Tumor-Lysis Syndrome in Relapsed or Refractory Multiple Myeloma Patients Treated with Proteasome Inhibitors
Authors: Suzuki Kazuhito , Nishiwaki Kaichi , Gunji Tadahiro , Katori Mitsuji , Hosoba Rika , Hirano Kei , Masuoka Hidekazu , Yano Shingo 
Published: October 2019

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.