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Biomedical subjects

Martha Q Lacy

Publications and source records attributed to Martha Q Lacy.

At least 19 recordsLinked to original sources
PubMed2006

The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis.

Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, is highly active in patients with multiple myeloma. We studied the toxicity and efficacy of lenalidomide in patients with AL. Patients with symptomatic AL, a measurable plasma cell disorder, and adequate hematologic and renal reserve were eligible. Patients received single-agent lenalidomide. If there was no evidence of progression after 3 months or of hematologic response after 3 cycles, dexamethasone was added. Twenty-three patients were enrolled. Thirteen were previously treated. Organ involvement was cardiac (64%), renal (73%), hepatic (23%), and nerve (14%). Within the first 3 cycles of therapy, 10 patients discontinued treatment: 4 early deaths, 3 adverse events, and 3 other causes. With a median follow-up of 17 months, 10 patients responded to treatment. In these patients, responses included 9 hematologic, 4 renal, 2 cardiac, and 2 hepatic. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3 or 4 adverse events at least possibly attributable to lenalidomide were neutropenia (45%), thrombocytopenia (27%), rash (18%), and fatigue (18%). In AL patients, we saw limited activity of single-agent lenalidomide, but significant activity of the combination with dexamethasone, which warrants further investigation.

Administration, Oral↗
PubMed2006

Expression of mRNA for a newly identified Pax5 exon is reduced in multiple myeloma.

Pax5 is a transcription factor that is critical in the bone marrow for differentiation and proliferation of B cells until the plasma cell stage. In Pax5(-/-) mice, B-cell development stalls at the pro-B-cell stage. Messenger RNA profiles of alternatively spliced isoforms of Pax5 in bone marrow frequently differ between multiple myeloma (MM) patients and healthy donors. We sought to determine if Pax5 mRNA profiles also differed in blood and unexpectedly detected the presence of a previously unreported exon that alters the amino acid code for the transactivating domain of Pax5 in CD138(-) B cells. This unique exon escapes detection by conventional analyses of RT-PCR products and may serve as a prototype for other exons, in other genes, that escape RT-PCR detection. Eight percent of tested human subjects were heterozygous for an allele with a nonsynonymous nucleotide substitution in the new exon, and one MM patient was homozygotic for this base difference. Subsequent analysis of plasma and B-cell populations from bone marrow revealed a markedly reduced mRNA expression of the new isoform in cells from MM patients when compared to cells from normal subjects.

Alternative Splicing↗
PubMed2006

Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points.

Flavopiridol downregulates anti-apoptotic regulators including Mcl-1, upregulates p53, globally attenuates transcription through inhibition of P-TEFb, binds to DNA, and inhibits angiogenesis. Eighteen myeloma patients were treated with 1-hour flavopiridol infusions for 3 consecutive days every 21 days. Immunoblotting for Mcl-1, Bcl-2, p53, cyclin D, phosphoRNA polymerase II and phosphoSTAT 3 was conducted on myeloma cells. Ex vivo flavopiridol treatment of cells resulted in cytotoxicity, but only after longer exposure times at higher flavopiridol concentrations than were anticipated to be achieved in vivo. No anti-myeloma activity was observed in vivo. As administered, flavopiridol has disappointing activity as a single agent in advanced myeloma.

Aged↗
PubMed2006

Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.

The immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor protein has been crude. We evaluated the utility of the FLC assay in a retrospective analysis of patients with AL undergoing peripheral blood stem cell transplantation (PBSCT). Ninety-three such patients had serial FLC measurements performed. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were studied. There was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio. FLC measurements both before and after PBSCT are important predictors of patient outcome.

Adult↗
PubMed2006

6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance.

IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and Waldenström macroglobulinemia (WM) are sometimes clinically difficult to distinguish. In our previous study, deletion of the long arm of chromosome 6 (6q) was found in about half of WM patients. To further clarify the area of minimal deletion at 6q (6q-) and to address the issue of whether 6q- occurs in IgM MGUS, 12 IgM MGUS and 38 WM patients were studied by fluorescence in situ hybridization using probes targeting different chromosomal segments of 6q. No 6q deletions were found in IgM MGUS samples. Of 38 successfully studied WM patients, 21 (55%) showed a deletion of 6q. The area of minimal deletion was between 6q23 and 6q24.3, but the deletion usually encompassed a large fragment of the 6q arm. These results indicate that 6q- can distinguish WM from IgM MGUS and is likely to be a secondary event.

