Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: a critical appraisal of the pre-antibody era.

Introduction

Multiple myeloma (MM) is often complicated by renal insufficiency (RI), which is defined as reduced clearance of creatinine (CrCl < 40 ml/min) or increased serum creatinine (Scr > 2 mg/dl) in MM patients [ 1 ]. The MM with RI have an inferior prognosis [ 2 ], which may be related to early mortality and disease complications caused by RI [ 3 , 4 ]. MM with dialysis-dependent RI have an even worse prognosis than those with mild RI [ 5 ]. Therefore, the inductive treatment options for MM with RI are of pivotal importance.

In general, high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HDM-ASCT) confers the best treatment outcomes and fewer adverse effects for transplantation-eligible MM patients [ 6 ]. Compared to MM patients treated with chemotherapy, the patients received HDM-ASCT can achieve longer event-free survival and a higher response rate [ 6 ]. In the new-drug era, the combination of novel medications for induction and consolidation therapy with HDM-ASCT benefits eligible MM patients more in survival outcomes than the traditional pharmaceuticals coupled HDM-ASCT [ 7 , 8 ].

However, whether HDM-ASCT benefits MM with RI is still controversial. Some research indicated that HDM-ASCT might result in increased treatment-related mortality (TRM) in MM with RI, therefore, the presence of RI limits the ASCT eligibility [ 9 ]. A meta-analysis published in 2019 reported that MM with RI received HDM-ASCT had an increased risk of mortality, while the survival benefit was controversial [ 10 ]. In recent years, several studies showed that HDM-ASCT in MM with RI did not significantly increase the toxicity and demonstrated the feasibility of HDM-ASCT in these patients [ 11 – 15 ]. Besides, recent data suggests that CD38 monoclonal antibodies are both safe and highly effective in MM patients with RI, including those on dialysis, with some patients experiencing rapid improvement in kidney function. Ongoing research is exploring the potential of incorporating CD38 monoclonal antibodies before and after ASCT, which could alter the treatment approach for MM patients with RI. Consequently, we performed a meta-analysis to assess how RI affects the safety and efficacy of ASCT in MM patients before the advent of monoclonal antibody treatments. Additionally, we compared the real-world clinical data from MM patients at our center with the results of the meta-analysis. This analysis aims to provide baseline data for comparing the effectiveness of new treatment strategies in the era of monoclonal antibody immunotherapy for MM patients with RI.

Methods

The systematic review and meta-analysis followed the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [ 16 ]. The protocol was registered on PROSPERO (CRD42021297282).

Search strategy and selection of studies

The literature search was conducted in PubMed, the Cochrane Library, and the EMBASE with the keywords of “multiple myeloma”, “renal insufficiency”, “renal failure” and “hematopoietic stem cell transplantation”. Relevant publications in English before December 2023 were collected. The references of the selected articles were retrieved manually to supplement the electronic database retrieval. A study was included when it met all the inclusion criteria: (1) include MM patients with a validated diagnosis of RI; (2) provide the outcomes of clinical response and survival after ASCT; (3) compare the outcomes after ASCT between MM patients with or without RI, or analyze the outcomes after ASCT in patients with MM and RI; (4) original research. The exclusion criteria were as follows: (1) studies of duplicated enrollment of patients; (2) patients in the study did not experience ASCT; (3) renal function of patients was not assessed; (4) studies without detailed data on clinical response and survival data; (5) patients in the study received monoclonal antibody therapy; (6) case reports, reviews, letters, and conference abstracts. Selection of studies was first undertaken by two reviewers and confirmed by two separate reviewers. Any disagreements were settled by consensus.

Data extraction

Data extraction was conducted by 2 reviewers, and the following information was collected: the first name of the corresponding author, publication year, country, study design, sample size, number of participants in each group, diagnosis of RI, median age, conditioning regimen, induction chemotherapy, clinical response and survival rate including TRM, overall response rate (ORR), partial response (PR) rate, very good partial response (VGPR) rate, complete response (CR) rate, overall survival (OS) and progression-free survival (PFS). Some studies compared MM patients who had different levels of RI with those who had normal renal function. For our analysis, we focused solely on data from patients with severe renal impairment and normal renal function.

