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Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents.
Cornell RF, Goldhaber SZ, Engelhardt BG, Moslehi J, Jagasia M, Harrell S, Rubinstein SM, Hall R, Wyatt H, Piazza G
(2020) Br J Haematol 190: 555-561
MeSH Terms: Aged, Comorbidity, Consolidation Chemotherapy, Factor Xa Inhibitors, Female, Hemorrhage, Humans, Immunologic Factors, Lenalidomide, Maintenance Chemotherapy, Male, Middle Aged, Multiple Myeloma, Myocardial Infarction, Pilot Projects, Proof of Concept Study, Prospective Studies, Pulmonary Embolism, Pyrazoles, Pyridones, Stroke, Thalidomide, Thrombophilia, Venous Thromboembolism, Venous Thrombosis
Show Abstract · Added May 29, 2020
Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.
© 2020 British Society for Haematology and John Wiley & Sons Ltd.
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25 MeSH Terms
Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma.
Cornell RF, Ky B, Weiss BM, Dahm CN, Gupta DK, Du L, Carver JR, Cohen AD, Engelhardt BG, Garfall AL, Goodman SA, Harrell SL, Kassim AA, Jadhav T, Jagasia M, Moslehi J, O'Quinn R, Savona MR, Slosky D, Smith A, Stadtmauer EA, Vogl DT, Waxman A, Lenihan D
(2019) J Clin Oncol 37: 1946-1955
MeSH Terms: Adult, Aged, Aged, 80 and over, Bortezomib, Cardiovascular Diseases, Disease-Free Survival, Electrocardiography, Female, Heart Diseases, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Multiple Myeloma, Natriuretic Peptide, Brain, Neoplasm Recurrence, Local, Oligopeptides, Prospective Studies, Proteasome Inhibitors, Risk Factors, Time-to-Treatment, Treatment Outcome, Troponin I, Troponin T
Show Abstract · Added November 12, 2019
PURPOSE - Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.
PATIENTS AND METHODS - Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
RESULTS - Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CONCLUSION - CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
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25 MeSH Terms
Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.
Fradley MG, Groarke JD, Laubach J, Alsina M, Lenihan DJ, Cornell RF, Maglio M, Shain KH, Richardson PG, Moslehi J
(2018) Br J Haematol 180: 271-275
MeSH Terms: Adult, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Cardiotoxicity, Electrocardiography, Female, Heart Diseases, Humans, Magnetic Resonance Imaging, Multiple Myeloma, Proteasome Inhibitors
Show Abstract · Added December 2, 2017
Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.
© 2017 John Wiley & Sons Ltd.
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11 MeSH Terms
A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG
(2017) Br J Haematol 178: 547-560
MeSH Terms: Antineoplastic Agents, Benchmarking, Bortezomib, Cardiovascular Diseases, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Dyspnea, Heart Failure, Humans, Multiple Myeloma, Proteasome Inhibitors, Retrospective Studies, Risk Factors
Show Abstract · Added December 2, 2017
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
© 2017 John Wiley & Sons Ltd.
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13 MeSH Terms
Cardiovascular and Thrombotic Complications of Novel Multiple Myeloma Therapies: A Review.
Li W, Garcia D, Cornell RF, Gailani D, Laubach J, Maglio ME, Richardson PG, Moslehi J
(2017) JAMA Oncol 3: 980-988
MeSH Terms: Antineoplastic Agents, Cardiovascular Diseases, Humans, Immunologic Factors, Lenalidomide, Multiple Myeloma, Proteasome Inhibitors, Risk Factors, Thalidomide, Thromboembolism, Thrombosis
Show Abstract · Added March 26, 2017
Importance - Multiple myeloma (MM) is the second most common hematological malignant abnormality. The introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has greatly improved the overall survival of patients with MM. Prevention and treatment of cardiovascular and thrombotic issues associated with novel MM therapies have emerged as important aspects of supportive care in patients with MM.