Aged↗
PubMed2006

A phase II trial of imatinib in patients with refractory/relapsed myeloma.

Although imatinib was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases including c-kit. As pre-clinical data, 126 patients with plasma cell disorders and 19 controls were evaluated for c-kit expression. Patients were eligible for the treatment trial if they had relapsed/refractory myeloma. The primary end-point of the study was response. Of the 145 studied before the trial, c-kit expression was present on the bone marrow plasma cells of control (11%), AL amyloid (53%), MGUS (47%), SMM (67%) and MM (42%) patients. Twenty-three MM patients were enrolled on the therapeutic trial (imatinib 400 mg daily) and 52% had positive c-kit staining. There were no responses. The median duration of treatment was 48 days (range: 12-349). Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imatinib is not an active agent in patients with relapsed or refractory multiple myeloma.

Aged↗
PubMed2006

Autologous stem cell transplantation and IgM amyloidosis.

High dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) is an accepted form of treatment for patients with AL amyloidosis. The purpose of the current study is to review the outcomes of IgM AL amyloidosis patients treated with high dose chemotherapy and autologous stem cell transplant and compare them to the outcomes of all AL amyloidosis subtypes treated similarly. We retrospectively reviewed the pretransplant characteristics, conditioning regimens and response to transplant of all twelve IgM AL amyloidosis patients who were transplanted at the Mayo Clinic between May 1999 and August 2005. Transplant related mortality was low at 8%. The overall hematologic response rate was 89%. The organ response rate was 67%. Overall median survival has not been reached as eleven patients are still alive. IgM AL amyloidosis patients appear to have similar outcomes after HDC and ASCT as other subtypes of AL amyloidosis suggesting that this therapy is an acceptable form of treatment for patients with IgM amyloidosis, and should be considered as a first line treatment option.

Aged↗
PubMed2006

Natural history of thromboembolism in AL amyloidosis.

To determine the natural history of thromboembolism in patients with biopsy-proven AL amyloidosis, medical records of 2,132 patients evaluated at Mayo Clinic between 1975 and 2000 were reviewed. Forty patients (21 male) were found to have objectively documented thromboembolism. The median age was 65 years. Four patients had a monoclonal gammopathy of undetermined significance, 20 had an unspecified plasma cell proliferative disorder, 11 had multiple myeloma, and 1 had Waldenström macroglobulinemia. Twelve patients had cardiac amyloid, and 20 had renal amyloid. Neither the extent of the amyloid nor the type of monoclonal protein was predictive of the development of thromboembolic events. Thromboembolism preceded the diagnosis of AL amyloidosis in 11 patients, occurred at the time of diagnosis or within 1 month after diagnosis in 11 patients, and occurred 1 month or more after diagnosis in 18 patients. Twenty-nine patients (73%) had venous thrombosis and 11 (28%) had arterial thrombosis. Eight patients (20%) died within 1 month after the thrombotic event, and 18 (45%) died within 1 year. The development of thrombosis in patients with AL amyloidosis appears to predict significant mortality within the first month and year after the event.

Aged↗
PubMed2006

Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1.

Interleukin-1beta (IL-1beta) is abnormally expressed by the plasma cells obtained from myeloma patients, and it is a potent inducer of the important myeloma growth factor, IL-6. We investigated whether levels of IL-1beta biologic activity might distinguish different groups of patients with smoldering multiple myeloma (SMM). We measured the ability of IL-6 production by bone marrow stromal cells to serve as a surrogate marker for IL-1beta biologic activity. Using this IL-1beta bioassay, we found that it is sensitive at < 1 pg/ml of recombinant IL-1beta and that IL-1beta biologic activity is detectable with either mature or pro-IL-1beta-transduced myeloma cell lines. Patients with active myeloma induced quantitatively higher levels of stromal cell IL-6 production when compared with those with monoclonal gammopathy of undetermined significance (MGUS). The bioassay distinguished two groups of SMM patients, those who were high producers, similar to patients with active MM, and those who were low producers, comparable to MGUS patients. IL-1 antagonists inhibited the paracrine IL-6 production by > or = 90% in the majority of patients with an elevated IL-6 level. Based on such studies, it may be possible to predict patients that will progress to active MM and to delay or prevent this progression with IL-1 antagonists.