Quality assessment

The assessment of the quality of case series and cohort studies has been evaluated using the Johanna Briggs Institute Scale for Case Series [ 17 ] and the Newcastle–Ottawa scale [ 18 ], respectively. Two independent reviewers assessed the quality of the studies using the checklists. Discrepancies were resolved through discussion.

MM patients for comparison

Clinical information from MM patients who underwent ASCT between March 2018 and January 2024 at West China Hospital of Sichuan University was retrospectively collected. Clinical data including pre-transplant estimated glomerular filtration rate (eGFR), TRM, post-transplant response, PFS, and OS were collected. Patients whose pre-transplant renal function data were unavailable were excluded. Based on the pre-transplant eGFR, patients were categorized into two groups: the RI group (eGFR < 60 ml/min/1.73m 2 ) and the normal renal function group (eGFR ≥ 60 ml/min/1.73m 2 ). The TRM, clinical response, and survival outcomes were then compared between the two groups.

Statistical analysis

Statistical analysis was done using Revman 5.3 and R-4.3.3 software. Odds ratio (OR) was used as the effect analysis statistic for dichotomous variables, and hazard ratio (HR) was used as the effect analysis statistic for time-to-event variables. If HR cannot be obtained directly from the original text, relevant parameters should be obtained to calculate HR indirectly according to the method provided by Parmar et al. [ 19 ]. When the paper provided Kaplan–Meier curves of PFS and OS, Engauge Digitizer was used to extract the survival probability of each time point. The data was then imported into the HR calculation table developed by Tierney et al. [ 20 ]. Furthermore, their estimated HR and 95%CI were used for analysis. Heterogeneity among studies was calculated using I 2 measures. When I 2 was less than 50%, the fixed-effect model was used; on the contrary, the source of heterogeneity was further analyzed by subgroup-analysis, and the random-effect model was used. The funnel plots were established to check publication bias. The PFS and OS were estimated using Kaplan–Meier method and compared by Renyi-type test.

Results

Study selection

Figure 1 showed the selection procedures. A total of 26 studies [ 2 , 11 – 14 , 21 – 41 ] were included in our analysis, and 13 [ 14 , 21 – 29 , 38 – 40 ] of them were selected for the qualitative analysis, and the other 13 [ 2 , 11 – 13 , 30 – 37 , 41 ] for the meta-analysis.

Characteristic and risk of bias of included studies

The characteristics of the studies included in the systematic review and meta-analysis are shown in Table 1 and Table 2 . Most included studies were conducted in North America and Europe. The definitions of RI in these studies were different, including Scr ≥ 2.0 mg/ml or 177 mmol/l, Scr ≥ 3 mg/dl, CrCl < 60 ml/min, CrCl < 30 ml/min, eGFR < 60 ml/min/1.73m 2 or dialysis dependent. The majority of studies reported different doses of melphalan for conditioning.

The bias risk assessment outcomes for the included case series, assessed using the Joanna Briggs Institute Scale for Case Series, are summarized in Table 3 . Eleven studies were identified as having a low risk of bias, whereas the other two were classified as having a moderate risk of bias. The results of the bias risk assessment for the included cohort studies, evaluated using the Newcastle–Ottawa scale, are provided in Table 4 . The scores of 13 cohort studies ranged from 7 to 8, indicating a low risk of bias.

Results of qualitative analysis

Thirteen retrospective studies [ 14 , 21 – 29 , 38 – 40 ], involving 630 MM patients with RI, of whom 368 were dialysis-dependent, reported outcomes such as TRM, clinical response, and survival, were analyzed (see Table 1 ).

