Tandem autologous hematopoietic stem cell transplantation for patients with multiple myeloma: a systematic review and meta-analysis

ABSTRACT

To evaluate whether patients with multiple myeloma (MM) could benefit from tandem autologous hematopoietic stem cell transplantation (auto-HSCT), PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched, and 10 eligible studies were included after data extraction and quality evaluation. Meta-analysis showed that compared to single autologous hematopoietic stem cell transplantation, tandem auto-HSCT does not improve OS, EFS or efficacy in MM patients, and may even lead to higher treatment-related mortality (TRM). MM patients who received autologous tandem allogeneic HSCT did not achieve better response compared to tandem autologous HSCT. In summary, compared to single autologous hematopoietic stem cell transplantation, tandem autologous hematopoietic stem cell transplantation cannot provide survival advantages for MM patients, and MM patients cannot benefit from autologous tandem allogeneic hematopoietic stem cell transplantation.

KEYWORDS:

• Tandem autologous transplantation
• multiple myeloma
• prognosis
• meta-analysis

Introduction

Multiple myeloma (MM) accounts for approximately 10% of hematologic malignancies and usually presents with CRAB (hypercalcemia, renal failure, anemia, bone lesions) caused by plasma cell disturbances [1,2]. Although the treatment of MM has entered the era of new drugs, such as proteasome inhibitors, immunomodulators and CD38 monoclonal antibodies, hematopoietic stem cell transplantation (HSCT) is still unshakable in its treatment [3–5].

Tandem HSCT is the second HSCT treatment within 6 months after the first HSCT [6]. Some clinical trials have proved that tandem autologous HSCT (auto-HSCT) could bring benefits to overall survival (OS) and progression-free survival (PFS) for MM patients compared to single auto-HSCT [7,8], however, some studies hold the opposite attitude, so the clinical application of tandem auto-HSCT is still controversial. Allogeneic HSCT (allo-HSCT) could prolong survival, however, the toxicity associated with transplantation is significant [9]. Auto-HSCT tandem with allo-HSCT has the theoretical advantage of utilizing grafts to combat myeloma effects, but data from prospective clinical trials have been inconclusive.

Therefore, we reported the results of a systematic review and meta-analysis of existing literature, compared the benefits of tandem auto-HSCT with single or tandem allo-HSCT on OS, event-free survival (EFS), PFS, treatment-related mortality (TRM) and response rate in multiple myeloma.

Methods

This systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [10].

Search strategy and selection criteria

PubMed, Web of Science, Embase and Cochrane Library were searched to find literature recorded from the establishment of the database until 30 November 2022. The keywords ‘multiple myeloma’, ‘myeloma’, ‘tandem transplant’, ‘double transplant’, ‘second transplant’, ‘HSCT’ ‘and autologous hematopoietic stem cell transplantation’ were used. No language restrictions were applied.

The inclusion criteria were (1) the enrolled patients were diagnosed as MM, (2) these studies were published before 30 November 2022, (3) the study included data from patients who received tandem auto-HSCT, single auto-HSCT or tandem allo-HSCT and (4) these studies provided available data on OS, EFS, PFS, TRM and remission HR/RR values and 95% CI.

The exclusion criteria were as follows: (1) duplicate articles, letters, editorials, expert opinions, case reports and reviews; (2) animal experiments and (3) the research design was not rigorous or the data was incomplete. If more than one study provided overlapping data, only the most comprehensive or latest studies were included.

The titles and abstracts of the retrieved articles were reviewed using the above inclusion and exclusion criteria. Articles that did not meet these criteria were also excluded. The full-text versions of the remained articles were carefully reviewed to determine their eligibility for inclusion.

Data extraction

Two researchers independently extracted the data from the eligible studies and resolved the discrepancies through discussion with the third researcher. Data were extracted and recorded in Excel files: first author’s surname, publication year, total number of patients, number of patients who received tandem/single auto-HSCT, induction regimen, conditioning regimen, maintenance therapy, follow-up time, OS, PFS, EFS, TRM and response rate.

Quality assessment

Two researchers independently evaluated the bias risk of the included studies. Cochrane Manual 5.1.0 is used for the assessment of RCT bias risk [11]. The Cochrane risk assessment tool included seven indicators, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases.

Statistical analysis

Risk ratio (RR) and hazard ratio (HR) are used as effective analysis statistics for binary and time event variables, respectively. Each effect size provides its 95% confidence interval (CI).

