A case of bortezomib-associated thrombotic microangiopathy in a multiple myeloma patient

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma. We present a case of a 70-year-old woman with multiple myeloma, who presented thrombotic microangiopathy with multi-organ involvement thrombotic microangiopathy (ocular, cardiac, and renal) after bortezomib initiation. A kidney biopsy confirmed the diagnosis of thrombotic microangiopathy. A temporal relation between bortezomib exposure and thrombotic microangiopathy onset was seen in the absence of other concurrent medication or disease known to cause thrombotic microangiopathy, and thrombotic microangiopathy was only resolved after drug discontinuation. The exact pathophysiological mechanism remains unknown. To our knowledge, this is the second biopsy-proven published case of bortezomib-associated thrombotic microangiopathy. Since bortezomib is extensively used for treating patients with multiple myeloma, prescribing clinicians should maintain a high index of suspicion of this potentially fatal complication.

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Renal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma

Case Reports in Hematology ◽

10.1155/2016/6020691 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Jan Van Keer ◽

Michel Delforge ◽

Daan Dierickx ◽

Kathelijne Peerlinck ◽

Evelyne Lerut ◽

...

Keyword(s):

Multiple Myeloma ◽

Thrombotic Microangiopathy ◽

Proteasome Inhibitor ◽

First Generation ◽

Causal Role ◽

Proven Case

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated.

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Bilateral Pleural Effusions due to Pulmonary Amyloidosis as the Presenting Manifestation of Multiple Myeloma

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2012.010 ◽

2012 ◽

Vol 4 (1) ◽

pp. e2012010

Author(s):

Abhishek Agarwal ◽

Sandeep Singla ◽

Meghana Bansal ◽

Bijay Nair

Keyword(s):

Multiple Myeloma ◽

Hematologic Malignancy ◽

Multiorgan Failure ◽

Pleural Effusions ◽

Imaging Studies ◽

Multiple Myeloma Patient ◽

Pulmonary Amyloidosis ◽

Undetermined Etiology ◽

High Index Of Suspicion ◽

Work Up

Multiple myeloma is a hematologic malignancy of plasma cell origin. Pleural effusion may develop in the setting of myeloma due to various reasons but is extremely uncommon as a presenting symptom. A 69-year-old Caucasian man presented with pleural effusions of undetermined etiology after extensive work up, and multiple failed pleurodesis. Lung biopsy revealed pulmonary amyloidosis and led to the diagnosis of multiple myeloma. Patient was started on chemotherapy but died within 6 weeks of his diagnosis due to multiorgan failure. Pulmonary amyloidosis should be suspected as a cause of intractable pleural effusions, even in patient who do not have evidence of lung involvement on imaging studies or typical features of multiple myeloma. Pleural effusions due to amyloidosis are often refractory to treatment, and a high index of suspicion is required for early diagnosis and treatment.

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Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

Journal of Onco-Nephrology ◽

10.1177/2399369319887979 ◽

2019 ◽

Vol 4 (1-2) ◽

pp. 41-45 ◽

Cited By ~ 1

Author(s):

Takeo Koshida ◽

Sylvia Wu ◽

Hitoshi Suzuki ◽

Rimda Wanchoo ◽

Vanesa Bijol ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Tyrosine Kinase Inhibitors ◽

Thrombotic Microangiopathy ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kidney Biopsy ◽

Kinase Inhibitor ◽

Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

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Comparison of the prognostic significance of 5 comorbidity scores and 12 functional tests in a prospective multiple myeloma patient cohort

Cancer ◽

10.1002/cncr.33658 ◽

2021 ◽

Author(s):

Sophia Scheubeck ◽

Gabriele Ihorst ◽

Katja Schoeller ◽

Maximilian Holler ◽

Mandy‐Deborah Möller ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Significance ◽

Functional Tests ◽

Myeloma Patient ◽

Multiple Myeloma Patient ◽

Patient Cohort ◽

Comorbidity Scores

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Abnormal radiological features in a multiple myeloma patient: a case report and radiological review of myelomas

Dentomaxillofacial Radiology ◽

10.1259/dmfr/74265829 ◽

2011 ◽

Vol 40 (8) ◽

pp. 513-518 ◽

Cited By ~ 15

Author(s):

S Ghosh ◽

P Wadhwa ◽

A Kumar ◽

KM Pai ◽

S Seshadri ◽

...

Keyword(s):

Multiple Myeloma ◽

Case Report ◽

Myeloma Patient ◽

Multiple Myeloma Patient ◽

Radiological Features

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Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽

10.1182/blood-2019-127893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1848-1848

Author(s):

Maria Karvouni ◽

Heyue Zhou ◽

Arnika Kathleen Wagner ◽

Qiangzhong Ma ◽

Alamdar H. Baloch ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Therapeutic Potential ◽

Ex Vivo ◽

Phase 1 ◽

Employment Equity ◽

Multiple Myeloma Patient ◽

Myeloma Cells ◽

Car T ◽

Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

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Clinically Suspected Cast Nephropathy: A Retrospective, Multi-Center, Real-World Study

Blood ◽

10.1182/blood-2019-124336 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5553-5553

Author(s):

Agoston Gyula Szabo ◽

Jonathan Thorsen ◽

Charlotte Toftmann Hansen ◽

Maja Ølholm Vase ◽

Manuela Teodorescu ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Serum Creatinine ◽