TRM

There were 12 studies [ 14 , 21 – 23 , 25 – 27 , 29 , 38 – 40 ] reporting TRM data, defined as treatment-related mortality within 100 days post-ASCT (Table 1 ). The reported TRM rates varied significantly across different studies, ranging from 0 to 17%. Studies with a higher proportion of patients receiving low-dose melphalan (no more than 140 mg/m 2 ) as a conditioning regimen tended to report lower TRM rates. Specifically, Badros et al. [ 27 ] compared the TRM rates in patients treated with melphalan of 140 mg/m 2 (MEL140) and 200 mg/m 2 (MEL200). It showed that the ratios of TRM in MEL140 group and MEL200 group were 5% and 7%, but the p value was not significant. In the study of Cornillon et al. [ 21 ] and Amanda et al. [ 14 ], more than half of included RI patients received new drugs such as bortezomib for induction therapy, and 80% of patients were treated with dose-reduced melphalan of no more than 140 mg/m 2 for conditioning agent, and these studies reported lower TRM rates of 6% and 0%. Additionally, the timing of ASCT can also affect TRM, which may be associated with reduced dosage of melphalan for conditioning regimen, the use of novel agents for induction therapy and improvements in supportive care. In the study by Amanda et al. [ 14 ], MM patients with RI who underwent ASCT in the older era had a TRM rate of 13%. These patients did not receive new drugs for induction therapy, and 87% of them received MEL200 for conditioning regimen. On the other hand, patients who received ASCT in new era had a lower TRM rate of 0%; most of these patients were treated with new drugs such as bortezomib during induction therapy, and 84% received MEL140 for conditioning regimen. Similarly, in the study by Garderet et al. [ 39 ], 98% of the patients received proteasome inhibitor-based induction therapy, and 90% received a melphalan dose of no more than 140 mg/m 2 , with a reported TRM rate of 2%.

ORR

The ORR rate of MM with RI after ASCT was high, ranging from 73 to 100% (Table 1 ). ASCT could also result in high rate of VGPR and above (about 50%) for dialysis-dependent patients [ 22 , 23 , 26 , 40 ]. Specifically, Badros et al. [ 27 ] reported comparable CR rates after ASCT between patients treated with MEL200 and MEL140 (35% and 33%, p = 0.90), showing that the intensity of the conditioning regimen at ASCT had no significant effect on CR rate. In the studies of Amanda et al. [ 14 ] and Garderet et al. [ 39 ], in which MM with RI had received bortezomib-based induction chemotherapy and dose-reduced melphalan for the conditioning regimen, both reported high rates of VGPR and above (79%; 91%) after ASCT.

Survival

The existing data showed an increase in survival time for MM patients as the study era progressed, with the longest median PFS being 56 months, and the longest median OS being 105 months. In 4 studies [ 22 , 23 , 26 , 40 ] which reported outcomes of dialysis-dependent patients, the longest median PFS was 45 months, and the longest median OS was 105 months. However, Glavey et al. [ 24 ] found that dialysis-dependent patients had worse OS outcomes than low-CrCl group patients (median OS: 29.3 and 64.7 months, p = 0.06). The result indicated that ASCT could benefit MM patients with RI in survival. Besides, with the use of new agents such as bortezomib-based regimens as induction chemotherapy and the advances in supportive care, the survival time of MM patients with RI who underwent ASCT could be gradually prolonged.

Results of meta -analysis

The effects of RI on TRM, clinical response, and survival after ASCT were analyzed in MM patients with RI and MM patients with NRF. A total of 13 retrospective cohort studies [ 2 , 11 – 13 , 30 – 37 , 41 ] were included in the meta-analysis, where the definition of RI and the timing of RI diagnosis varied across different studies (Table 2 ). Overall, these studies reported comparisons between three types of MM patients diagnosed with RI at different times and MM patients with NRF. The three types of MM patients with RI included those diagnosed with RI at the time of MM diagnosis, those diagnosed with RI at the time of MM diagnosis but who recovered normal renal function before transplantation, and those with persistent RI at the time of transplantation. We will subsequently analyze and compare these three groups of MM patients separately with those having NRF.

MM patients with RI at transplantation vs MM patients with NRF

Ten studies [ 2 , 12 , 13 , 31 , 33 – 37 , 41 ] compared the clinical responses and survival outcomes post-autologous transplantation between MM patients with RI at the time of transplantation and MM patients with NRF. A total of 3414 MM patients were included, with 327 patients having RI at transplantation and 3087 patients having NRF.

