Efficacy and safety of tandem autologous stem cell transplantation in multiple myeloma: a retrospective single-center analysis

To the Editor: Upfront autologous stem cell transplantation (ASCT) has been an integral part of the management of young and eligible older patients with newly diagnosed multiple myeloma (NDMM) for over three decades. Tandem stem cell transplantation was defined as two planned sequential ASCTs within 3 to 6 months. More than two decades after its introduction, trials exploring the utility of tandem transplants have yielded mixed results. The role of tandem ASCT in multiple myeloma (MM) remains unclear and controversial. In the EMN02/HOVON95 study, as compared with single ASCT, both prolonged progression-free survival (PFS) and overall survival (OS) were seen in the tandem ASCT arm.[1] However, long-term follow-up of the STaMINA (BMT CTN 0702) trial showed no PFS or OS difference between single and tandem transplants.[2] Despite these discordant results, an upfront tandem ASCT should be considered in patients with high-risk cytogenetics in MM.[3] To our knowledge, there are limited data concerning tandem ASCT for patients with MM in China. To review the real-world efficacy and safety of tandem ASCT in patients with NDMM treated in our center, we conducted a single-center retrospective analysis. This study was conducted in accordance with the tenets of the Declaration of Helsinki. All patients provided informed consent for research. The study protocol was approved by the Ethics Committee of Fujian Medical University Union Hospital (No. 2021KY193). We reviewed the medical records of patients with NDMM who received tandem transplants as frontline therapy after induction therapy in Fujian Medical University Union Hospital from November 2014 to January 2021. Fifty patients were enrolled in this study. High-risk cytogenetics were defined as the presence of t(4;14), t(14:16), t(14:20), del 17p, or amplification 1q by fluorescence in situ hybridization at the time of diagnosis. The treatment response was evaluated based on the International Myeloma Working Group consensus response criteria. PFS was defined as the time from the first transplantation to disease progression or death. OS was defined as the time from the first transplantation to death due to any cause. Transplant-related mortality (TRM) was defined as death from any cause other than progression or relapse. High-risk cytogenetic abnormalities were observed in 60% of the patients. Detailed demographics and disease-related characteristics at diagnosis are available in Supplementary Table 1, https://links.lww.com/CM9/B345. All patients received a triplet induction regimen including at least one novel agent for 4 to 6 cycles. The detailed treatment regimens are also illustrated in Supplementary Material, https://links.lww.com/CM9/B345. Stem cell mobilization and collection were performed according to standard procedures, using EA (etoposide 100 mg/m2 qd d1–3 + cytarabine 0.5/m2 q12h d1–3) followed by granulocyte colony-stimulating factor. The conditioning regimen before ASCT was high-dose melphalan (140–200 mg/m2, depending on renal function). Patients with high-risk cytogenetics underwent two cycles of previous induction regimen as consolidation therapy, if not ≥CR was achieved after the second transplantation. Forty-five (90%) patients received post-ASCT maintenance therapy (MT) for a median duration of 14.5 (range 1–62) months from the start of maintenance. MT regimens included immunomodulatory drugs (IMiDs) in the majority of patients (62.2%, 20 patients with lenalidomide and 8 patients with thalidomide), followed by PIs in 12 patients (26.7%, 7 patients with bortezomib and 5 patients with ixazomib), and both IMiDs and PIs in 5 patients (11.1%). Five (10%) patients did not receive MT because of economic factors and drug intolerance. Statistical analyses were performed using SPSS software (24.0,IBM Corp.; Armonk, NY, USA). PFS and OS were calculated using the Kaplan–Meier method, and log-rank tests with 95% confidence intervals (95% CIs) were used to compare time-dependent outcome measures. Potent covariates with an impact on PFS and OS were estimated using Cox regression analysis with the respective hazard ratios (HRs). Statistical significance was considered at a two-sided P < 0.05. The median CD34+ cell yield was 43.88 × 106/kg (range 7.1–111.2). Administration of high-dose melphalan was followed by an infusion of a median of 16.8 × 106/kg of CD34+ cells/kg in the first transplant and 15.2 × 106/kg in the second transplant. After induction therapy, all patients achieved partial response (PR) or better, and 43 (86%) patients achieved very good partial response (VGPR) or better. The percentages of stringent complete remission (sCR), complete remission (CR), VGPR, and PR before the first transplant were 8%, 44%, 34%, and 14%, respectively. After the first transplant, the percentages of sCR, CR, VGPR, and PR were 28%, 34%, 36%, and 2%, respectively. At the last follow-up, all patients achieved ≥VGPR, and 82% of patients achieved CR or better. With a median follow-up of 34.4 months (range 6.3–81.2) from the first transplant, the median PFS was 52.4 months (95% CI: 22.9–81.9), and the median OS was not reached. At the time of the last follow-up, 18 patients had progressed and 9 died; estimated 3-year and 6-year OS rates were 82.1% and 72.9%, respectively, and the estimated 3-year and 6-year PFS rates were 64.4% and 47.3%, respectively. There was also no significant difference in PFS based on sex, platelet counts, hemoglobin, subtype, β2-microglobulin, renal function, International Staging System (ISS) stage [Figure 1A], Revised-ISS (R-ISS), cytogenetic risk [Figure 1B], induction regimens, and remission status pre-first transplant. The difference in OS did not reach statistical significance regarding the aforementioned factors, including ISS stage [Figure 1C] and cytogenetic risk [Figure 1D]. Tandem transplantation was utilized to further improve the depth of response and long-term outcomes in the era of conventional chemotherapy and was proven to improve PFS and OS, especially in patients who did not achieve CR after the first autologous transplantation. However, currently available data cannot define the role of tandem ASCT in myeloma. The phase 3 EMN02/HO95 clinical trial demonstrated that tandem transplantation improved the depth of the response by 25%, with >50% of the patients achieving CR or better.