Biomedical subjects

Raman Desikan

Publications and source records attributed to Raman Desikan.

11 recordsLinked to original sources

PubMed2006

Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow-up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0.002), postenrolment (P < 0.001) and at relapse (P = 0.004); elevations of serum C-reactive protein (CRP) (P = 0.003) and lactate dehydrogenase (P = 0.029), anaemia (P = 0.029) and they more often completed two transplants within 12 months (P = 0.019). Postenrolment overall survival (OS) and event-free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0.001 and 0.037 respectively) and in the presence of low CRP at baseline (P = 0.001 and 0.017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0.001), IgA isotype (P = 0.002), International Staging System stage 3 (P = 0.014), and when patients had two protocol transplants prior to relapse (P = 0.038). Ten-year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high-dose melphalan, were applied together upfront for the management of myeloma.

Aged↗

PubMed2004

Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.

OBJECTIVES: To determine the progression-free survival at 12 weeks, to evaluate the toxic effects, and to analyze the biological activity of thalidomide in patients with relapsed multiple myeloma (MM) after high-dose chemotherapy and stem cell transplantation. PATIENTS AND METHODS: From 1999 to 2001, we performed a multicenter prospective phase 2 study in patients with MM that relapsed after high-dose chemotherapy and stem cell transplantation to evaluate the efficacy of oral thalidomide, with dose escalation from 200 to 600 mg/d over 12 weeks and a subsequent maintenance phase of 200 mg/d for up to 1 year. Outcome was correlated with serum and plasma levels of vascular endothelial growth factor and serum levels of tumor necrosis factor alpha, soluble intercellular adhesion molecule 1, interferon gamma, interleukin (IL) 2, and IL-6 during treatment. RESULTS: Thirty patients were treated (19 men and 11 women; median age, 58 years). The median number of prior therapies was 5, and the median duration from diagnosis of MM to study enrollment was 4.3 years. The 12-week progression-free survival rate was 67% (95% confidence interval [CI], 48%-86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28%-60%) with a median duration of 6 months. Attributable toxicities included constipation, fatigue, rash, and neuropathy, which was dose limiting in 8 patients (27%). Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Although responses were observed with lower doses, possibly eliminating the need to escalate the dose, responses were also seen in patients who completed the dose escalation. Some patients had disease progression while receiving the maintenance dose of 200 mg/d. Analysis of biomarker assays did not identify any biomarker associated with greater response, but a significant increase in levels of soluble intercellular adhesion molecule 1, IL-2, and interferon gamma was seen with thalidomide therapy. CONCLUSION: The optimal thalidomide dose varies, and adverse effects can be dose limiting. The dose of thalidomide therapy should be based on the individual patient to ensure that it is well tolerated and that a response is achieved.

Disease Progression↗

PubMed2003

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression.

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Infection--an underappreciated cause of bone pain in multiple myeloma.

Bone pain, especially back pain, is a common presenting feature of myeloma patients. We report three multiple myeloma patients with exacerbations of back pain and referred shoulder pain resulting from vertebral infections. Two patients were treated with surgery, and one patient had computerized tomography-guided percutaneous needle aspiration for diagnostic purposes. All three patients received a prolonged course of antibiotics. Vertebral infection resolved with this treatment in all three patients without any recurrence. Previous dexamethasone therapy, together with an episode of bacteraemia, appears to be a predisposing factor for vertebral infection. Magnetic resonance imaging enabled the diagnosis in all three patients.

Aged↗

PubMed2003

Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience.

Despite the superiority of high-dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants < or =12 months apart and survived > or =2 months after the second transplant. With a median follow-up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety-five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2.9 years. The median overall survival from relapse was 2.4 years. In one-quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P<0.001, Hazard Ratio (HR): 3.84] and beta-2 microglobulin levels >4 mg/l at relapse (P<0.001, HR: 2.87) were significant for poor survival after relapse. The median survival after relapse was 5.1, 1.3 and 0.7 years in patients with none (44%), one (46%) and two (10%) poor-risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor-risk features enjoyed meaningful survival prolongation when appropriately treated.