TRM

Eight studies [ 2 , 12 , 33 – 37 , 41 ] reported the data of TRM, but the doses of melphalan ranged from 100 ~ 200 mg/m 2 . When a meta-analysis of TRM was conducted regardless of melphalan doses, MM with RI at transplantation had higher TRM than MM with NRF (fixed-effects OR 5.95, 95%CI 3.10–11.43, p < 0.001, I 2 = 0%) (Fig. 2 a). Three studies [ 34 , 36 , 41 ] made comparisons between MM patients with severe RI (dialysis-dependent or eGFR < 30 ml/min/1.73m 2 ) at transplantation and MM with NRF. The meta-analysis showed that TRM was comparable between RI and NRF groups when melphalan was controlled no more than 140 mg/m 2 in MM with RI (fixed-effects OR 2.56, 95%CI 0.59–11.09, p = 0.21, I 2 = 0%) (Fig. 2 b).

ORR

Among included studies, 6 studies [ 2 , 12 , 13 , 34 , 35 , 41 ] reported ORR, and another 6 studies [ 12 , 13 , 31 , 34 , 35 , 41 ] reported CR after ASCT. The evaluation of the response to transplantation was determined by the best response status achieved after transplantation or the status at 100 days after transplantation. According to the meta-analysis results, the ORR for the group with NRF is greater than that for the group with RI at transplantation, with a p -value of 0.05 (fixed-effects OR 0.65, 95%CI 0.42–1.00, p = 0.05, I 2 = 0%) (Fig. 2 c). The meta-analysis showed that CR rates were comparable between MM with RI at transplantation and NRF (fixed-effects OR 1.17, 95%CI 0.84–1.61, p = 0.35, I 2 = 4%) (Fig. 2 d).

Survival

A total of 9 studies [ 2 , 12 , 13 , 31 , 33 – 37 , 41 ] with data of PFS could be pooled in the meta-analysis. The treatment-free survival was reported in the research by Sweiss et al. [ 31 ], but it was excluded from the meta-analysis of PFS. The meta-analyses of PFS at 2 and 5 years after transplantation showed that the PFS was comparable between MM patients with RI at transplantation and those with NRF (fixed-effects HR/2y 1.13, 95%CI 0.92–1.38, p = 0.23, I 2 = 0%; fixed-effects HR/5y 1.20, 95% CI 0.99–1.45, p = 0.07, I 2 = 5%) (Fig. 3 a and b).

Nine studies [ 2 , 12 , 13 , 31 , 33 – 36 , 41 ] were available for the meta-analysis of OS. The meta-analysis showed that the OS was poorer after ASCT in MM with RI at transplantation than in MM with NRF (fixed-effects HR/2y 2.66, 95% CI 1.91–3.72, p < 0.001, I 2 = 19%; fixed-effects HR/5y 1.68, 95% CI 1.35–2.10, p < 0.001, I 2 = 0%) (Fig. 3 c and d).

Funnel plots were evaluated for all included studies for survival analysis. The two sides of the funnel are symmetrical, and no significant publication bias was found. The funnel plots are presented in Supplementary Figs. 1–4.

MM patients with RI at diagnosis vs MM patients with NRF

Three studies [ 11 , 32 , 42 ] comparing the clinical outcomes after ASCT between MM patients with RI at diagnosis and those with NRF were analyzed. A total of 154 MM patients with RI at diagnosis and 780 patients with NRF were included. However, since none of the three studies reported TRM and only one reported ORR, a meta-analysis of TRM and treatment response could not be conducted. There were no significant differences in 2-year and 5-year PFS between the 2 groups (fixed-effects HR/2y 1.12, 95%CI 0.79–1.60, p = 0.52, I 2 = 0%; random-effects HR/5y 1.32, 95%CI 0.89–1.97, p = 0.16, I 2 = 75%) (Fig. 4 a and b). The meta-analysis of OS showed that there was no significant difference in 2-year OS between the two groups (fixed-effects HR/2y 1.13, 95%CI 0.86–1.5, p = 0.38, I 2 = 5%) (Fig. 4 c), however, the 5-year OS was poorer in patients with RI at diagnosis compared to those without (fixed-effects HR/5y 1.21, 95%CI 1.09–1.35, p < 0.001, I 2 = 48%) (Fig. 4 d).

