Tumor-Lysis Syndrome in Relapsed or Refractory Multiple Myeloma Patients Treated with Proteasome Inhibitors

Abstract <Introduction> Tumor-lysis syndrome (TLS) describes a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells. TLS is a potentially life-threatening complication in rapidly proliferating, bulky tumor, or highly chemo-radiosensitive cancers. In contrast, TLS is the rare complication among patients with multiple myeloma (MM). TLS seems to occur more frequently in MM patients receiving bortezomib (BOR) and carfilzomib (CFZ) than in those receiving other cytotoxic agents. We retrospectively investigated the frequency, risk factors, and clinical outcome among the relapsed or refractory MM (RRMM) patients treated with proteasome inhibitors (PI), such as BOR, CFZ, and ixazomib (IXA), in our institute. <Methods> Between November 2005 and December 2017, seventy-two RRMM myeloma patients treated with BOR, CFZ, or IXA, in our institute. The number of patients treated PI was defined as below. Relapse or refractory disease and response criteria were defined according to the International Myeloma Working Group criteria. Patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and primary plasma cell leukemia were excluded. We evaluated TLS by the Cario-Bishop grading classification. After starting of PI, the following parameters were recorded and evaluated for prognosis: serum hemoglobin concentration (Hb), serum level of lactate dehydrogenase (LDH), creatinine (Cr), uric acid (UA). The cutoff levels of LDH, Cr, and UA were the upper normal limit. Anemia was defined by the CRAB criteria. Hepatosplenomegaly and plasmacytoma were evaluated using computed tomography. We analyze these two groups in terms of patient characteristics, laboratory findings, response, and survival. Fisher's exact tests were used to compare differences between the two groups. We analyzed prognostic factors for survival in significant poor predictors of laboratory parameters and well-established prognostic factors by Cox regression analysis. Overall survival (OS) and time to next treatment (TTNT) were analyzed by the Kaplan-Meier method. <Results> Median age of the patients was 71 years (range, 41-86) at the time of PI treatment. Median number of prior treatments was 2 (range, 1-8). The number of patients treated 53 of BOR, 10 of IXA, 4 of BOR + CFZ, 3 of CFZ + IXA, 1 of BOR + IXA, and 1of BOR + CFZ + IXA, respectively. TLS occurred in 13 patients (18.1%); such as 8 of BOR (13.3%), 4 of CFZ (40.0%), and 1 of IXA (6.7%). TLS occurred more frequently in the patients treated with twice weekly CFZ plus dexamethasone (CFZ 56mg/m2) than twice weekly CFZ, lenalidomide, plus dexamethasone (CFZ 27mg/m2); 50% and 25%, respectively. Median day of TLS after PI was 8 (range, 4-21). Median day of TLS in BOR, CFZ, and IXA were 7.5, 5.5, and 13 days, respectively. Two patients received rasbricase after TLS occurred. There was no patient who underwent hemodialysis for TLS. The mortality related with TLS was none. The significant factors associated TLS were anemia, high LDH level, prior treatments of 2 or more and hepatosplenomegaly according to univariate analysis. In multivariate analysis, high LDH level (Odds ratio; 12.9, P=0.027) and hepatosplenomegaly (Odds ratio; 13.4, P=0.035) was related with TLS significantly. There was no significant difference between overall response rate in the TLS group and non-TLS group (46.4% vs 64.8%, P=0.117). In median follow-up was 12.9 months, the median TTNT of the TLS group was significantly shorter than that of the non-TLS group (1.9 vs 7.0 months, P = 0.009, Figure 1a). The median OS of the TLS group was significantly shorter than that of the non-TLS group as well (5.8 vs 46.4 months, P = 0.017, Figure 1b). <Conclusion> Our analysis revealed that 18.1% of RRMM patients treated with PI developed TLS although TLS was manageable by prophylaxis.gh LDH level and hepatosplenomegaly were identified with significant risk factors for TLS. TLS was not associated with good response of treatment. The TTNT and OS in the TLS group was significantly shorter than those in the non-TLS group. We considered that TLS might be related with progressive disease without activity of treatment in RRMM patients treated with PI. Among the RRMM patients with high LDH level, TLS is one of common adverse events in first cycle of PI but tolerable. Disclosures No relevant conflicts of interest to declare.

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

10.21203/rs.3.rs-22557/v1 ◽

2020 ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Primary Therapy ◽

Novel Therapies ◽

Tumor Lysis ◽

Number Of Patients ◽

Increased Risk

Abstract Background Many novel medicines such as proteasome inhibitors have been developed during the last decade to treat multiple myeloma. Although multiple myeloma is defined as a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. In fact, there have been some prior reports of bortezomib-induced TLS in patients with multiple myeloma. However, almost all of them have been case reports or case series. Thus, we investigated the risk factors for TLS in multiple myeloma patients. Methods We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between LTLS and several parameters previously reported to be associated with increased risk. Results This study included 210 patients, seventeen (8.1%) and seven (3.3%) patients with LTLS and CTLS, respectively. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between the patients with and without LTLS. Multivariate analyses revealed that LTLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of LTLS (odds ratio = 8.51, P = 0.046). Conclusion In the present study, we investigated the risk factors for developing TLS in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male multiple myeloma patients. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, as an increasing number of novel therapies can achieve high antitumor responses.

