Tandem Autologous Stem Cell Transplantation Research Articles

A pilot study of post-consolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children’s Oncology Group.

10004 Background: Post-consolidation anti-GD2 antibody-based immunotherapy has improved survival for newly diagnosed patients (pts) with high-risk neuroblastoma (HRNBL). However, nearly half of newly diagnosed pts relapse. Based upon the efficacy of anti-GD2 antibody dinutuximab given with chemotherapy (chemoimmunotherapy) in the relapse setting, we hypothesized that post-consolidation chemoimmunotherapy may further improve frontline outcomes. ANBL19P1 first assessed the feasibility of delivering chemoimmunotherapy after tandem high-dose chemotherapy with autologous stem cell transplant (ASCT). Methods: Pts <31 years old with HRNBL who received 4-6 cycles of Induction chemotherapy +/- up to 4 cycles of post-Induction chemotherapy or chemoimmunotherapy, underwent tandem ASCT, had no evidence of progressive disease (PD), and met organ function criteria were eligible. Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6. Therapy was deemed feasible if the 95% confidence interval (CI) placed on the percentage of pts that completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contained 75%, and if the interim monitoring rules for feasibility and excessive toxicity were not triggered. Event-free (EFS) and overall survival (OS) were determined from time of enrollment. Results: From 11/30/20-6/30/23, 40 eligible pts enrolled and started protocol therapy. 87.5% (n=35) were ≥18 months old and 97.5% (n=39) had INRG Stage M disease, at diagnosis. 87.5% (95% CI 73.9%, 94.5%) completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks, exceeding the feasibility benchmark of 75%. Feasibility and monitoring rules were not triggered. Five pts were removed from protocol therapy prior to Cycle 4 [physician determination (n=2), pt/parent refusal of further therapy (n=2), and PD (n=1)]. No unacceptable toxicities or deaths on protocol therapy were reported. Toxicities of interest are summarized (Table). One-year EFS and OS were 90.0±5.0% and 97.5±2.7%, respectively (median follow-up time for pts without event=1.2 years). Conclusions: Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial. Clinical trial information: NCT04385277 . [Table: see text]

The Efficacy and Safety of Tandem Transplant Versus Single Stem Cell Transplant for Multiple Myeloma Patients: A Systematic Review and Meta-Analysis.

While high-dose therapy and autologous stem cell transplant (ASCT) remain integral to the primary treatment of newly diagnosed transplant-elble multiple myeloma (MM) patients, the challenge of disease progression persists. The primary objective of this meta-analysis is to evaluate the efficacy and safety of tandem ASCT compared to single ASCT. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing tandem ASCT with single ASCT in patients with newly diagnosed MM. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials databases for studies published up to January 2024. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), complete response rate (CRR), and treatment-related mortality (TRM). We used a random-effects model to calculate pooled hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs). Study quality was assessed using the Cochrane risk of bias tool and Newcastle-Ottawa Scale. Twelve studies involving 5057 patients met the inclusion criteria. Tandem ASCT was associated with a significantly higher CRR compared to single ASCT (HR 1.33, 95% CI 1.03-1.71, I2 = 15%), but no significant differences were observed in PFS (HR 0.75, 95% CI 0.42-1.34, I2 = 14%), OS (HR 0.60, 95% CI 0.33-1.10, I2 = 27%), or the ORR (RR 0.80, 95% CI 0.59-1.08, I2 = 33%). However, tandem ASCT was associated with a significantly higher risk of TRM (RR 1.78, 95% CI 1.00-3.18, I2 = 0%). Tandem ASCT improves the CRR but does not provide significant benefits in terms of PFS, OS, or ORR compared to single ASCT in patients with newly diagnosed MM. Moreover, tandem ASCT is associated with a higher risk of TRM. The decision to pursue tandem ASCT should be made on an individual basis, carefully weighing the potential benefits and risks in light of each patient's unique clinical situation. Future research should focus on identifying patient subgroups most likely to benefit from tandem ASCT and exploring strategies to optimize the efficacy and safety of this approach in the context of novel agent-based therapies.

Contribution of post-transplantation therapy to sustained MRD negativity in multiple myeloma: a retrospective analysis.