If HR cannot be directly obtained from the original text, it can be indirectly calculated using the method provided by Parmar et al. to obtain relevant parameters. If the original text provided the survival curves related to PFS and OS [12], the Engauge Digitizer software was used to extract the survival probability at each time point, then the data were input into the HR calculation spreadsheet template developed by Tierney [13], and its estimated HR and 95% CI were used for analysis. If HR cannot be extracted by the above methods, the RR was extracted according to the number of event occurrences instead of HR.

Stata17.0 (Stata Corp, College Station, TX, USA) and Review Manager (version 5.4, The Cochrane Collaboration, Oxford, UK) were used to analyze RR/HR of OS, PFS, EFS, TRM, response and their 95% CI. Data were analyzed using fixed or random effects meta-analysis to generate a forest diagram. The chi-square Q test and I² statistic were used to evaluate heterogeneity. If heterogeneity was obvious (I² > 50%), a random-effects model was used. If I²≤ 50%, a fixed-effects model was used. Sensitivity analyses were performed to detect whether individual studies significantly affected the results of the pooled effect sizes by removing one study per round.

The possibility of publication bias was first assessed by visual inspection of funnel plots and further evaluated using Begg’s test and Egger's test. If there was publication bias in the included articles, the ‘fill and trim’ method was used to further evaluate the possible effect of publication bias on the pooled RR/HR. A two-sided P value of ≤ 0.05 was considered significant for all analyses except heterogeneity tests.

Results

Article screening

PubMed, Web of Science, Embase and Cochrane Library were comprehensively searched using subject words and random words. A total of 1282 relevant references were retrieved. Forty-four articles were found in PubMed, 286 in Embase, 285 from the Web of Science and 667 in Cochrane Library. After eliminating duplicate articles, 1067 articles were retained, and their titles and abstracts were screened to determine their applicability for this meta-analysis. After a preliminary screening of titles and abstracts, the full text of 110 articles was evaluated further according to the predesigned inclusion and exclusion criteria; 10 articles were finally included in the quantitative analysis [7,8,14–21]. The process to select the eligible studies is shown in Figure 1.

Figure 1. The PRISMA flow diagram of article screening and selection.

Ten articles were finally included in the quantitative analysis, of which six compared tandem auto-HSCT with single auto-HSCT (covering 2149 patients) [7,8,14–17] and the other four compared auto-allo-HSCT with tandem auto-HSCT (covering 1599 patients) [18–21]. The characteristics of these 10 studies are described in Tables 1 and 2, respectively.

Table 1. Characteristics of the included studies comparing patients who received tandem or single auto-HSCT.

Author	Published year	Number of patients	N (tandem/single auto-HSCT)	Age	Male/Female	Induction regimen	Conditioning regimen		Maintenance therapy	Follow-up	Efficiency
							Tandem	Single
Attal	2003	399	200/199	52.0/52.0	223/176	VAD	Melphalan 140 mg/m^2、 melphalan140 mg/m^2+ TBI	Melphalan 140 mg/m^2+ TBI	Interferon-α	36-93 months	OS/PFS/TRM/response
Cavo	2007	321	158/163	52.3/52.9	194/127	VAD	Melphalan 200 mg/m^2、 BU4mg/kg + melphalan 120 mg/m^2	Melphalan 200 mg/m^2	Interferon-α	2-112 months	OS/PFS/TRM/response
Fermand	2009	227	114/113	50.0/50.0	–	VAD	Melphalan 140 mg/m^2 ±TBI	Melphalan 140 mg/m^2+ TBI	–	120 months	OS/PFS/TRM/response
Mai	2016	358	181/177	56.3/54.8	212/146	VAD、VID、 VCAP	Melphalan 200 mg/m^2	Melphalan 200 mg/m^2	Interferon-α	134 months	OS/PFS/response
Stadtmaue	2019	504	247/257	56/56	–	RVD、VCD	Melphalan 200 mg/m^2	Melphalan 200 mg/m^2	Lenalidomide	38 months	OS/PFS/response
Straka	2021	340	188/152	–	210/130	Anthracycline、Bortezomib	Melphalan 100/140/200 mg/m^2	Melphalan 100/140/200 mg/m^2	Bortezomib	51 months	OS/PFS/response

Table 2. Characteristics of the included studies comparing patients who received auto-allo HSCT with tandem auto-HSCT.