Board Of Directors ◽

Kidney Biopsy ◽

Population Based ◽

First Line ◽

Advisory Committees ◽

Cast Nephropathy ◽

Initiation Of Therapy

INTRODUCTION Myeloma cast nephropathy (CN) is the most common form of monoclonal immunoglobulin-mediated kidney disease, resulting from the precipitation of excessive amounts of monoclonal serum free light chains (sFLC) and causing around 70% of the cases of dialysis-dependent renal failure in multiple myeloma (MM)(Heher et al. 2013; Nasr et al. 2012; Sanders et al. 1991). In patients with acute renal failure, the finding of a high sFLC concentration with an abnormal sFLC ratio raises the clinical suspicion of CN (Hutchison et al. 2011). Although the histopathologic diagnosis of CN is established by renal biopsy, in routine clinical practice, the diagnostic yield of this procedure is often outweighed by the urgent need of anti-myeloma treatment and the risk of procedure-related complications. Recruitment of patients with CN into clinical trials is challenging and therefore real-world data on clinically suspected CN are necessary to understand the clinical characteristics, treatment and prognosis of these patients (Bridoux et al. 2017; Hutchison et al. 2019). METHODS We searched the population-based Danish Multiple Myeloma Registry for patients diagnosed with MM according to the International Myeloma Working Group criteria between 1st of January 2013 and 31st of December 2017 with a serum creatinine concentration of 200 µg/L or higher and a sFLC concentration of 1000 mg/L or higher at diagnosis. We conducted a retrospective patient chart review in eight Danish centers and assessed baseline characteristics, biopsy results, and overall survival. Anti-myeloma treatment, sFLC levels and renal function were registered during the first 12 months after MM diagnosis. RESULTS We identified 181 patients (176 with accessible clinical records). The median age was 72 years, the median serum creatinine was 384 µg/L, the median involved sFLC concentration was 5960 mg/L and dialysis dependent renal failure was present in 35%. Pre-myeloma estimated glomerular filtration rate (eGFR) was available in 80%, the median eGFR was 66 ml/min/1.73 m2. A kidney biopsy was carried out in 21% of patients and showed CN in 70% of cases. The median time from first sFLC measurement to initiation of therapy was 4 days. The number of lines of therapy ranged between zero and six. 173 patients received one, 35 patients received two and 14 patients received three lines of therapy during the first 12 months from diagnosis. High-dose melphalan with autologous stem cell transplantation (HDT-ASCT) was carried out in 45 (26%) patients. Bortezomib was administered as part of the first-line regimen in 163 (94%) patients. The most common first-line regimens were bortezomib-dexamethasone (n=67) and cyclophosphamide-bortezomib-dexamethasone (n=46). The first line of therapy resulted in very good partial response or better in 50% (Figure 1A), but was discontinued due to death, toxicity or progressive disease in 38% of patients. Dialysis dependency, eGFR and involved sFLC concentration were assessed at the end of the first cycle, at three months, six months and 12 months after initiation of therapy. At all these time points, achievement of renal recovery was associated with the magnitude of reduction of involved sFLC (Figure 1B). The median overall survival was 3.3 years (Figure 1C). At 12 months after diagnosis, 68% of patients were alive and 15% were dialysis dependent. Reduction of the initial involved sFLC concentration to ≤ 10% at three months was strongly associated with longer OS in a multivariate cox regression analysis adjusted for age and HDT-ASCT; hazard ratio 0.42, p=0.003. CONCLUSION In conclusion, we assessed a population-based cohort of newly diagnosed MM patients presenting with a serum creatinine of 200 µg/L or higher together with a sFLC of 1000 mg/L or higher. Although CN could have been clinically suspected in these cases, a kidney biopsy was only performed in one fifth of the population. Bortezomib-based therapy was initiated quickly and resulted in deep responses in most patients. Approximately one third of patients died within a year from MM diagnosis. Achievement of early and deep reduction in involved sFLC resulted in longer OS. Figure 1 Disclosures Szabo: Janssen: Consultancy. Vangsted:Takeda: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Celgene: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Plesner:Celgene: Consultancy; AbbVie: Consultancy; Genmab: Consultancy; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding.

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A Rare Case of Rituximab Induced Allergic Interstitial Nephritis with a Good Response to Glucocorticoids

10.33169/biomcase.bacroaoj-2-122 ◽

2021 ◽

Vol 2 (2) ◽

pp. 80-83

Author(s):

Vrushali Dabak

Keyword(s):

Interstitial Nephritis ◽

Kidney Biopsy ◽

Central Nervous System Lymphoma ◽

Hematologic Malignancies ◽

Drug Induced ◽

First Case ◽

Autoimmune Conditions ◽

Anti Cd20 ◽

High Index Of Suspicion ◽

Wide Usage

Rituximab is a chimeric anti-CD20 monoclonal antibody that has been widely used to treat CD 20 positive hematologic malignancies and some autoimmune conditions. Although usually well tolerated, an increasing number of serious complications related to rituximab have been noted with its wide usage. We report a 67-year-old man who developed biopsy-proven Allergic Interstitial Nephritis (AIN) after treatment with rituximab for his Primary Central Nervous System Lymphoma (PCNSL). Rituximab-induced AIN was confirmed by kidney biopsy, and his kidney function improved to his baseline with supportive care and four weeks of steroid treatment. While rare, AIN could be a possible adverse effect of rituximab. To our knowledge, this is the first case report of a biopsy-proven AIN from rituximab. The association of AIN and rituximab in our case necessitates a high index of suspicion to facilitate early detection of AIN and timely discontinuation of the offending medication. Keywords: Rituximab; Drug induced allergic interstitial nephritis.

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