Post-transplantation therapy is commonly performed in patients with myeloma and can prolong progression-free survival (PFS). However, whether post-transplantation therapy contributes to achieving and continuing MRD-negativity remains controversial. This retrospective analysis aimed to evaluate the clinical impact of post-transplantation therapy, including tandem autologous stem cell transplantation (ASCT), in myeloma patients. The subjects were 79 patients (median age: 62years) who received induction therapy, including bortezomib and/or lenalidomide, of whom 58 underwent post-transplantation therapy. At the median follow-up time of 50months, the 4-year PFS rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (60.6% vs. 28.6%, P = 0.012). Multivariate analysis revealed post-transplantation therapy to be a significant prognostic factor for long PFS. Tandem ASCT followed by consolidation and/or maintenance therapies improved PFS and OS. The minimal residual disease (MRD)-negative rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (50.9% vs. 16.7%, P = 0.006). Post-transplantation therapy contributed to sustained MRD-negativity, which predicted long PFS and overall survival. Patients frequently discontinued post-transplantation therapy due to adverse events within 4months. In conclusion, post-transplantation therapy improved PFS and contributed to sustained MRD-negativity in myeloma patients.

Lenalidomide Maintenance after VTD Induction and Autologous Stem Cell Transplantation: An Italian Real-Life Study of 558 Patients

According to 2021 ESMO guidelines, treatment of newly diagnosed (ND) transplant eligible (TE) Multiple Myeloma (MM) patients is settled by an induction phase followed by single or tandem autologous stem cell transplantation (ASCT) and Lenalidomide (Len) maintenance. Len maintenance was approved in Italy in May 2018 due to the results of the meta-analysis by McCarthy et al. of three large randomized clinical trials. Before the approval of daratumumab-bortezomib-thalidomide-dexamethasone (D-VTD) regimen, VTD triplet combination was the most used induction regimen across Italian centers. In addition, given the data from the EMN02 trial, in the last years tandem ASCT has been a consolidated practice especially for high-risk cytogenetic patients. However, only a minority of patients enrolled in the meta-analysis of McCarthy received VTD induction and in most of them a single ASCT has been performed. In this context, the aim of this real-life study was to evaluate the efficacy and the safety of Len maintenance after VTD plus single or tandem ASCT in ND TE MM patients. The study cohort included 558 patients with a median age of 59 years (24-74) followed in 21 Italian referral centers. Baseline clinical and biological features are reported in table 1. ISS III and R-ISS III were detected in 111/518 (21.4%) and 44/405 (10.9%) cases, respectively, moreover, 30/327 (9.2%) patients showed R2 ISS stage IV. FISH analysis was available in 408 patients with 70 of them displaying high risk (HR) alterations [including t(4;14), t(14,16) and del17p]. Among the 338 standard risk patients, information about 1q status was available for 320 of them, with 60 patients harboring +1q abnormalities (18.75%). All patients received VTD induction (median number of cycles 4) and single or tandem ASCT was performed in 63.7% and 36.3% of cases, respectively. A median number of 22 cycles of Len maintenance was administered. Complete response (CR) and stringent CR (sCR) rates before starting Len were 31.8% and 14.2%, respectively (overall 46%) and increased with maintenance to 39.6% and 16.6%, respectively (overall 56.2%). Most importantly, 2-year CR and sCR rates in evaluable patients were superimposable (40.6% and 14.9% respectively, 55.5% overall). One hundred ninety-seven patients (35.3%) discontinued treatment, mostly due to progressive disease (134/197, 68.0%). Toxicities were mostly hematological with neutropenia found in 50.4% of cases (grade ≥3 in 17.2%), followed by thrombocytopenia and anemia in 24.4% and 16.1% of cases, respectively (grade ≥3 in 2.1% and 1.8% of cases, respectively). Non-hematological adverse events were primarily gastrointestinal (31.2%, grade ≥3 in 2.3%) and infections (42.3%, grade ≥3 in 3.9%) while skin related disorders affected 7.9% of patients. With a median follow up of 30 months, the 2-year PFS and OS from starting maintenance were 80.6% and 96.7%, respectively. No significant PFS difference was found according to age (>65 years vs ≤65 years, p=0.5924) or ASCT (single vs tandem, p=0.4694). Patients with low-risk disease including ISS I and R-ISS I showed improved PFS as compared to patients with ISS >I and R-ISS >I (2y PFS 84.6% vs 76.6%, p=0.0587 and 87.8% vs 72.7%, p=0.0195, respectively). By R2-ISS, low risk disease (R2-ISS I) confirmed a better outcome as compared to R2-ISS II-III (2y PFS 88.9% vs 72.2%, p=0.0333) and to R2-ISS IV (2y PFS 47.2%, p<0.0001). Finally, considering cytogenetic risk status, standard risk patients displayed a significantly prolonged PFS as compared to high-risk patients (2y PFS 81.6 % vs 56.3%, p<0.0001) and an improved although not significant outcome than patients harboring isolated +1q (2y PFS 77.2%, p=0.09). Moreover, we demonstrated that the accumulation of HR cytogenetic abnormalities reduces patients' outcome, in detail the PFS of patients with at least 2 HR abnormalities was significantly lower than patients with only 1 and without HR aberrations, respectively [2y PFS 44.8% (≥2) vs 73.5% (1), p=0.0301, and 2y PFS 44.8% (≥2) vs 82.8% (0), p<0.0001, figure 1]. To our knowledge, this is the first study evaluating the safety and efficacy of Len maintenance after VTD plus single or tandem ASCT. Our results provide evidence that patients with clinical and biological low risk disease, and more specifically those with R2- ISS I, benefit the most from Len maintenance with a favorable safety profile.

