mycophenolic-acid and Multiple-Myeloma

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diabetic Nephropathies; Disease Progression; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Pancreas Transplantation; Plasmacytoma; Postoperative Complications; Prednisone; Reoperation; Rituximab; Spinal Neoplasms; Tacrolimus; Thalidomide

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Drug Eruptions; Feasibility Studies; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Lenalidomide; Lymphocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Prospective Studies; Remission Induction; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity.. A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response.. Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5 g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3 g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease.. MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.

Topics: Aged; Bone Marrow; Chromatography, High Pressure Liquid; Disease Progression; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Guanosine Triphosphate; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Plasmacytoma; Salvage Therapy

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Acute; Lymphocyte Transfusion; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Myeloproliferative Disorders; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Tissue Donors; Vidarabine; Whole-Body Irradiation

Despite prophylaxis with immunosuppressive drugs, severe graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic stem cell transplantation. T cell depletion of the graft has decreased incidence and severity of GVHD but has resulted in a higher incidence of graft failure and relapse. To reduce the risk of severe GVHD, but at the same time to maintain the graft-versus-tumor effect, we administered a fixed low number of 1 x 10(5) donor T cells per kilogram of body weight to recipients of CD34(+) cell-enriched allogeneic peripheral blood stem cells (PBSCs). Donor lymphocyte infusions (DLI) were then given in incremental doses when mixed chimerism persisted or signs of relapse occurred. A total of 23 patients receiving allografts from related and unrelated donors were treated according to this protocol after myeloablative or reduced intensity conditioning. One patient did not engraft and 3/20 evaluable patients developed acute (a) GVHD > or = grade II, with a corresponding estimated cumulative incidence of 15.6% (95% CI 0-30.5%). DLI (n = 13) induced aGVHD > or = II in 6 patients, but the severity of the syndrome was reduced. Overall GVHD-related mortality was low (13%). The probability of disease-free survival and overall survival at 2 years was 0.40 (95% CI 0.21-0.75) and 0.36 (95% CI 0.21-0.63). Progression-free survival and overall survival was significantly better in patients with acute or chronic myelogenous leukemia compared to patients with lymphoproliferative disorders (p = 0.002; p = 0.02). We conclude that the combination of allografts with a T cell content of about 1 x 10(5)/kg and escalating doses of DLI is a viable transplant strategy in patients with myeloid leukemias, which results in stable engraftment and a reduction of mortality from aGVHD.

Topics: Adult; Antigens, CD; Antigens, CD34; CD3 Complex; Cell Separation; Cyclosporine; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Stem Cell Transplantation; Survival Analysis; Time Factors; Transplantation, Homologous

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)

Topics: Adult; Aged; Aging; Cause of Death; Cyclosporine; Female; Graft Rejection; Graft vs Tumor Effect; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Neutrophils; Platelet Count; Remission Induction; Survival Rate; T-Lymphocytes; Transplantation Conditioning; Whole-Body Irradiation

Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.

Topics: Adrenal Cortex Hormones; Aged; Antilymphocyte Serum; Deprescriptions; Female; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lenalidomide; Maintenance Chemotherapy; Multiple Myeloma; Mycophenolic Acid; Polycystic Kidney, Autosomal Dominant; Tacrolimus; Thalidomide

Bortezomib can be used to successfully treat acute kidney injury in the renal transplant allograft due to light chain cast nephropathy from recurrent multiple myeloma.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biopsy; Bone Marrow; Boronic Acids; Bortezomib; Female; Humans; Immunoglobulin kappa-Chains; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Multiple Myeloma; Mycophenolic Acid; Protease Inhibitors; Pyrazines; Recurrence; Syndecan-1; Tacrolimus

Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies. In primary myeloma cells, IMP dehydrogenase (IMPDH) was shown to be consistently overexpressed. We therefore tested the IMPDH inhibitor mycophenolate mofetil (MMF) currently available as a clinical therapeutic agent for its antimyeloma activity in vitro. MMF depleted intracellular guanosine 5'-triphosphate (GTP) levels in myeloma cells. We showed apoptosis induction in myeloma cell lines and primary myeloma cells between 1 and 5 mumol/L MMF. MMF was also cytotoxic at this concentration in dexamethasone-resistant and Mcl-1-overexpressed myeloma cell lines shown by the tetrazolium salt XTT assay along with cell survival measured by a modified flow cytometric assay. Apoptosis was not inhibited by the presence of an antioxidant, suggesting that MMF-induced apoptosis is less likely to be associated with reactive oxygen species. However, apoptosis was abrogated by exogenously added guanosine, which activates an alternative pathway for GTP formation, implicating that this effect is directly mediated by IMPDH inhibition. MMF-induced G1-S phase cell cycle arrest and its apoptosis induction mechanism were associated with a caspase-dependent pathway as shown by alteration of mitochondrial membrane potential and cytochrome c release followed by activation of the caspases. MMF-induced apoptosis was also inhibited by a pan-caspase inhibitor Z-VAD-fmk. MMF-treated myeloma cells showed an up-regulation of Bak, which most likely together with Bax resulted in the release of cytochrome c. In summary, MMF attenuates G1-S phase cell cycle progression and activates the pathway of mitochondrial dysfunction, leading to cytochrome c release followed by activation of caspases.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Guanosine; Humans; IMP Dehydrogenase; Multiple Myeloma; Mycophenolic Acid; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; STAT3 Transcription Factor

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

Topics: Adolescent; Adult; Aged; Chimerism; Cytomegalovirus; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Liver; Liver Function Tests; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Nausea; Neutropenia; Recurrence; Serum Albumin; Transplantation Conditioning; Transplantation, Homologous; Virus Activation

Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.