MM patients with RI at diagnosis but normal renal function before ASCT vs MM patients with NRF

Three studies [ 2 , 12 , 35 ] comparing MM patients with RI at diagnosis but normal renal function before ASCT to MM patients with NRF were included for meta-analysis, including 170 patients with RI and 795 patients with NRF. Despite most patients receiving MEL200 for conditioning regimen, there was no significant difference in TRM between the two groups (fixed-effects OR 1.37, 95%CI 0.47–3.96, p = 0.56, I 2 = 0%) (Fig. 5 a). Regarding treatment response, there was no significant difference in the post-transplant ORR and CR rate between the two groups (fixed-effects OR 1.61, 95%CI 0.75–3.42, p = 0.22, I 2 = 0%; fixed-effects OR 1.31, 95%CI 0.91–1.9, p = 0.14, I 2 = 0%) (Fig. 5 b and c). The meta-analysis of PFS showed no significant differences in the risk of a poorer PFS from 2 to 5 years after ASCT in MM patients with RI at diagnosis but normal renal function before ASCT than those with NRF (fixed-effects HR/2y 1.33, 95%CI 0.98–1.79, p = 0.06, I 2 = 0%; fixed-effects HR/5y 1.14, 95%CI 0.87–1.51, p = 0.34, I 2 = 0%) (Fig. 5 d and e). However, the meta-analysis revealed that MM patients with RI had significantly lower 2-year and 5-year OS rates compared to patients with NRF (fixed-effects HR/2y 2.24, 95%CI 1.62–3.1, p < 0.001, I 2 = 24%; fixed-effects HR/5y 1.81, 95%CI 1.41–2.31, p < 0.001, I 2 = 2%) (Fig. 5 f and g).

Results of real-world data

A total of 97 newly diagnosed MM patients who underwent ASCT at West China Hospital of Sichuan University were included in the study, of whom 51 (52.6%) were males, with a median age of 53 years (range 24–67). At diagnosis, the median hemoglobin and platelet levels were 108 g/L and 176*10 9 /L, respectively; the median albumin, LDH, and beta 2-microglobulin levels were 41.5 g/dL, 180 IU/L, and 3.7 mg/dL, respectively. The International Staging System (ISS) stage was 1–2 for 65 patients (67%) and stage 3 for 32 patients (33%); for the Revised-ISS stage, 69 patients (71.2%) were stage 1–2, and 28 patients (28.9%) were stage 3. For pre-transplant induction therapy, 58.8% of patients received a proteasome inhibitor-based induction regimen, 39.1% received a regimen based on proteasome inhibitors plus immunomodulatory drugs, and only 2.1% received a regimen based solely on immunomodulatory drugs. Based on pre-transplant eGFR levels, 16 patients were in the RI group, and 81 patients were in the NRF group. The median pre-transplant eGFR in the RI group was 40.2 ml/min/1.73m2 (range 20.7–55.8). Compared to patients in the NRF group, those in the RI group had lower hemoglobin levels and higher LDH and beta 2-microglobulin levels at diagnosis, and a significantly higher proportion of stage 3 ISS. There were no significant differences between the two groups in terms of gender, age, platelet count, albumin level, R-ISS stage, or induction regimen. Details were shown in Supplementary Table 1. In the NRF group, 96.3% of patients received MEL200 as the conditioning regimen, whereas 62.5% of patients in the RI group received MEL140. No TRM occurred in either group. The post-transplant ORR was 100% in the RI group and 97.5% in the NRF group ( p = 1.00). The CR rate post-transplant was 68.7% in the RI group and 60.5% in the NRF group, with no significant statistical difference ( p = 0.59). After a median follow-up of 30.3 months (range 3.5–72), survival analysis showed no significant difference in PFS between the two groups ( p = 0.29) (Fig. 6 a). Despite the lack of a statistically significant difference in OS between the two groups ( p = 0.37, Fig. 6 b), MM patients with RI had a slightly shorter 5-year restricted mean survival time. Specifically, the 5-year restricted mean survival time for the RI group was 54.7 months, compared to 55.8 months for those with NRF.