Obtaining M Protein Immune Reconstitution As Soon As Possible after Tandem Autologous Hematopoietic Stem Cell Transplantation Improves the Prognosis of Patients with Newly Diagnosis Multiple Myeloma

Objective: In the era of new drug therapy, autologous hematopoietic stem cell transplantation after induction therapy is the standard of care for patients with multiple myeloma, and Tandem autologous hematopoietic stem cell transplantation is a treatment option to improve the prognosis of patients with high-risk cytogenetics, and obtaining M protein immune reconstitution as soon as possible after double transplantation can further improve the survival of such patients. METHODS: A total of 12 patients with newly diagnosed multiple myeloma diagnosed from June 1, 2019 to April 30, 2021 at the First Affiliated Hospital of Sun Yat-sen University were included, and all patients underwent tandem autologous hematopoietic stem cell transplantation after induction therapy containing bortezomib, and the prognostic survival of patients who obtained M-protein reconstitution after transplantation was analyzed Results: 58.3% (7/12) of patients obtained M protein immune reconstitution after Tandem transplantation, the most common type of M protein was IgG-type M protein, the median time to obtain M protein immune reconstitution was 3 months (2-9 months) after Tandem transplantation, the median duration of reconstitution was 3 months (3-6 months), and all patients were R-ISS stage II-III, 83.3% (10/12) of patients had high-risk cytogenetics, all patients achieved at least VGPR efficacy after transplantation, with a higher CR rate in the M protein immune reconstitution group (71.4% vs 60.0%, P=0.679), although not statistically significant, and a median survival time of 2 years in the immune reconstitution group CONCLUSION: Tandem transplantation is a treatment option to improve prognosis in patients with high-risk cytogenetic multiple myeloma, and patients who received M protein immune reconstitution after Tandem transplantation significantly improved survival time.

Total Therapy (TT)-4: A Phase 3 Trial Comparing L-TT4 and S-TT4 and Tandem Auto Transplants in Standard Risk Multiple Myeloma