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

10.21203/rs.3.rs-22557/v4 ◽

2020 ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Novel Therapies ◽

Tumor Lysis ◽

Factors Associated ◽

Increased Risk ◽

Male Patients

Abstract Background: Novel agents such as proteasome inhibitors have been developed for several years to treat multiple myeloma. Although multiple myeloma is a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. Previous studies, mostly case reports or case series, have reported bortezomib-induced TLS in patients with multiple myeloma. This study aimed to investigate risk factors associated with TLS development in multiple myeloma patients.Methods: We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between TLS and several parameters previously reported to be associated with increased risk.Results: This study included 210 patients with multiple myeloma, of which ten (4.8%) had LTLS and seven (3.3%) had CTLS. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between patients with and without TLS. Multivariate analyses revealed that TLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of TLS (odds ratio = 8.51, P = 0.046).Conclusion: In the present study, we investigated the risk factors associated with TLS development in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male patients with multiple myeloma. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, since a significant number of novel therapies can achieve high antitumor responses.

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: a retrospective study

BMC Cancer ◽

10.1186/s12885-020-07592-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Novel Therapies ◽

Tumor Lysis ◽

Factors Associated ◽

Increased Risk ◽

Male Patients

Abstract Background Novel agents such as proteasome inhibitors have been developed for several years to treat multiple myeloma. Although multiple myeloma is a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. Previous studies, mostly case reports or case series, have reported bortezomib-induced TLS in patients with multiple myeloma. This study aimed to investigate risk factors associated with TLS development in multiple myeloma patients. Methods We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between TLS and several parameters previously reported to be associated with increased risk. Results This study included 210 patients with multiple myeloma, of which ten (4.8%) had LTLS and seven (3.3%) had CTLS. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between patients with and without TLS. Multivariate analyses revealed that TLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of TLS (odds ratio = 8.51, P = 0.046). Conclusion In the present study, we investigated the risk factors associated with TLS development in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male patients with multiple myeloma. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, since a significant number of novel therapies can achieve high antitumor responses.

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

10.21203/rs.3.rs-22557/v3 ◽

2020 ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Novel Therapies ◽

Tumor Lysis ◽

Factors Associated ◽

Increased Risk ◽

Male Patients

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

10.21203/rs.3.rs-22557/v2 ◽

2020 ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Novel Therapies ◽

Tumor Lysis ◽

Factors Associated ◽

Increased Risk ◽

Male Patients

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P0568INCIDENCE AND RISK FACTORS OF ACUTE KIDNEY INJURY AND TUMOR LYSIS SYNDROME IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH BORTEZOMIB

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0568 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

SEUNGMIN SONG ◽

Hyo jin Boo ◽

Hye Ryoun Jang ◽

Wooseong Huh ◽

Dae Joong Kim ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Acute Kidney Injury ◽

High Risk ◽

Multivariate Analyses ◽

Tumor Lysis Syndrome ◽

Kidney Injury ◽

Renal Amyloidosis ◽

Tumor Lysis ◽

Β2 Microglobulin

Abstract Background and Aims Nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been described frequently, while tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been increased after introduction of the drug. This study compared the incidence and risk factors of acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate the drug-related nephrotoxicity. Method From 2006 to 2017, 276 patients who underwent first cycle of bortezomib-based chemotherapy for MM were identified in single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network (AKIN) criteria within 7 days after first chemotherapy. Results The age was 65 [56-72] years old, and 47% (n=131) of participants were female and baseline estimated glomerular filtration rate (eGFR) was 61.3 [34.1-89.1] mL/min/1.73m2. The incidences of AKI and laboratory TLS were 17% (n=47) and 13% (n=36), respectively. Ten (3.6%) subjects corresponded to the both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category (30∼59, odds ratio [OR]=3.063 [1.278-7.339]; 15∼29, OR=3.417 [1.088-10.726]; <15, OR=10.080 [2.677-37.951] vs ≥ 60), lower serum albumin level (OR=0.491 [0.278-0.868], P=0.0144) and renal amyloidosis (OR=11.174 [3.974-31.420], P<0.0001) were predictors of development of AKI. MM stages and β2-microglobulin were not associated with AKI occurrence. Regarding laboratory TLS, MM stage and β2-microglobulin were higher in those with TLS. In multivariate analyses, β2-microglobulin levels (OR=1.194 [1.066-1.337], P=0.0021) and any chromosomes abnormalities at high risk (OR=0.115 [0.026-0.503], P=0.0041) were associated with higher risk of TLS. Conclusion Development of AKI was often observed without being accompanied by TLS in patients with MM after treatment of bortezomib. In addition, risk factors of AKI and TLS were widely different. These findings implicated the potential nephrotoxicity of bortezomib besides TLS in patients with decreased kidney function. The efforts to prevent bortezomib associated AKI are needed in patients at high risk.