[1] PFS and OS were significantly improved after the second transplantation, with approximately 30% reduction in the risk of death and progression. The study showed significant improvements in the 3-year PFS (73% vs. 64%) and 3-year OS (89% vs. 82%) in favor of tandem ASCT compared with single ASCT. Tandem ASCT could neutralize adverse cytogenetic and high R-ISS prognoses. In contrast, another phase 3 trial, BMT-CTN 0702, showed no significant difference in survival outcomes between single and tandem transplantation.[2] Tandem ASCT did not have an advantage over single ASCT among high-risk patients. Despite these inconsistent conclusions, it is congruously recommended that tandem ASCT should be advisable in patients with high-risk cytogenetics. In this study, there was no significant difference in PFS and OS based on ISS stage and cytogenetic risk, indicating that high-risk patients could benefit from tandem transplantation. Our analysis using real-world information may further strengthen the role of tandem autologous transplantation in patients at high risk according to cytogenetics and disease characteristics.[4]Figure 1: The cumulative incidences of PFS and OS based on ISS stages, cytogenetics risk, LDH, and MT. (A, B, E,G) Kaplan–Meier curve presenting PFS. (C, D, F, H) Kaplan–Meier curve presenting OS. ISS: International staging system; LDH: Lactate dehydrogenase; MT: Maintenance therapy; OS: Overall survival; PFS: Progression-free survival.Serum LDH is an adverse prognostic factor for myeloma; elevation of LDH is associated with hypercalcemia, thrombocytopenia, anemia, renal insufficiency, and ISS stage II–III.[5] Moreover, novel agent-based therapy[5] or bortezomib-based induction followed by ASCT[6] could not overcome the poor prognosis of elevated LDH. Consistent with the literature, our study showed that patients with an initial elevated LDH level had a significantly shorter PFS (P = 0.0275, Figure 1E) and OS (P = 0.0034, Figure 1F) than patients with normal LDH levels. The LDH level was a predictor in univariate analysis but not in multivariate analysis for PFS (P = 0.775, HR 1.24, 95% CI: 0.28–5.4) and OS (P = 0.112, HR 4.86, 95% CI: 0.69–34.3), suggesting that frontline bortezomib-based induction followed by tandem transplantation could not abolish the adverse impact of elevated LDH. MT has been one of the successful strategies to delay disease progression and prolong survival by deepening and sustaining the response achieved with ASCT.[7] Importantly, a pooled analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto)-MM-03-05 and RV-MM-PI-209 trials revealed that even in patients with CR, MT significantly improved PFS and OS.[8] A meta-analysis conducted by Munshi et al[9] demonstrated that thalidomide and lenalidomide maintenance therapies could improve the rate of MRD negativity. We demonstrated that patients without MT had worse PFS (P < 0.0001, Figure 1G) and OS (P = 0.0086, Figure 1H) when compared with patients receiving post-ASCT MT. Lack of MT was also an independent adverse factor in univariate and multivariate analyses for PFS (P = 0.003, HR 0.092, 95% CI: 0.019–0.442), and was a predictor in univariate analysis but not in multivariate analysis for OS (P = 0.135, HR 0.191, 95% CI: 0.022–1.68). No significant difference in PFS and OS was observed among the diverse maintenance strategies after ASCT in our study. Finally, our study also demonstrated low toxicity of tandem ASCT in real-world patients, with a 100-day TRM of 0%. During the first transplant, the median time to neutrophil and platelet engraftment was 11 days (range 10–17) and 13 days (range 9–22), respectively. The median times to neutrophil and platelet engraftment during the second transplant were 12 days (range 11–26) and 17 days (range 9–84), respectively. Complications in the first transplant (n = 50) included oral mucositis (n = 5, 10%), engraftment syndrome (n = 12, 24%), and respiratory tract or intestinal infections (n = 14, 28%). In the course of the second transplant, engraftment syndrome (n = 15, 30%), respiratory tract or intestinal infection (n = 18, 36%), and bacteremia (n = 4, 8%) were common complications. The median duration of antibiotic therapy was 7 days and 10 days in the first and second transplants, respectively. Due to the significant improvement in survival among patients with MM, second primary malignancies have become an increasingly relevant long-term risk in MM survivors.[10] The use of ASCT is associated with a potential increase in hematologic and some solid tumors owing to alkylator therapy before ASCT. In our study, one patient without exposure to lenalidomide developed acute lymphoblastic leukemia (ALL) 4.5 years after the second transplant. It is important to recognize the limitations of this retrospective study. First, the retrospective design of the study is a limitation. Second, the sample size was relatively small, and the number of patients with abnormal LDH or without MT was <10, therefore, the conclusions drawn may be biased. Third, the follow-up time varied greatly, and the outcome index might have changed with the extension of the follow-up time. In conclusion, we showed that upfront tandem ASCT could overcome the adverse prognosis of ISS stages and unfavorable cytogenetic risk and would be feasible and effective for patients with MM in the real world, accompanied by low and controllable toxicity. Nevertheless, this study did not require a single transplant cohort to compare tandem transplants with single transplants. Therefore, our conclusion must be confirmed by a match between single and tandem transplants in the future. Funding This work was supported by grants from the Department of Science and Technology of the Fujian Province Project (Nos. 2017I0004 and 2017Y9057), the Fujian provincial health technology project (No. 2021ZD01005), and the National Key Clinical Specialty Discipline Construction Program (No. 2021-76), the Fujian Provincial Clinical Research Center for Hematological Malignancies (No. 2020Y2006) and the Fujian Provincial Key Clinical Specialty Discipline Construction Program, Conflicts of interest None.