BACKGROUND: In the context of the TT4 study, a phase 3 trial was conducted to investigate whether a modified fixed duration treatment approach, known as L-TT4, could reduce toxicity while maintaining efficacy in tandem transplants for low-risk multiple myeloma (MM) defined by gene expression profiling. Here we report final analysis of TT4 study with long-term follow up of 11.7 years. METHODS: Treatment modification involved reducing the number of induction and consolidation cycles from 2 cycles each in the standard S-TT4 regimen to 1 cycle in L-TT4. The transplant regimen in L-TT4 was further adjusted by administering melphalan in a fractionated schedule of 50mg/m2 per day for 4 days (MEL50x4), instead of a single high-dose (MEL200) to reduce toxicity. To compensate for the potential decrease in effectiveness, bortezomib, thalidomide and dexamethasone (VTD) added for synergy between MEL50x4 and VTD. Maintenance was with 3 years of bortezomib, lenalidomide and dexamethasone The goal of this trial was to evaluate the impact of these modifications on toxicity levels and treatment outcomes in patients undergoing tandem transplants for multiple myeloma. Patients were enrolled in the period of August 2008 until March 2016. Data cut-off was July,2023. Results: Our study consisted of 380 patients after excluding 2 patients who were identified as high-risk gene expression profile (S-TT4:238, L-TT4:142). Median age was 58.7 years (range: 30-76 years) with 11.6% of enrolled patients identified as African Americans. 91.4% of enrolled patients completed at least one auto transplant and 78.3% of patient completed tandem transplants. The median follow-up duration for all patients of 11.66 years (interquartile range: 10.11-13.27 years). Median progression free survival (PFS) was 6.54 years (95% confidence interval (CI): 5.75-7.72 years)) with 10-year PFS of 39% (95% CI: 34.3-44.4%). Median overall survival (OS) was 12.6 years (95% CI: 11.6 years-not reached (NR)) with 10-year OS of 58.4% (95% CI:53.5%-63.7%). No statistically significant difference between S-TT4 vs. L-TT4 (median PFS: 7.33 years (95% CI: 6.01-9.44 years), median OS: 13.1 years (95% CI:12.30 years-NR) vs. (median PFS: 5.74 years (95% CI: 4.63-7.41 years),median OS:11.8 years (95% CI:9.21 years-NR) with OS hazard ratio of L-TT4 vs. S-TT4 of 1.17 (95% CI: 0.86-1.58, p=0322). [Figure] PFS HR of L-TT4 vs. S-TT4 of 1.21 (95% CI: 0.94-1.56, P=0.132). Early mortality (defined as death in the first year of enrollment) occurred in 6.1% of enrolled patients. No difference in treatment related mortality was found between L-TT4 and S-TT4. Grade III-V toxicities and maximum grade for system organ classes with at least 5% of the population experiencing an event showed no difference between L-TT4 vs. S-TT4 in all adverse events except grade III/IV infections which was higher in L-TT4 (60% vs. 44%, p=0.002). Secondary acute myeloid leukemia (AML) and/or myelodysplastic syndrome (MDS) occurred in 21 (5.5%) patients with the median time from diagnosis to diagnosis of AML and/or MDS of 4.5 years. AML and/or MDS was more frequently seen in patients assigned to L-TT4 when compared to S-TT4 though this difference was not statistically significant (7% vs. 4.6, P=0.317 ) Conclusion: Fixed duration therapy including multi-agent chemotherapy and tandem autologous stem cell transplantation and 3 years of extended therapy resulted in excellent patients' outcomes with median OS of 12.6 years and at least one in three patients being progression free for at least 10 years. Conditioning with single high-dose (MEL200) as used in S-TT4 resulted in similar outcomes compared to fractionated MEL50x4 combined with VTD with better safety profile and thus should be the preferred approach.

Incidence of Secondary Primary Malignancies after Long-Term Follow up of Multiple Myeloma Patients Treated with Autologous Stem Cell Transplantation - Report from Croatian Cooperative Group for Hematologic Malignancies (KroHem)

Background: Autologous stem cell transplantation (ASCT) after induction treatment is standard of care for multiple myeloma (MM) for the last 30 years. Two transplantations up-front (so-called tandem transplant) were standard of care for all MM patients. With the use of new antimyeloma agents (such as proteasome inhibitors, immunomodulators and especially monoclonal antibodies) this approach has changed and tandem transplant is now reserved mainly for patients with high-risk disease, defined by revised international staging system (R-ISS). There have been reports which cast further doubts on the value of the more aggressive tandem ASCT approach, as well as reports suggesting higher incidence of secondary primary malignancies (SPM) after high dose therapy and ASCT. Aims: To describe long-term outcomes of MM patients treated with ASCT (single, delayed, and tandem) and the rate of secondary primary malignancies. Methods: a retrospective analysis of outcomes of 577 MM patients who underwent 865 ASCT procedures between 1993 and 2017 was performed. Data were collected from 3 transplant centres and 9 other haematological centres in which MM patients were treated pre- and post-transplant. During that period treatment strategies changed significantly from single to tandem to salvage second ASCT. Results: there were 577 patients included. Median age at first transplant was 58 years (range 22 - 74). There were 295 female and 282 male patients. 346 patients received VAD (vincristine, doxorubicin, dexamethasone) and 231 received bortezomib and/or thalidomide (PI/IMiD) based regiments as induction therapy. All patients received high dose melphalan for pretransplant conditioning, 32 in combination with total body irradiation. Tandem ASCT (defined as second transplantation performed within 6 months after the first) was performed in 226 patients, single ASCT in 262 and salvage second (after relapse and/or progression) in 89 patients. Median overall survival (OS) for the entire group is 81.9 months and median progression free survival (PFS) 38.9 months. Tandem ASCT in comparison to single and second salvage transplantation resulted in statistically significant better OS (115 vs. 83 vs. 67 months respectively, p < 0.0001) and PFS (48 vs. 32. vs. 28 months respectively, p < 0.0001). There was no difference in outcomes regarding type of induction therapy, VAD vs. PI/IMiD based: median OS was 83 vs. 80 months, respectively (p=0.39) and median PFS was 39 vs. 38 months, respectively (p=0.15). 17.6% percent of patients who were treated with tandem ASCT are progression-free more than 10 years after the procedure while 10-year OS is 31.9%. 51 patients (8.8%) developed secondary malignancies (SPM). Most common SPM were lung carcinoma (10 patients), colorectal carcinoma (7 patients), myelodysplastic syndrome/acute myeloid leukaemia (6 patients), breast carcinoma (4 patients) and melanoma (4 patients). Of those 19 died due to SPM (3% of the entire patient group). There was no correlation between number of ASCT and SPM (p=0.87). Conclusion: in our group of patients tandem ASCT resulted in superior OS and PFS in comparison to single and/or salvage ASCT. Interestingly, we did not observe benefit of new drugs (PI/IMiD) in induction therapy regarding outcomes. This peculiar result might be due to rather late availability of these drugs in front line settings (bortezomib and thalidomide since 2015) and time period taken for analysis (up to 2018). SPM rate was similar to other reports and did not show significant correlation with number of ASCT. More than 15% of patients treated with tandem ASCT experienced very prolonged PFS and almost 32% had OS longer than 10 years.