Author	Published year	Number of patients	N (auto-allo-HSCT/Tandem auto-HSCT)	Age	Male/Female	Induction regimen	Conditioning regimen		Follow-up	Efficiency
							Auto-allo	Tandem auto
Garban	2006	284	65/219	54/58	146/138	VAD	Bu-Fluda-ATG	Melphalan, DXM ± B-E8	56 months	OS/EFS/TRM/response
Htut	2018	582	178/404	51/56	348/234	novel agents/VAD	Melphalan ± topotecan/amifostine	Melphalan ± topotecan/amifostine	102 months	OS/TRM
Krishnan	2011	623	187/436	53/55	371/252	–	Melphalan ± TBI	Melphalan 200 mg/m^2	40 months	OS/EFS/TRM/response
Rosinol	2000	110	25/85	52/55	–	–	Melphalan + Flu	Melphalan + CBV	62 months	OS/EFS/TRM/response

The quality of the included literature was assessed using the Cochrane risk assessment tool. Figure 2 shows that all included literature was of moderate quality.

Figure 2. Quality assessment of included studies using Cochrane risk assessment criteria. Red indicates high risk, yellow represents unclear risk and green means low risk.

Tandem auto-HSCT and single auto-HSCT

OS

To compare the OS between patients who received tandem or single auto-HSCT, six studies were used for meta-analysis. As shown in Figure 3, the random-effects summary RR compared the OS between tandem and single auto-HSCT was 0.94 [0.88, 1.01] (p = 0.08), indicating that no significant difference in the OS between tandem and single auto-HSCT.

Figure 3. Meta-analysis of the benefits between tandem and single auto-HSCT in MM patients. (A) OS between tandem and single transplant. (B) EFS between tandem and single transplant. (C) TRM between tandem and single transplant. (D) Response rate between tandem and single transplant.

The heterogeneity test I² = 52%>50%, suggesting moderate heterogeneity. Sensitivity analysis was used to further analyze the sources of heterogeneity and found that the removal of Attal et al. ’s study had no significant impact on the results, as the pooled RR was 0.99 [0.92,1.07] (Figure 4) with the heterogeneity results I²= 0. It is found that the study of Attal et al. is the main source of heterogeneity.

Figure 4. Meta-analysis of the treatment benefits between tandem and single auto-HSCT in MM patients after sensitivity analysis. (A) OS between tandem and single auto-HSCT after sensitivity analysis. (B) Response rate between tandem and single auto-HSCT after sensitivity analysis.

EFS

To compare the EFS between patients who received tandem or single auto-HSCT, six studies were used for meta-analysis. As shown in Figure 3, the fixed-effects summary RR compared EFS between these two groups was 0.94 [0.88, 0.99] (p = 0.17), indicating that there is no difference in EFS between tandem and single auto-HSCT. No heterogeneity was observed among the included studies.

TRM

To compare the TRM between patients who received tandem or single auto-HSCT, three studies were enrolled for meta-analysis. As shown in Figure 3, the fixed-effects summary RR compared TRM between tandem and single auto-HSCT was 1.48 [0.86, 2.53], indicating that tandem auto-HSCT resulted in a higher TRM in patients with MM. No heterogeneity was observed among the included studies.

Response rate

To compare the response rate between patients who received tandem or single auto-HSCT, six studies were used for meta-analysis. As shown in Figure 3, the random-effects summary RR compared the response rate between tandem and single auto-HSCT was 0.90 [0.83, 0.98], indicating that the response rates of tandem and single auto-HSCT were similar.

There was moderate heterogeneity in the studies, with I² = 53%>50%. The results of sensitivity analysis suggested that the removal of Cavo et al. ’s study had no significant impact on the results, as the pooled RR was 0.94 [0.85, 1.04] (p = 0.14) (Figure 4), but the heterogeneity results suggest I²< 50, indicating that the study of Cavo et al. was the main source of heterogeneity.

Auto-allo-HSCT and tandem auto-HSCT

OS

To compare the OS between patients who received auto-allo-HSCT and tandem auto-HSCT, four studies were enrolled for meta-analysis. As shown in Figure 5, the fixed-effects summary RR compared the OS between the two groups was 1.10 [0.98, 1.22] (p = 0.10), indicating that auto-allo-HSCT had no significant advance on the OS compared to tandem auto-HSCT. No heterogeneity was observed in the studies.

Figure 5. Meta-analysis of the benefits between autologous tandem allogeneic HSCT and tandem auto-HSCT in patients with multiple myeloma. (A) OS between the two groups. (B) PFS between the two groups. (C) TRM between the two groups. (D) Response between the two groups.

PFS

To compare the PFS between patients who received auto-allo-HSCT and tandem auto-HSCT, four studies were included for meta-analysis. The fixed-effects summary RR compared the PFS between the two groups was 1.06 [0.95, 1.20] (p = 0.29), indicating that there was no significant difference in PFS between auto-allo-HSCT and tandem auto-HSCT. No heterogeneity was observed in the included studies, as the I²= 0.