Topics: Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Chronic Disease; Cyclosporine; Disease Progression; Disease-Free Survival; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous

We investigated whether a T cell-reduced allogeneic stem cell transplant (SCT) with minimal conditioning and subsequent donor lymphocyte infusions (DLI) could reduce the incidence and severity of GVHD while retaining stable engraftment. Five patients with hematological malignancies (three MM, one CLL, one Chediak-Higashi syndrome) were conditioned with TBI (200 cGy). One patient additionally received fludarabine (120 mg/m(2)). CsA and mofetyl-mycophenolate (MMF) were administered to prevent GVHD. All patients were grafted with >3 x 10(6)/kg highly purified CD34(+) cells together with 2 x 10(6)/kg CD3(+) cells (three patients) or 1 x 10(5)/kg CD3(+) cells (two patients). Quick hematopoietic recovery and initial mixed donor chimerism was observed. Treatment-related toxicity was minimal in all but one patient who died of treatment-refractory GVHD on day 112. The four other patients only achieved partial donor T cell chimerism. BM and PBMC donor chimerism was lost between day 40 and 209 despite DLI. Three patients are alive with disease and one is in CR. We conclude that T cell-reduced SCT using 200 cGy as the conditioning regimen does not result in stable hematopoietic engraftment. Predominant donor T cell chimerism is not a prerequisite for initial allogeneic hematopoietic proliferation. However for sustained long-term engraftment it is of major importance.

Topics: Adult; Chediak-Higashi Syndrome; Cyclosporine; Fatal Outcome; Female; Follow-Up Studies; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Depletion; Lymphocyte Transfusion; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; T-Lymphocytes; Time Factors; Transplantation Chimera; Transplantation, Homologous; Treatment Failure; Vidarabine; Whole-Body Irradiation

Nuclear run-on experiments were used to verify the hypothesis that extinction of expression of Ig synthesis in L cell x myeloma hybrids occurs at the transcriptional level. Both the H chain enhancer and promoter have been shown to be the targets for extinction in myeloma x T cell hybrids. To examine the expression of genes containing the immunoglobulin heavy chain gene (IgH) enhancer in stably transfected non-B cells, we used a vector with two selectable markers, one of which (gpt providing resistance to mycophenolic acid) either lacks an enhancer or contains the IgH enhancer, the other (neo providing resistance to G418) contains an SV40 enhancer. Stable transfectants of both myeloma (J558L) and L cells selected using G418 were tested to determine if they are also mycophenolic acid resistant. When the IgH enhancer is positioned 3' to the gpt gene, transfected J558L are mycophenolic acid resistant whereas stably transfected L-cells are mycophenolic acid sensitive. However, when large numbers of L cell transfectants are exposed to mycophenolic acid for a prolonged period, resistant subclones emerge. When the 700-bp IgH enhancer fragment was used, the majority of the subclones examined had amplified the vector, between 3 and 38 copies; when a 400-bp subfragment was used no change in the integrated genes was seen. In both cases, in the mycophenolic acid resistant subclones, increased accumulation of gpt and neo mRNA is seen. However, the gpt specific transcripts are heterogeneous in size whereas the neo transcripts are of a discrete size. The heterogeneity of the gpt transcripts results at least in part from heterogeneous initiation. When HXM-resistant L cell subclones are fused to the gamm 2b, k myeloma 4T001, extinction of Ig production occurs; therefore these cells are still capable of negatively regulating Ig expression. These results are discussed from the standpoint of both cis and trans regulatory elements and factors in non-lymphoid cells.

Topics: Animals; Clone Cells; Drug Resistance; Enhancer Elements, Genetic; Fibroblasts; Gene Expression Regulation; Genes, Immunoglobulin; Genomic Library; Hybrid Cells; Immunoglobulin Heavy Chains; Mice; Multiple Myeloma; Mycophenolic Acid; Plasmids; RNA, Messenger; T-Lymphocytes; Transcription, Genetic; Transfection

Topics: Adenocarcinoma; Administration, Oral; Animals; Carcinoma 256, Walker; Cyclophosphamide; Dogs; Injections, Intramuscular; Injections, Intraperitoneal; Injections, Intravenous; Lethal Dose 50; Leukemia, Experimental; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Multiple Myeloma; Mycophenolic Acid; Neoplasms, Experimental; Osteosarcoma; Rats; Rats, Inbred Strains; Sarcoma, Experimental

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Caproates; Carcinoma; Esophageal Neoplasms; Female; Hodgkin Disease; Humans; Injections, Intraperitoneal; Injections, Intravenous; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Stomach Neoplasms