Efficacy and Safety of Single Versus Tandem Autologous Stem Cell Transplantation in Multiple Myeloma: A Single-Center Retrospective Analysis in China

Background: Currently, there is a lack of comparative data on the efficacy and safety of single or tandem ASCT in China. This study aimed to review the efficacy and safety of single or tandem ASCT in MM patients without selection criteria for specific studies. Methods: Utilizing matched case-control study, we retrospectively analyzed the clinical data of 80 newly diagnosed MM (NDMM) patients who underwent ASCT in our department between November 2014 and June 2021, with 40 patients in each group receiving either single or tandem ASCT. Results: In single ASCT group, the percentage of ≥CR before or post ASCT was 50% and 70%, respectively. In tandem ASCT group, the percentage of ≥CR pre ASCT was 47.5%, while the percentage of ≥CR after 1 st and 2 nd ASCT was 65% and 85%, respectively. From 1 st transplantation, the median progression-free survival (PFS) was 33.2 and 71.1 months for the single and tandem arm, respectively (P=0.0099), and the median overall survival (OS) for the single and tandem arm was 38.3 and 75.8 months, respectively (P=0.0519). In the single and tandem group, 7-year PFS was 29.9% and 57.0%, while 7-year OS was 26.3% and 43.5%, respectively. The median PFS was 23.2 and 61.2 months for the single and tandem arm in patients with high risk (P=0.038), while the median OS was 32.4 months and 65.8 months, respectively (P=0.045). No transplant-related mortality occurred in both cohorts. The median times to neutrophil and platelet engraftment for single group were 11 days and 13 days, respectively. In the tandem group, the median times to neutrophil engraftment post 1 st and 2 nd transplantations were 11 days and 12 days, respectively, while the mean engraftment times for platelets were 12 days and 17 days. Mucositis, engraftment syndrome, and infection were common but manageable complications. Conclusion: Upfront tandem ASCT could deepen the depth of response and prolong PFS in MM patients and could be performed feasibly and safely in patients with myeloma, especially when novel agents are not available in China.