Discussion

RI is a pejorative factor for the prognosis of MM patients [ 43 ]. Although RI is not considered as an exclusion criterion for HDM-ASCT, MM with RI might have diminished administration for HDM-ASCT in the real world [ 44 ]. Given the inconsistent conclusions of previous retrospective studies and the lack of timeliness of a previous meta-analysis [ 10 ], we conducted this meta-analysis and systematic review to analyze TRM, clinical response and survival in MM patients with RI before the advent of monoclonal antibody treatments. The findings of this study have potential implications for clinical practice, including better treatment decisions and patient management by clinicians.

The results of the meta-analysis indicated that reducing the dose of melphalan was safe for MM with RI at transplantation undergoing ASCT. Lowering the dose of melphalan can decrease TRM, and when the dose of melphalan didn’t exceed 140 mg/m 2 , the TRM for MM patients with RI was comparable to that of MM patients with NRF. Besides, the toxicity results of ASCT in MM with RI in new drug era and pre-era were compared in a study from the University of Toronto [ 14 ]. The study showed that the TRM rate in the new era was significantly lower than that in the old era, mainly due to the widespread use of MEL140 for the conditioning regimen, the novel agents for induction therapy, and the improvement of supportive care. Additionally, research from the University of Florida College of Medicine examined the effects of MEL140 and MEL200 on results in MM patients undergoing ASCT and showed that MM patients treated with MEL140 achieved similar long-term survival to those who received MEL200 [ 45 ]. All of this suggested that ASCT is safe and effective for MM patients with RI when the dose of melphalan is lowered. In clinical practice, RI should not be a contraindication for MM patients undergoing ASCT, and clinicians now routinely and empirically reduce the dose of melphalan for MM patients with RI considering the reduced toxicity and similar efficacy.

The results of the meta-analysis showed that the ORR in the NRF group is slightly higher than that in the RI at transplantation group, with a p -value of 0.05. This is inconsistent with the results of a previous meta-analysis [ 10 ]. It is important to note that a p -value of 0.05 is a borderline result, indicating that the difference observed, although statistically significant, may not be strong. Therefore, caution should be exercised in interpreting these results, and future studies with larger sample sizes may be warranted to confirm these findings. However, ASCT can enable MM with RI to achieve equivalent CR rates to MM with NRF. In addition, owing to the use of bortezomib-based induction, patients were able to attain deeper response rates after ASCT [ 14 , 21 ]. Besides, compared to RI patients who only received novel agents without ASCT [ 46 ], the response rates were better in MM with RI treated with novel agents and ASCT [ 21 ]. All these suggested that ASCT remained a necessary regimen to upgrade outcome of MM with RI.

As for the survival outcomes, ASCT can enable MM with RI to achieve comparable PFS to MM with NRF when the PFS rate was maintained at a high level. According to quantitative analysis, the PFS rates for MM with RI and NRF were comparable. However, this conclusion is inconsistent with a previous meta-analysis [ 10 ], which showed that MM with RI had poorer PFS than MM with NRF after ASCT. There might be 2 possible reasons for this discrepancy. 1) We two meta-analyses included different studies. Seven new studies [ 11 , 30 – 32 , 36 , 37 ] were additionally included in our meta-analysis. 2) We two meta-analyses used different methods to calculate PFS. In our study, data of PFS each year after ASCT were extracted from the survival curves and subgroup analyses were conducted, while the previous meta-analysis did not take time into account. In addition, compared to traditional medications with ASCT, the combination of new agents, such as bortezomib-based induction, may increase the response rate and event-free survival in MM patients with RI [ 47 ].

