tacrolimus 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

This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days -9 and -2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day -5 and tacrolimus (Tk) from -3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2-4 and 3-4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD.

Topics: Bortezomib; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Tacrolimus; Transplantation Conditioning

A phase HI comparative trial of tacrolimus- vs. cyclosporine-based graft-vs.-host disease (GVHD) prophylaxis for human leukocyte antigen (HLA)-identical sibling bone marrow transplantation showed less GVHD but poorer survival in the tacrolimus arm. To test the comparability of the two treatment arms with respect to baseline survival prognosis, a matched control study using exclusively cyclosporine-treated patients from the International Bone Marrow Transplant Registry (IBMTR) database was performed. Controls were matched (2:1) based on age (within 5 years), disease, and pretransplant disease status. Two-year survival for tacrolimus-treated clinical trial patients was similar to that of their cyclosporine-treated matched controls (27 and 24%, respectively), and 2-year survival of the cyclosporine-treated clinical trial patients was similar to that of their cyclosporine-treated matched IBMTR controls (42 and 45%, respectively). Consistent with the clinical trial results, the cyclosporine-treated IBMTR controls matched to the tacrolimus group had significantly poorer 2-year survival than the cyclosporine-treated IBMTR controls matched to the cyclosporine group (24 and 45%, respectively; p < 0.01). No significant difference was seen in GVHD between the cyclosporine-treated clinical trial patients and their matched controls; however, the tacrolimus-treated clinical trial patients had significantly less GVHD than their cyclosporine-treated IBMTR controls (p < 0.01). These results support the hypothesis that the survival difference in the phase III trial resulted from an imbalance in the underlying risk factors for death in the two groups rather than from the randomized immunosuppressive regimen.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Prospective Studies; Survival; Tacrolimus

The immunophilin FKBP12 binds to TGF-β family type I receptors, including the BMP type I receptor ALK2. FKBP12 keeps the type I receptor in an inactive state and controls signaling activity. Removal of FKBP12 with drugs such as the FKBP-ligand FK506 enhances BMP activity in various cell types. In multiple myeloma cells, activation of SMAD1/5/8 leads to apoptosis. We hypothesized that removing FKBP12 from ALK2 in myeloma cells would potentiate BMP-induced ALK2-SMAD1/5/8 activity and in consequence cell death.. Multiple myeloma cell lines were treated with FK506, or other FKBP-binding compounds, combined with different BMPs before analyzing SMAD1/5/8 activity and cell viability. SMAD1/5/8 activity was also investigated using a reporter cell line, INA-6 BRE-luc. To characterize the functional signaling receptor complex, we genetically manipulated receptor expression by siRNA, shRNA and CRISPR/Cas9 technology.. FK506 potentiated BMP-induced SMAD1/5/8 activation and apoptosis in multiple myeloma cell lines. By using FKBP-binding compounds with different affinity profiles, and siRNA targeting FKBP12, we show that the FK506 effect is mediated by binding to FKBP12. Ligands that typically signal via ALK3 in myeloma cells, BMP2, BMP4, and BMP10, did not induce apoptosis in cells lacking ALK3. Notably, BMP10 competed with BMP6 and BMP9 and antagonized their activity via ALK2. However, upon addition of FK506, we saw a surprising shift in specificity, as the ALK3 ligands gained the ability to signal via ALK2 and induce apoptosis. This indicates that the receptor complex can switch from an inactive non-signaling complex (NSC) to an active one by adding FK506. This gain of activity was also seen in other cell types, indicating that the observed effects have broader relevance. BMP2, BMP4 and BMP10 depended on BMPR2 as type II receptor to signal, which contrasts with BMP6 and BMP9, that activate ALK2 more potently when BMPR2 is knocked down.. In summary, our data suggest that FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells, partly by switching an NSC into an active signaling complex. FKBP12 targeting compounds devoid of immunosuppressing activity could have potential in novel treatment strategies aiming at reducing multiple myeloma tumor load. Video Abstract.

Topics: Activin Receptors, Type I; Bone Morphogenetic Proteins; Humans; Multiple Myeloma; RNA, Small Interfering; Tacrolimus; Tacrolimus Binding Protein 1A

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

Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of

Topics: Animals; Calcineurin; Cell Line, Tumor; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Panobinostat; Tacrolimus; Xenograft Model Antitumor Assays

We retrospectively evaluated single-institute outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a reduced-intensity conditioning regimen consisting of fludarabine (125 mg/m²) and melphalan (140 mg/m²) for multiple myeloma. Twenty-three patients (median age: 46 years) were evaluated. Stem cell sources were bone marrow or peripheral blood stem cells from siblings (n = 4) and bone marrow from unrelated donors (n = 19). For graft-versus-host disease prophylaxis, cyclosporine A or tacrolimus with short-term methotrexate was given. Disease status at time of transplant was complete response in four patients, very good partial or partial response in 13, and stable or progressive disease in six. The median follow-up period of 7 survivors at analysis was 73.2 months (range 46.0-158.9 months). During the follow-up, disease recurrence or progression was observed in 21 patients, and was primary causes of death in 88% of the patients. The 5-year overall survival and progression-free survival rates were 38.6% (95% CI 19.3-57.7%) and 5.4% (95% CI 0.4-21.6%), respectively. Although allo-HSCT with this conditioning could be safely performed, further refinement of this approach aiming at more effective eradication of myeloma cells is clearly warranted.

Topics: Acute Disease; Adult; Allografts; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; Retrospective Studies; Tacrolimus; Transplantation Conditioning; Treatment Outcome

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C(0) (trough) and C(max) (maximal) levels: group A (n = 21; 68%) with a C(max)-C(0) value of <10 ng/mL, and group B (n = 10; 32%) with a C(max)-C(0) value of >or=10 ng/mL. Although the C(0) and C(12) values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC(0-12)) was significantly greater in group B than group A (200.9 +/- 36.3 vs 155.1 +/- 43.1 ng.h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 +/- 6.70 vs 18.17 +/- 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Body Weight; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Tacrolimus; Young Adult

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

Topics: Erythema Multiforme; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multiple Myeloma; Prednisone; Tacrolimus

Topics: Aged; Busulfan; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Topics: Acute Disease; Administration, Topical; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Mouth Mucosa; Multiple Myeloma; Tacrolimus; Time Factors; Transplantation Conditioning

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Topics: Acute Disease; Adult; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Isoantibodies; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma; Male; Methotrexate; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Tacrolimus; Transplantation, Homologous