Stem Cell Utilization in the Era of Novel Therapies for Multiple Myeloma

Introduction: Stem cell collection is recommended for patients with newly diagnosed multiple myeloma (NDMM) deemed eligible for autologous stem cell transplantation (ASCT). Standard practice at most institutions is to collect an adequate number of stem cells for at least 2 ASCTs, but the benefit of maintaining extra stem cells in storage for future use beyond an initial ASCT warrants re-evaluation in the current era of novel therapies and evolving MM clinical practice. To address this, we reviewed the utilization rates and indications for the use of stored stem cells (SSC) at our institution. Methods: We conducted a single-center, retrospective study of 1470 patients with NDMM who collected sufficient stem cells for at least 2 ASCTs and underwent at least one ASCT at Memorial Sloan Kettering Cancer Center between January 2007 and December 2022. From this cohort, we assessed rates of stem cell utilization for second, non-tandem (salvage) ASCT and/or stem cell boost over time and determined progression-free survival (PFS) and overall survival (OS) from the time of salvage ASCT using the Cox proportional hazard model. Results: The median patient age atinitial ASCT was 61 years (range 24-81), with 58% male, 25% International Staging System stage III, and 42% (542/1283) with at least one high-risk cytogenetic alteration. Granulocyte-colony stimulating factor, either with or without plerixafor, was used for stem cell mobilization in 70% (834/1193) of patients, with the remaining patients undergoing chemotherapy-based mobilization, including high-dose cyclophosphamide (15%) or other multiagent chemotherapy regimens (15%). The median total CD34 + cell collection yield was 10.3 × 10 6/kg (interquartile range, IQR, 8-13). During the entire study period, SSC were used for 14.6% (214/1470) of patients, with 11.2% (n=165) for a salvage ASCT and 2.1% (n=31) for a stem cell boost. Seven patients received both a salvage ASCT and a boost. An additional 25 patients had upfront tandem ASCT (none since 2015) and were excluded from this analysis. Notably, from 2019 to 2022, the annual utilization of salvage ASCT increased compared to pre-2019 levels (median=21, range 11-27 vs. pre-2019 median=7, range 4-12), as did stem cell boosts (median=4, range 1-6 vs. pre-2019 median=1, range 0-3), despite a decline in numbers during the COVID-19 pandemic (Figure 1). The median age at SSC use was 61 years (range 29-78). The median number of prior lines of therapy (LOT) before the use of SSC was 4 (IQR: 2-7) for salvage ASCT and 6 (IQR: 1-6.5) for boosts. The median infused stem cell dose (CD34+ cells/kg) was 4.4 × 10 6 (range 3.2-5.7) for salvage ASCT and 3.1 × 10 6 (range 2.2-3.6) for boosts. The median PFS after salvage ASCT was 16 months (95% confidence interval, CI, 12-21), and the median OS was 37 months (95% CI 29 - 53). On multivariable analyses, receipt of fewer lines of therapy was the sole favorable prognostic factor for PFS and OS. Among patients with ≤ 3 prior LOT, the median PFS after salvage ASCT was 32 months (95% CI 22-42), while those with > 3 LOT had a median PFS of 8.0 months (95% CI 5.8-12) (Figure 2). Post-treatment therapy after salvage ASCT or stem cell boost most commonly included various MM triplet regimens, chimeric antigen receptor T-cell therapy, and bispecific T-cell engagers. Conclusion: While overall rates of SSC utilization at our institution remain low, rates have increased in recent years, as both salvage ASCT and stem cell boosts provide effective platforms for treating disease and treatment-related refractory cytopenias as a bridge to next therapy for patients with advanced MM. Ultimately, institutional practices for stem cell collection and storage require optimizing the balance of clinical utility with resource allocation and costs of maintaining SSC.

Survival of Patients with Multiple Myeloma Treated with Bortezomib-Based Triplets and Autologous Hematopoietic Stem Cell Transplant As First Line in Latin America