Of notice, although MM with RI could achieve comparable PFS after ASCT to those with NRF, the OS of MM patients with RI after ASCT was still inferior to those with NRF, even in those whose renal function had returned to normal before transplantation. This result may be attributed to the fact that MM patients with RI who experience disease progression after transplantation, as opposed to those with NRF, had poorer organ function, more comorbidities, fewer treatment options, and a poorer response to treatment. In the pre-antibody immunotherapy era, MM patients with RI had poorer long-term OS following transplantation, highlighting the need for enhanced treatment strategies for these patients. Recent research indicates that novel therapies, including CD38 monoclonal antibodies and chimeric antigen receptor T (CAR-T) cell therapy, significantly improve treatment outcomes for MM patients, and are safe for those with RI [ 48 – 50 ]. These findings suggest that such therapies may potentially improve OS in MM patients with RI. Thus, further investigation is required to explore the role of antibody immunotherapy in MM patients with RI and to integrate these therapies into current treatment protocols.

Consistent with the results of the meta-analysis, data from our center also indicate that pre-transplant renal insufficiency does not affect TRM, treatment response, or PFS. However, our data show no significant difference in OS between the RI and non-RI groups, which is inconsistent with the meta-analysis results. This discrepancy may be due to the small sample size of the RI group in this real-world analysis. Larger future studies may be needed to further validate the reliability of these meta-analysis findings.

However, there are some limitations. First, there were only 3 cohort studies on MM patients with RI at the time of diagnosis and patients with RI at diagnosis but normal renal function before ASCT, and the limited sample size might affect the accuracy of the meta-analysis in those groups. Secondly, the included studies had different definitions of RI and some studies only included patients who were dialysis-dependent, and the effect of ASCT on patients with different degrees of RI could not be analyzed. Thirdly, the melphalan dose for the conditioning regimen was arbitrary, which might be the main source of heterogeneity in meta-analysis. What’s more, it would be ideal to conduct a meta-regression analysis to explore the influence of confounding factors such as the different definitions of RI, publication year, and sample size on the results. However, due to the limited number of studies included in the meta-analysis, performing a reliable meta-regression analysis is challenging, which may reduce the reliability of the results. Finally, all the studies included in meta-analysis were retrospective cohort studies. Since there is no prospective randomized study on this topic, the quality of this meta-analysis may be deficient.

In conclusion, this meta-analysis and systematic review is performed in the context of non-antibody immunotherapy and shows that ASCT is generally safe and efficacious in MM with RI with a reduced dose of melphalan. MM with RI can achieve comparable TRM, CR rates and PFS to those with NRF after ASCT. RI is no longer a contraindication for MM patients undergoing ASCT, but it is recommended to reduce the dose of melphalan for MM patients with RI. Nevertheless, the lower OS in MM patients with RI underscores the need for further research to improve OS in these patients. With the advent of antibody immunotherapy, it may be a solution to this problem.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 44 KB)

Acknowledgements

Not applicable.

Author Contributions

Yan Li, Xinyi Zhang and Li Zhang contributed to conceptualization; Yan Li and Xinyi Zhang helped in methodology, formal analysis and investigation, writing—original draft preparation. Li Zhang and Yuhuan Zheng helped in writing—review and editing; Yuhuan Zheng done funding acquisition; Zhongqing Zou, Yanqiu Xiong, Xinyuan Gu and Ruiji Zou helped in resources; Zhongqing Zou, Yanqiu Xiong, Xinyuan Gu and Ruiji Zou done data curation; Li Zhang, Jing Tan and Ting Niu done supervision; Li Zhang and Ting Niu helped in project administration.

Funding

This work was supported by grants to YZ from the National Natural Science Foundation of China (No. 82070219) and Sichuan University faculty start fund.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interests

The authors declare no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of West China Hospital, Sichuan University, with the need for written informed consent waived.

Consent to publish

Not applicable.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yan Li and Xinyi Zhang have contributed equally to this work.

Contributor Information

Li Zhang, Email: Drzhangli2014@sina.com.

Yuhuan Zheng, Email: yuhuan_zheng@163.com.

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Associated Data

Supplementary Materials

Supplementary file1 (DOCX 44 KB)

Data Availability Statement

No datasets were generated or analyzed during the current study.