Observations - We searched PubMed and the Cochrance database for studies published from March 2001 to January 2016. Emerging evidence suggests that both IMiDs and PIs can have cardiovascular (CV) sequelae, which include thromboembolic complications, cardiac, and vascular toxic effects. These complications occur against the backdrop of a high prevalence of CV disease in the MM population as well as the adverse cardiac and vascular effects of MM itself.
Conclusions and Relevance - This review provides an overview of the incidences, clinical presentations, and mechanisms of CV complications in the MM population. We conclude that more research is needed for better screening and preventive strategies to abrogate these toxic effects and improve patient care.
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11 MeSH Terms
Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.
Nyman JS, Merkel AR, Uppuganti S, Nayak B, Rowland B, Makowski AJ, Oyajobi BO, Sterling JA
(2016) Bone 91: 81-91
MeSH Terms: Animals, Bone Diseases, Bone and Bones, Bortezomib, Cancellous Bone, Cell Count, Cell Line, Tumor, Disease Models, Animal, Drug Therapy, Combination, Mice, Inbred C57BL, Multiple Myeloma, Osteoblasts, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta, Tumor Burden
Show Abstract · Added July 18, 2016
Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease.
Published by Elsevier Inc.
2 Communities
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16 MeSH Terms
Cardiovascular Complications of Novel Multiple Myeloma Treatments.
Li W, Cornell RF, Lenihan D, Slosky D, Jagasia M, Piazza G, Moslehi J
(2016) Circulation 133: 908-12
MeSH Terms: Aged, Antineoplastic Combined Chemotherapy Protocols, Cardiovascular Diseases, Female, Humans, Multiple Myeloma, Treatment Outcome
Added March 6, 2016
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7 MeSH Terms
Venous thromboembolism in hematopoietic stem cell transplant recipients.
Chaturvedi S, Neff A, Nagler A, Savani U, Mohty M, Savani BN
(2016) Bone Marrow Transplant 51: 473-8
MeSH Terms: Allografts, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Lenalidomide, Multiple Myeloma, Postoperative Complications, Thalidomide, Venous Thromboembolism
Show Abstract · Added April 25, 2016
Venous thromboembolism (VTE) is an increasingly recognized problem in the post-hematopoietic stem cell transplantation (HSCT) setting, with a lack of high-quality evidence-based data to recommend best practices. Few patients with hematologic malignancies and even fewer post-HSCT patients were included in randomized trials of VTE prophylaxis and treatment. Prior VTE, GVHD, infections and indwelling venous catheters are risk factors for thrombosis. The increasing use of post-transplant maintenance therapy with lenalidomide in patients with multiple myeloma adds to this risk after autologous HSCT. These patients are also at high risk of bleeding complications because of prolonged thrombocytopenia and managing the competing risks of bleeding and thrombosis can be challenging. This review aims to provide a practical, clinician-focused approach to the prevention and treatment of VTE in the post-HSCT setting.
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9 MeSH Terms
The challenge of cross-trial comparisons using limited data.
Laubach JP, Faber EA, Voorhees P, Moslehi J, Varga C, Niculescu L, Anderson KC, Richardson PG
(2014) Haematologica 99: e145-6
MeSH Terms: Female, Humans, Male, Multiple Myeloma, Oligopeptides, Proteasome Inhibitors
Added March 4, 2015
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6 MeSH Terms
Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines.
Geeleher P, Cox NJ, Huang RS
(2014) Genome Biol 15: R47
MeSH Terms: Algorithms, Antineoplastic Agents, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Models, Genetic, Multiple Myeloma, Predictive Value of Tests
Show Abstract · Added February 22, 2016
We demonstrate a method for the prediction of chemotherapeutic response in patients using only before-treatment baseline tumor gene expression data. First, we fitted models for whole-genome gene expression against drug sensitivity in a large panel of cell lines, using a method that allows every gene to influence the prediction. Following data homogenization and filtering, these models were applied to baseline expression levels from primary tumor biopsies, yielding an in vivo drug sensitivity prediction. We validated this approach in three independent clinical trial datasets, and obtained predictions equally good, or better than, gene signatures derived directly from clinical data.
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14 MeSH Terms