Background In transplant-eligible newly diagnosed multiple myeloma (NDMM), triplet combinations including proteasome-inhibitors and immunomodulators are the backbone of induction therapy before autologous stem cell transplant (ASCT). Post-ASCT maintenance with lenalidomide is the standard of care. This approach yields deep responses and long overall survival. In Latin America (LATAM) there is scarce data about the outcome of bortezomib-based triplets and ASCT. The aim of this study was to evaluate overall survival (OS) in Latin American transplant-eligible NDMM patients induced with bortezomib-based triplets and ASCT. Methods Retrospective international multicenter cohort study. Patients older than 18 years with MM, who received bortezomib-based triplets followed by ASCT as first line, between 2010 and 2022 were analyzed. Data were collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes. Descriptive statistics were performed. Comparisons of characteristics between groups were made using the Chi-square test, Student´s T-test and ANOVA, as appropriate. Survival analysis was performed using Kaplan-Meier curves, comparisons between groups by Log Rank method, and calculations of the risk relationships by Cox regression. Statistical analysis was performed by using IBM SPSS version 25.0. Results A total of 279 patients with NDMM were included, 124 from Argentina, 20 from Chile, 30 from Mexico, 20 from Paraguay, 43 from Peru, 33 from Uruguay, and 9 from Venezuela. Median age was 57 years (range 29-75) with a male predominance (54.8%). Most patients (58%) were treated in private centers. 56.1% were IgG subtype, 24.8% IgA and 17.3% light chain MM. According to the ISS, 69.2% were classified as ISS II or III. Bone disease was the most frequent myeloma-defining events (75.9%), followed by anemia (61.4%), renal failure (24.2%), and hypercalcemia (20.1%). Fluorescence in situ hybridation (FISH) analysis was performed in 53.4% of patients (only 41% with plasma cell sorting), del17p was the most frequent anomaly found (17.4%), followed by t(4;14) (6%), and t(14;16) (2%). The most frequently used induction regimen was cyclophosphamide-bortezomib-dexamethasone (CyBorD) (38.7%), followed by bortezomib-thalidomide-dexamethasone (VTD) (33.7%), and bortezomib-lenalidomide-dexamethasone (VRD) (27.6%). Very good partial remission (VGPR) or better was achieved in 88.3% for VRD, 81.9% for VTD, and 76.8% for CyBorD (p=0.138). Median time from diagnosis to ASCT was 261.5 days. Only 7 patients received tandem ASCT as first-line consolidation. Maintenance treatment was administered to 88.2% of patients and was based on lenalidomide, thalidomide, bortezomib, and lenalidomide+bortezomib in 67.9%, 16.3%, 8.9% and 3.3%, respectively. Treatments and responses are shown in detail in Table 1. With a median follow-up of 45 months (range 7-140), median progression-free survival (PFS) was 33 months (95% CI, 26.7 - 39.3). Median PFS according to treatment was 21 months (95% CI, 14.3 - 27.7) for VRD, 35 months (95% CI, 22.2 - 47.8) for VTD, and 36 months (95% CI, 28 - 44) for CyBorD, p=0.004. Median OS of the whole cohort was not reached (NR), and 86% at 45 months; 75 months for VRD (95% CI, 44 - 106), and NR for CyBorD and VTD (p=0.284) (Figure 1). In the multivariate analysis hypercalcemia (p=0.01) and extramedullary disease (p=0.03) were the only independent risk factors. Discussion FISH was performed only in half of our patients, and the majority without plasma cell sorting. The main used regimen was CyBorD. Although better PFS was obtained with CyBorD, no significant differences in responses or OS were found between VRD, VTD or CyBorD. The reason why VRD PFS and OS were lower merits further study. We report a high rate of maintenance treatment.

Successful Transjugular Portosystemic Shunt Treatment of Pediatric Sinusoidal Obstruction: Case Report and Review of Literature.

In adults with medically refractory sinusoidal obstruction syndrome (SOS), a transjugular intrahepatic portosystemic shunt (TIPS) has been used successfully to improve portal hypertension and symptoms such as ascites. There is limited data on the use of TIPS for SOS in pediatric patients. The index case was reviewed retrospectively. PubMed and Medline databases were searched to identify other cases. A 4-year-old male with high-risk neuroblastoma, developed SOS after tandem autologous stem cell transplant. He was medically managed with defibrotide, diuretics, and peritoneal drainage, but, due to refractoriness, he underwent TIPS day +54 following bone marrow transplant. Hepatic venous pressure gradient improved from 17 to 8 mm Hg following TIPS placement with significant improvement in the patient's clinical status and ascites. However, 15 months later, his shunt remained patent, and he remains clinically well with stable liver enzymes. A literature review identified 13 pediatric cases of TIPS for SOS due to varied causes. TIPS caused a median hepatic venous pressure gradient of 9 mmHg (range, 2-38 mm Hg). The mortality following the procedure was 15%, with 2 cases who died at 2- and 11-days post-TIPS. At the time of the last follow-up (range 8-25 months), 5 patients were alive, and 8 were lost to follow-up. We present here a pediatric case of SOS due to stem cell transplant treated successfully with TIPS with a review of the literature. A timely, individualized application of TIPS can be effective in treating children with medication-refractory SOS.

Autologous followed by allogeneic versus tandem-autologous transplantation in high-risk, newly diagnosed multiple myeloma: a systematic review and meta-analysis

ABSTRACTObjectives:High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM.Methods:Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models.Results:Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51–1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67–5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%).Conclusion:Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

OA-42 Second primary malignancies after tandem autologous hematopoietic stem cell transplantation for patients with multiple myeloma treated on earlier total therapy protocols

OA-42 Second primary malignancies after tandem autologous hematopoietic stem cell transplantation for patients with multiple myeloma treated on earlier total therapy protocols

P-147 Obtaining M protein immune reconstitution as soon as possible after tandem autologous hematopoietic stem cell transplantation improves the prognosis of patients with newly diagnosis multiple myeloma

P-147 Obtaining M protein immune reconstitution as soon as possible after tandem autologous hematopoietic stem cell transplantation improves the prognosis of patients with newly diagnosis multiple myeloma

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

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

Mechanisms of endothelial injury and transplant-associated thrombotic microangiopathy in tandem autologous hematopoietic stem cell transplant for neuroblastoma.