Disease-Free Survival↗

PubMed2002

Predicting long-term (> or = 5 years) event-free survival in multiple myeloma patients following planned tandem autotransplants.

Although outcome in multiple myeloma (MM) patients has improved significantly with the introduction of autotransplants (AT), the curability of this approach remained to be demonstrated. Therefore, we analysed outcome and prognostic factors using a logistic regression model in 515 consecutive newly diagnosed and previously treated patients intended to receive melphalan-based tandem transplants with follow up of > or = 5 years. One quarter of patients had event-free survivals (EFS) > or = 5 years with no further relapses seen after 7 years (46 patients on plateau). On multivariate analysis, factors associated with EFS > or = 5 years were absence of chromosome 11 and 13 abnormalities (odds ratio: 6.1), < or = 12 months of preceding standard-dose therapy (SDT) (OR: 2.6) and beta-2 microglobulin (B2M) level < or = 2.5 mg/l at time of first AT (OR: 1.7). Patients with only favourable variables (25%) had a 7-year EFS in excess of 35%, compared with 15% and 10%, respectively, with one (43%) or two unfavourable variables (27%), and 0% for 5% of patients with three unfavourable variables (P < 0.0001). Using a 1-year landmark analysis to allow for guaranteed time and thereby excluding early treatment failures, attaining a complete remission (CR) had no significant effect on long-term survival. Our data are consistent with cure in MM patients with a CR duration . or = 7 years and re-establishment of a monoclonal gammopathy of undetermined significance (MGUS) phase in those with persistent evidence of disease post transplantation, but without disease progression > or = 7 years.

Antineoplastic Agents, Alkylating↗

PubMed2002

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.

Adult↗

PubMed2002

Optimizing dendritic cell-based immunotherapy in multiple myeloma.

Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells.

Aged↗

PubMed2002

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Nephrotic proteinuria associated with high-dose pamidronate in multiple myeloma.

Five patients receiving increased dose or frequency of pamidronate beyond the recommended dose (90 mg/monthly) exhibited nephrotic proteinuria (range 3.96-24 g/24 h). On dose reduction or discontinuation, three of these patients showed decreased proteinuria to normal levels (< 1 g/24 h), and proteinuria decreased to 4.5 g/24 h from a peak of 24 g/24 h in one patient. One patient on haemodialysis (hence not evaluable) had proteinuria of 2 g/24 h and elevated creatinine levels. One other patient continued to show elevated creatinine levels (272.8 micro mol/l). Renal biopsies obtained in two patients revealed focal segmental glomerulosclerosis.

Antineoplastic Agents↗

PubMed2002

Waldenström's macroglobulinaemia: current therapy and future approaches.

Waldenström's macroglobulinaemia is a rare B-cell malignancy. It is prevalent in the sixth and seventh decades, the median age at diagnosis being 63 years. Conventional treatment has involved alkylator therapy, especially chlorambucil given daily at a low dose or intermittently at a higher dose. Purine analogues, used initially as salvage therapy in refractory disease, are increasingly used for initial therapy. However, purine analogue therapy entails significant complications, including immunosuppression, pancytopenia and autoimmune haemolysis. Moreover, it is unclear whether purine analogues extend survival. All of these need to be considered before initiation of therapy. More recently, anti-CD20 monoclonal antibody and thalidomide have been used with a 30% response in treated patients. High-dose therapy with stem cell support achieves a partial response in a majority of patients receiving this modality of therapy. The median survival of 5 years has not improved considerably since the introduction of purine analogues. Complete response is still uncommon; using all available modalities of therapy may increase the complete response rate and improve survival. Great strides in understanding the malignant cell, the microenvironment and the potential interactions have identified potential targets for therapy in multiple myeloma. These agents may also be useful in Waldenström's macroglobulinaemia. Since this is a rare malignancy, all patients should be treated with well-designed clinical protocols to achieve improvement in outcome.

Antibodies, Monoclonal↗