrated a Bcl-xl expression similar to normal plasma cells ("normal pattern"), while 12 (30%) patients demonstrated an elevated expression in a subgroup of the malignant plasma cells. At relapse, no change in Bcl-xl expression was observed as compared to pretreatment sample. No correlation was observed between the Bcl-xl expression and the level of CRP and b2m. In addition, no significant correlation was observed between the Bcl-xl expression and the MVD, but MVD was significantly increased as compared to normal bone marrow biopsy specimens (p=0.02). Patients with an elevated or normal Bcl-xl expression showed no statistically significant difference in overall and event-free survival. In summary, these data indicate that Bcl-xl is elevated in a subgroup of MM patients that so far did not correlate with CRP, b2m, MVD, and clinical outcome.

Gene Expression Profiling of Plasma Cell Dyscrasias: The Role of IGH Translocations in the Heterogeneity of Multiple Myeloma.

Multiple Myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy ofundetermined significance, MGUS) or progress from intra-medullary to extra-medullaryforms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analyzed the gene expression profiles of plasma cells isolated from 7 MGUS, 39 MM and 6 PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct signatures have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis related functions. In addition, we identified a set of cancer germ-line antigens specifically expressed in a sub-group of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

Cytobiological studies in multiple myeloma.

Multiple myeloma (MM) is a heterogeneous disease in which the median survival time varies from a few months to more than 10 years. Clinical, kinetic, and immunological studies reflected such a heterogeneity. In clinical studies beta 2-microglobulin (beta 2-M), which is a well-known prognostic factor, was evaluated as an expression of tumor burden: a linear increase has been observed from stage I to stage III. No clear cutoff was detected between monoclonal gammopathy of undetermined significance (MGUS) and stage I MM. Kinetic studies have been performed by 3[H]thymidine or 5-bromo-2-deoxyuridine incorporation in bone marrow plasma cells. An analysis has been carried out between beta 2-M and the labeling index (LI). No correlation has been observed between these 2 parameters which identify different subgroups of poor prognosis patients. MGUS always showed an LI less than 1% allowing a clear distinction from stage I MM. A reduced survival time has been observed in patients with an LI greater than 2%. A subgroup of MM patients characterized by an LI greater than 2% and a decrease of M component greater than 50% within 3 months (early responders) has been identified. These patients showed a median survival time of about 10 months. Immunological studies identified a sharp decrease of 5' nucleotidase (5'NT) enzymatic activity in peripheral blood lymphocytes. This enzymatic defect is the biochemical marker of the expansion of a T subpopulation expressing low levels of 5'NT. This subpopulation was characterized by monoclonal antibodies and is represented by activated suppressor cells (OKM1+, DR+). Such an unbalancement in the T cell subpopulation was evident in poor prognosis patients. Clinical, kinetic and immunological studies identified new prognostic parameters that will be useful in the future therapeutic strategy of MM.