Bone Marrow Cells↗
PubMed2006

Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia.

We sought to define prognostic factors for survival in Waldenstrom macroglobulinaemia (WM). Of 585 patients diagnosed with WM and seen at Mayo Clinic between 1960 and 2001, 337 symptomatic patients met the inclusion criteria and were analysed for overall and disease-specific survival. The median survival from the time of diagnosis was 6.4 years. The median disease-specific survival was 11.2 years. Univariate analysis for overall survival identified the following adverse prognostic factors: age >65 years (P < 0.001), organomegaly (P < 0.001), elevated beta2-microglobulin (<0.001), anaemia (Hb < 10.0 g/dl) (P = 0.01), leucopenia (<4.0 x 10(9)/l) (P = 0.03), thrombocytopenia (<150 x 10(9)/l) (P = 0.01), serum albumin <40 g/l (P = 0.001), and quantitative IgM < 0.4 g/l (P = 0.04). On multivariate analysis, age >65 years and organomegaly were associated with poor prognosis. A prognostic model was built based on these two variables. Patients at high risk (1-2 risk factors, median survival 4.2 years) experienced worse survival than patients at low risk (0 risk factors, median survival 10.6 years), P < 0.001. The prognostic model was validated in 204 patients who were not included in the analysis cohort. Beta2-microglobulin > or =4 mg/l was associated with a threefold increase in the risk of death when added to the prognostic model. We describe a simple prognostic model for overall survival for newly diagnosed patients with WM.

Adult↗
PubMed2006

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with multiple myeloma.

Multiple myeloma, for all practical purposes, remains an incurable malignancy; however, 5-year survival has improved substantially during the past 30 years. A major contribution to improved outcome is the use of high-dose chemotherapy and stem cell transplantation. This multifaceted approach to therapy requires an understanding of appropriate induction therapy, techniques for stem cell mobilization, appropriate conditioning and supportive care. Also of importance are prognosis, features that predict outcome, the suitability of transplant candidates, and post-transplantation maintenance therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Cyclophosphamide mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma.

PURPOSE: Patients with multiple myeloma who undergo autologous stem cell transplantation (ASCT) and exhibit a complete response (CR) have a superior overall survival and time to progression (TTP). High-dose cyclophosphamide is often used before ASCT for mobilization of hematopoietic stem cells. We hypothesized that cyclophosphamide might further improve CR rates in patients undergoing ASCT. We searched the Mayo Clinic myeloma transplantation database for patients who had stem cell mobilization with hematopoietic growth factor alone or cyclophosphamide and growth factor. The impact of cyclophosphamide on CR rates and TTP was evaluated. PATIENTS AND METHODS: A cohort of 201 patients was identified: 127 mobilized with cyclophosphamide and growth factor and 74 with growth factor alone. There were no statistically significant differences between the 2 cohorts in regard to age, sex, b2-microglobulin level, plasma cell labeling index, cytogenetics, conditioning regimen, or disease status at time of transplantation. RESULTS: Complete response rates were 37.4% and 41.3% (P = 0.6115) for patients mobilized with cyclophosphamide combined with growth factor and growth factor alone, respectively, and TTPs were 19.9 months and 20.9 months (P = 0.59). In a multivariate analysis for TTP, cytogenetics and CR rates were the only independent variables (P = 0.0012 and P < 0.0001, respectively). CONCLUSION: We conclude that high-dose cyclophosphamide does not increase overall CR rates or improve TTP for patients with myeloma undergoing ASCT.

Adult↗
PubMed2006

Response to rituximab in patients with type II cryoglobulinemia.

Type II cryoglobulinemia (CG) is a heterogeneous, generally indolent disorder caused by a monoclonal antibody with activity against polyclonal antibodies and is commonly associated with hepatitis C, lymphoproliferative disorders (LPDs), or autoimmune diseases. It can lead to substantial morbidity, including renal failure, cutaneous ulcers, or neuropathy. Medical records were reviewed for 8 patients with previously treated symptomatic CG who were part of a prospectively held dysproteinemia database. Patients subsequently received 14 total courses of rituximab treatment (standard infusion, 375 mg/m2 for 4 or 8 doses) between February 1999 and March 2005. One patient had essential CG, and 1 had Gaucher disease with hypersplenism. Six patients had an LPD, and 4 of them had concomitant disorders (2 with hepatitis C and 2 with Sjogren syndrome). Treatment indications included purpura, LPD, cutaneous ulcers, and renal failure. Clinical improvement was evaluated by improved cryocrit, total complement, C4, and rheumatoid factor. Six patients had some clinical improvement. Cutaneous manifestations were the most responsive; renal disease and lymphoma were more refractory. Laboratory values showed improvement after 7 of 12 available treatment courses. No adverse reactions were noted. Overall, rituximab appears to be a safe and effective therapy.

