Myeloma New Horizons Multiple Myeloma Renal Insufficiency: A systematic review and meta-analysis of all randomized trials from 2005 to 2019

In order to assess the proportion and prognosis of multiple myeloma (MM) patients with renal insufficiency (RI), as well as the impact on the treatment effect, a systematic review and meta-analysis published in Leuk Lymphoma in 2021 on all patients from 2005 to 2019 MM-related randomized controlled trials (RCT) are analyzed to evaluate the prevalence, inclusion criteria and results of renal insufficiency in patients with MM
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In MM-related RCT studies, the reports and enrollment status of RI patients were inconsistent
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The author advocates increasing the enrollment rate of RI patients, and clearly and clearly report their enrollment criteria and results
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The editor will take you to learn more about the analysis results
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Research background RI is a common and serious complication of MM patients
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The incidence of RI in newly diagnosed MM patients is 20%-50%, and half of the diagnosed MM patients usually progress to varying degrees of RI during the course of the disease
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Once RI appears in MM patients, the prognosis is often poor, and it is necessary to reduce the dose of therapeutic drugs or even interrupt the treatment
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New drugs for the treatment of MM, especially proteasome inhibitors (PI) and anti-CD38 antibodies, may improve or even reverse the RI caused by MM and improve the overall prognosis
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Therefore, the need for safe and effective treatment of MM-related RI patients has not yet been met
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Except for a few drugs, many new drugs developed and approved in the past 15 years can cause nephrotoxicity
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Clinical trials that bring new drugs approved are inconsistent in inclusion/exclusion criteria and RI report results
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The International Myeloma Working Group (IMWG) defines RI as creatinine clearance <40ml/min or serum creatinine>2mg/dl
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However, even for clinical trials of new drugs, there is still a lack of RI information for patients with MM included in the study
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The purpose of this systematic review and meta-analysis is to determine the trend of reporting RI in MM patients
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This article is limited to the analysis of MM-related randomized controlled clinical trials (RCT), and in-depth study of RI reports and outcomes in these trials
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This article does not use the traditional definition of RI, but explores the threshold of renal function included and reported in each randomized controlled trial
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  Research methods A comprehensive literature search was conducted on PubMed, Cochrane, Web of Science, and meeting minutes as of January 28, 2020, and all phase III RCTs performed in MM patients between January 2005 and December 2019 were included
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The research objectives include: 1.
Determine the inconsistency of the inclusion criteria of MM-related randomized controlled trials (kidney function-related) between 2005-2019; 2.
Determine the RI (defined as the deadline for each study) for MM-related RCT studies between 2005-2019 Prevalence; 3.
To compare the disease-related outcomes of MM patients with and without RI included in the RCT study from 2005 to 2019, including progression-free survival (PFS), overall survival (OS), and overall response rate ( ORR)
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  Research results A total of 123 RCTs and 55234 MM patients were screened out for analysis on the included studies and characteristics related to kidney-specific variables
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Table 1 shows the characteristics of the study and the related characteristics of the report of kidney-specific variables: different time periods and different types of studies reported less information on the enrollment criteria, the prevalence of RI in the enrolled patients, and the outcome of RI patients, and they were different in different time periods.
There is no statistically significant difference in reports between studies
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Compared with studies related to transplant patients, studies related to patients who are not suitable for transplantation are more likely to report the prevalence of RI in the enrolled patients (41.
9% vs.
18.
8%, p=0.
02); compared to studies evaluating the efficacy of new drugs, evaluating transplantation The efficacy study reported that the prevalence of RI was lower in the enrolled patients (7.
7% vs.
36.
1%, p=0.
04)
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Inclusion criteria analysis Only 84 of the 123 RCT trials (68.
3%) included RI as the trial inclusion criteria
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Among 84 RCT trials, only 12 (14.
2%) included patients with all grades of RI (including dialysis), and the other 5 (5.
9%) excluded patients with other grades of RI on dialysis; 38 RCTs used different creatinine clearance rates as the inclusion criteria: The most common is 30 ml/min (n=21), followed by 40 ml/min (n=6), 15 ml/min (n= 4), 50 ml/min (n= 3), 45 ml/min (n =2), 20 ml/min (n=1), 60 ml/min (n=1); 29 RCTs use different absolute values ​​of creatinine as the entry criteria: the most common 2 mg/dl (n= 8), followed by 3 mg/dl (n= 7), 2.