TRM

To compare the PFS between patients who received auto-allo-HSCT and tandem auto-HSCT, four studies were included for meta-analysis. The fixed-effects summary RR compared the TRM between the two groups was 3.60 [2.25, 5.75] (p <0.001), indicating that TRM in patients who received auto-allo-HSCT was higher compared to tandem auto-HSCT. No heterogeneity was observed in the included studies with I²= 0.

Response rate

To compare the response rate between patients who received auto-allo-HSCT and tandem auto-HSCT, three studies were used for meta-analysis. As shown in Figure 5, the random-effects summary RR compared the response rate between the two groups was 1.32 [1.12, 1.55], indicating that auto-allo-HSCT had a slightly better response than tandem auto-HSCT.

There was moderate heterogeneity with I² = 75%>50%. The results of sensitivity analysis suggested that the removal of Rosinol et al.'s study had no significant impact on the results, as the pooled RR was 1.24 [1.05,1.46] (Figure 6), but the heterogeneity results showed I²= 0, indicating that the study of Rosinol et al. was the main source of heterogeneity.

Figure 6. Meta-analysis of the response between autologous tandem allogeneic HSCT and tandem auto-HSCT in patients with multiple myeloma after sensitivity analysis.

Publication bias

Funnel plots were examined in the above analysis, and no publication bias was found.

Discussion

The application of tandem auto-HSCT in MM patients is still controversial. With the emergence of new drugs and their integration with existing treatments, the survival rate of MM patients has significantly improved over the past decades [22,23]. Early use of HSCT in MM patients is increasing, as it is found that HSCT could improve the median survival rate of MM patients [24–26]. In addition, some clinical studies found similar clinical benefits between early HSCT (after 4 cycles of induction therapy) and delayed HSCT (as salvage treatment in the event of recurrence) [27,28].

A systematic review and meta-analysis, published in 2009 [29], found that tandem HSCT did not improve OS or EFS in previously untreated MM patients. Another phase 3 randomized clinical trial evaluating single and tandem HSCT showed that tandem HSCT was superior to single HSCT for PFS, but not for OS [30]. A meta-analysis that compared tandem and auto-HSCT followed by allo-HSCT in MM patients indicated that compared with tandem auto-HSCT, auto-allo-HSCT was associated with higher TRM and complete remission (CR) without improvement in PFS or OS [31]. Kharfan-Dabaja reported [32] that despite higher CR rates, there was no improvement in OS with auto-allo HSCT which resulted in higher NRM.

Our meta-analysis reviewed 10 studies to evaluate the efficacy of tandem HSCT in MM patients from different perspectives. According to our pooled results, tandem HSCT did not improve OS, EFS or response rate in MM patients, and even resulted in higher TRM compared to single HSCT. Tandem auto-HSCT did not provide a survival advantage for MM patients compared with single HSCT. Patients who received auto-allo HSCT had better response rates but higher TRM compared to tandem auto-HSCT. There was no survival benefit in patients receiving auto-allo HSCT despite better response.

However, several limitations of this study need to be considered carefully. First, we could not obtain the whole original data and only used the abstract data, namely, RR or HR values provided by each study. Second, some of the results were moderately heterogeneous. Although the source of heterogeneity was found through sensitivity analysis and analyzed after elimination, it was still necessary to consider the impact of heterogeneity on the results. The third limitation is that some studies did not provide sufficient baseline data for definitive subgroup analysis.

Conclusion

Although some of the results were moderately heterogeneous, current evidence suggested that tandem HSCT did not improve OS, EFS or response in patients with MM, and even had a higher TRM compared to single HSCT. Autologous tandem allogeneic HSCT resulted in better responses but higher TRM compared to tandem HSCT. In summary, tandem transplantation is not recommended. However, some potential sources of bias, such as the papers used, were already quite outdated and use porting methods that will no longer be used, such as TBI, which increased TRM. Tandem ASCT is an option especially for myeloma patients with high-risk cytogenetic abnormality even after novel agents were approved according to several guidelines.

Authors’ contributions

H.L., Y.Z. and K.G. acquired and analyzed the data and wrote the paper. C.T. critically revised the manuscript. All authors approved all versions including the final version, and are responsible for the accuracy and integrity of all aspects of the manuscript.

Ethics approval and consent to participate

This study was subject to approval by the Research Ethics Committee of Tianjin Medical University Cancer Institute and Hospital and Institute of Hematology and Blood Diseases Hospital.

Consent for publication

Not applicable.

Availability of data and material

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

C.T. is supported by the Natural Science Foundation of Xinjiang Autonomous Region: [Grant Number 2022D01A09].