Antibodies, Monoclonal↗
PubMed2006

Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma.

Bisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is Increasingly recognized as a serious complication of long-term bisphosphonate therapy. Issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the Interest of patient safety and will be reexamined as new data emerge regarding risks and benefits.

Bone Density Conservation Agents↗
PubMed2006

Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy.

Bisphosphonate chemotherapy is commonly used in the treatment of bone diseases such as osteoporosis, Paget disease, and multiple myeloma and to limit bone pain and hypercalcemia associated with malignant metastatic bone lesions. The introduction of bisphosphonate therapy has improved the quality of life in a vast majority of patients, showing clear medical efficacy. However, since 2003 a growing number of reports have described necrotic bone lesions (osteonecrosis of the jaw [ONJ]) affecting maxillofacial bones in patients who have received chemotherapy with intravenous bisphosphonate therapy. Unfortunately, the development of ONJ has been refractory to conventional treatment modalities. Several treatment options have been proposed for ONJ, most of which focus primarily on conservative management with local irrigation and empirical long-term antibiotic therapy. However, results of treatment have been associated with high failure rates, progression of disease, and continued decline in patients' quality of life. We describe 2 patients in whom primary surgical salvage was performed successfully for ONJ. Our experience indicates that with appropriate technique, primary surgical treatment may offer benefit to selected patients with ONJ.

Aged↗
PubMed2005

Clinical implication of centrosome amplification in plasma cell neoplasm.

The mechanisms underlying aneuploidy in multiple myeloma (MM) are unclear. Centrosome amplification has been implicated as the cause of chromosomal instability in a variety of tumors and is a potential mechanism causing aneuploidy in MM. Using immunofluorescent (IF) staining, centrosome amplification was detected in 67% of monoclonal gammopathies, including monoclonal gammopathy of undetermined significance (MGUS). We also investigated the gene expression of centrosome proteins. Overall, gene expression data correlated well with IF-detected centrosome amplification, allowing us to derive a gene expression-based centrosome index (CI) as a surrogate for centrosome amplification. Clinically, MM patients with high CI (> 4) are associated with poor prognostic genetic and clinical subtypes (chromosome 13 deletion, t(4; 14), t(14;16), and PCLI > 1%, P < .05) and are shown here to have short survival (11.1 months versus 39.1 months, P < .001). On multivariate regression, a high CI is an independent prognostic factor. Given that centrosome amplification is already observed in MGUS and probably integral to early chromosomal instability and myeloma genesis, and patients with more extensive centrosome amplification have shorter survival, the mechanisms leading to centrosome amplification should be investigated because these may offer new avenues for therapeutic intervention.

Adult↗
PubMed2005

Flow cytometric detection of circulating myeloma cells before transplantation in patients with multiple myeloma: a simple risk stratification system.

Detection of circulating myeloma cells (CMCs) by flow cytometry in patients with multiple myeloma (MM) indicates active disease. We hypothesized that detection of CMCs at the time of stem-cell collection prior to autologous stem-cell transplantation (ASCT) identifies patients at high risk of rapid progression. A cohort of patients undergoing ASCT was identified. CMCs were determined by gating on CD38+/CD45- cells using flow cytometry. The impact of CMCs on overall survival (OS) and time to progression (TTP) was evaluated in univariate and multivariate analyses. Of 246 patients undergoing ASCT, 95 had CMCs. Complete response (CR) rates after transplantation were 32% and 36% for patients with and without CMCs, respectively (P = .50). OSs were 33.2 and 58.6 months (P = .01) whereas TTPs were 14.1 and 22 months, respectively (P = .001). On multivariate analysis, CMCs remained independent of cytogenetics and disease status at time of transplantation (P = .03). CMCs and cytogenetics were combined in a new scoring system. Patients with neither, one, or both parameters had a median OS of 55, 48, and 21.5 months and a median TTP of 22, 15.4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management.

Adult↗