5 mg/dl (n= 5), 3.
4 mg/dl (n=2), 5 mg/dl (n=2), 5.
6 mg/dl (n=2) , 1.
8 mg/dl (n=1), 1.
2 mg/dl (n=1) and 1.
5 times the upper limit of normal (n=1)
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The proportion of patients with renal insufficiency (RI) included in the study Among the 123 studies, only 38 (30%) studies clearly reported the proportion of patients with RI
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The criteria for distinguishing patients with renal insufficiency and normal renal function are very different.
The most common criteria is creatinine clearance ≤60 ml/min (n=14), or serum creatinine> 2 mg/dl (n=11)
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Outcomes of Patients with Renal Insufficiency In 38 studies that reported the number of patients with RI, a total of 21,298 patients were enrolled, and only 6,033 (28.
3%) patients met the RI criteria.
For example, the MM-003 study (pomalidomide + low-dose dextran) Methsone vs.
high-dose dexamethasone for recurrent myeloma) enrolled 455 patients, and 154 (33.
9%) patients had a creatinine clearance rate of <60ml/min
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11 RCTs reported the results of a subgroup analysis of disease progression and death in MM patients with RI, and analysis of 6 studies that included patients with relapsed/refractory MM showed that MM patients with RI had a high relative risk of disease progression and death (RR) For MM patients without RI, RR=1.
20 (1.
003-1.
431), Z=1.
99, p=0.
05; analysis of 5 studies involving newly diagnosed MM patients showed that the RR of disease progression or death in MM patients with RI was also higher than that of patients without RI.
MM patients with RI, RR=1.
07 (1.
001-1.
046), Z=1.
99, p=0.
05; 9 RCTs performed PFS (risk ratio) analysis on patients with RI, and 3 studies compared patients with and without RI HR of disease progression and/or death: Compared with patients without RI, the combined HR of disease progression/death in patients with RI was 1.
63 (1.
36-1.
94), p = 0.
001
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PFS subgroup analysis results The most common renal function standard creatinine clearance rate ≤ 60 ml/min was used to perform PFS subgroup analysis on 6 RCTs: compared with patients with creatinine clearance rate> 60 ml/min, creatinine clearance rate ≤ 60 ml/min The patient's disease progression/death RR was 1.
08 (1.
01-1.
16), Z=2.
04; P=0.
04
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OS results 3 RCTs reported the survival of patients with RI: Compared with patients without RI, patients with RI had a higher risk of death RR=1.
37 (1.
21-1.
55), Z=4.
98, p=0.
0001; the other 3 RCT reports: Compared with patients without RI, the risk ratio of OS in patients with RI was 1.
88 (1.
66-2.
20), Z=7.
78, p=0.
00001
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In a systematic review of 123 trials of MRD data related to renal function, no trial reports of MRD data in patients with RI were found
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Renal function-related remissions: Five studies reported ORR in patients with RI: Compared with patients with RI, patients without RI had a higher ORR rate (RR=1.
15, 95% CI 1.
01-1.
32, Z=2.
02, p=0.
04 )
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  Conclusion This study is the first to comprehensively analyze myeloma-related RCT studies in the past 15 years, and clarify the significant differences between the enrollment criteria and test reports of patients in the study
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The analysis results show that the current MM-related trials lack a clear report on the proportion of RI patients included, and there is considerable ambiguity and inconsistency in the entry criteria related to renal function in different trials, and there is also a lack of such patients suffering from RCTs.
Rate report
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Compared with patients without RI, the relapse/refractory and first-line treatment of MM patients with RI in the RCT study had worse outcomes
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There is still an urgent need for more RI patients to join the RCT study, and patient enrollment criteria (using standardized definitions, such as IMWG definitions) and outcome reports need to be more standardized and unified
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References: 1.
Mohyuddin GR, Koehn K, Shune L, Aziz M, Abdallah AO, McClune B, Ganguly S, McGuirk J, Kambhampati S.
Renal insufficiency in multiple myeloma: a systematic review and meta-analysis of all randomized trials from 2005–2019[J].
Leuk Lymphoma.
2021 Jun;62(6):1386-1395.
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