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Carfilzomib Induced Tumor Lysis Syndrome and Other Adverse Events

Journal of Pharmacy Practice ◽

10.1177/0897190018802129 ◽

2018 ◽

Vol 33 (2) ◽

pp. 213-216 ◽

Cited By ~ 1

Author(s):

El Bitar Sandy ◽

Chanudi Weerasinghe ◽

Terenig Terjanian

Keyword(s):

Multiple Myeloma ◽

Targeted Therapy ◽

Adverse Events ◽

Safety Profile ◽

Tumor Lysis Syndrome ◽

Proteasome Inhibitors ◽

Second Line ◽

Rare Occurrence ◽

Tumor Lysis ◽

Line Setting

In the area of multiple myeloma (MM) therapy, proteasome inhibitors (PI) have emerged with promising responses both in the first- and second-line setting. Carfilzomib (CFZ) is a second-generation, selective PI approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) in patients who received 2 prior therapies or have evidence of disease progression within 60 days of completion of last therapy. Its safety profile reported adverse events (AEs) ranging from drug-related AEs (nausea and vomiting), hematologic AEs (neutropenia and thrombocytopenia), and nonhematologic AEs (electrolyte imbalances). As CFZ use is gaining popularity, various hematological, renal, cardiovascular, pulmonary, and neurological toxicities have been reported. We are presenting this case to describe a rare occurrence of tumor lysis syndrome (TLS) with the use of this novel targeted therapy.

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Carfilzomib-induced tumor lysis syndrome in relapsed multiple myeloma: a report of two cases

Tumori Journal ◽

10.1177/0300891618793817 ◽

2018 ◽

Vol 105 (6) ◽

pp. NP24-NP27

Author(s):

Esra Terzi Demirsoy ◽

Elif Birtas Atesoglu ◽

Necmi Eren ◽

Ayfer Gedük ◽

Ozgur Mehtap ◽

...

Keyword(s):

Multiple Myeloma ◽

Case Report ◽

Proteasome Inhibitor ◽

Tumor Lysis Syndrome ◽

Proteasome Inhibitors ◽

Hematologic Malignancies ◽

Metabolic Abnormalities ◽

Fatal Complication ◽

Tumor Lysis ◽

Proven Efficacy

Background: Tumor lysis syndrome (TLS) is a potentially fatal complication of cancer therapy characterized by severe electrolyte and metabolic abnormalities such as hyperphosphatemia, hyperkalemia, and hypocalcaemia. TLS usually occurs in aggressive hematologic malignancies such as Burkitt lymphoma and acute leukemia. TLS has rarely been observed in multiple myeloma (MM). Case report: We present 2 patients with relapsed MM who developed TLS after the first cycle of carfilzomib treatment. Conclusion: Carfilzomib is a next-generation proteasome inhibitor with proven efficacy in relapsed/refractory MM. Recently, increasing frequency of TLS has been reported in MM, especially after treatment with proteasome inhibitors. The potential complications of TLS should be considered especially during the first cycle of carfilzomib treatment.

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An Analysis of Dental Implants Survival and Success

Revista de Chimie ◽

10.37358/rc.18.9.6554 ◽

2018 ◽

Vol 69 (9) ◽

pp. 2465-2466

Author(s):

Iustin Olariu ◽

Roxana Radu ◽

Teodora Olariu ◽

Andrada Christine Serafim ◽

Ramona Amina Popovici ◽

...

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Medical History ◽

Retrospective Cohort Study ◽

Odds Ratio ◽

Retrospective Cohort ◽

Demographic Data ◽

Kaplan Meier ◽

Number Of Patients ◽

Health Related

Osseointegration of a dental implant may encounter a variety of problems caused by various factors, as prior health-related problems, patients� habits and the technique of the implant inserting. Retrospective cohort study of 70 patients who received implants between January 2011- April 2016 in one dental unit, with Kaplan-Meier method to calculate the probability of implants�s survival at 60 months. The analysis included demographic data, age, gender, medical history, behavior risk factors, type and location of the implant. For this cohort the implants�survival for the first 6 months was 92.86% compared to the number of patients and 97.56% compared to the number of total implants performed, with a cumulative failure rate of 2.43% after 60 months. Failures were focused exclusively on posterior mandible implants, on the percentage of 6.17%, odds ratio (OR) for these failures being 16.76 (P = 0.05) compared with other localisations of implants, exclusively in men with median age of 42 years.

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