Not available.

Curability of multiple myeloma (MM) based on relative survival rate (RSR) in patients (pts) treated on earlier total therapy (TT) protocols.

8059 Background: Long term overall survival (OS) follow-up data in pts with MM treated on clinical trials is limited. TT approach uses all MM-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. We report the longest follow up of MM trials (TT1 (NCT00580372), TT2 (NCT00083551), TT3a (NCT00081939) and TT3b (NCT00572169)) reported to date with RSRs to assess for curability. Methods: Pts treated on TT1, TT2, TT3a and TT3b were followed at the University of Arkansas for Medical Sciences after completion of therapy including multi-agent chemotherapy, high dose melphalan followed by tandem autologous stem cell transplantation (ASCT) and fixed duration maintenance therapy with introduction of thalidomide (thal) (TT2+thal vs TT2-thal), bortezomib (TT3a) and lenalidomide (TT3b). Expected survival rate was defined as probability of a population surviving from yr to yr. RSR was defined as ratio between observed survival of trials to expected survival in population adjusting for age and sex based on enrollment year. Data cut-off was October 10, 2022. Results: 1379 pts were enrolled (TT1:231, TT2:668, TT3a:303, TT3b:177) with median follow up duration of 16.6 years (yrs) (TT1:25 yrs, TT2:18.4 yrs, TT3a:16.2 yrs, TT3b:14.2 yrs). 10-yr PFS increased from 8.8% (TT1) to 15.5% (TT2-thal) to 25.1% (TT2+thal) to 32.9% (TT3a) to 42.4% (TT3b). Median OS improved over time (TT1:5.8 yrs, TT2:10.4 yrs, TT3a:11.9 yrs, TT3b:10.1 yrs). 15-yrs OS improved from 24.2% in TT1, 33% in TT2, 40% in TT3a and 37% in TT3b. 20-yr OS is 24.4% for pts treated on TT2 protocol. Outcomes were better for standard risk disease defined by low-risk gene expression profiling (GEP) with 20-yrs OS of 30% in TT2 and 15-yrs OS of 45% in TT3a. RSRs approach 1 at 10-15 yrs for TT1, but this occurs earlier, at 5-10 yrs, for TT2+Thal, TT3a and TT3b [Table]. No difference in RSR between TT3a and TT3b was noted. Relative excess risk (RER) showed an estimated 23%, 44% and 54% lower excess mortality when comparing TT2 (+ thal), TT2 (-thal) and TT3a with TT1, respectively. Conclusions: In the longest follow up duration of any MM clinical trial, a subset of MM pts are cured as evidenced by RSRs approaching 1. Approximately one third of pts treated on TT2 protocol and one-half pts treated on TT3a are alive at 20 year and 15 yrs from initial diagnosis, respectively. Incorporation of immunomodulatory drugs and proteasome inhibitors along with tandem ASCT resulted in cumulative improvement of OS as evidenced by lower RER of mortality. Clinical trial information: NCT00580372 , NCT00083551 , NCT00081939 , NCT00572169 . [Table: see text]

Single or tandem autologous stem cell transplantation for treating Chinese patients with refractory/relapsed classical Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is the standard treatment strategy for refractory or relapsed classical Hodgkin lymphoma (R/R cHL). However, a single transplantation is insufficient to cure the disease because of unfavorable risk factors. Herein, we evaluated the outcomes of single or tandem ASCT in patients with R/R cHL, especially in high-risk patients. We retrospectively analyzed R/R cHL patients who underwent single or tandem ASCT between April 2000 and June 2021 at the Beijing Cancer Hospital and Peking University International Hospital. A total of 134 patients were enrolled. Patients were allocated to a favorable-risk group (group A, n = 33), an unfavorable-risk group (group B, n = 81) that underwent single ASCT, and an unfavorable-risk group that underwent tandem ASCT (group C, n = 20). The median follow-up time was 99 months (range, 91-107 months), and no treatment-related deaths occurred after single or tandem ASCT. However, 27 patients (2 in group C) died during the follow-up period. The groups A, B, and C had 5-year progression-free survival (PFS) rates of 77.05%, 45%, and 74.67%, respectively (p = 0.0014), and 5-year overall survival (OS) rates of 89.85%, 76.06%, and 95%, respectively (p = 0.18). Neither the median PFS rates of groups A and C nor the OS rates of all groups were reached. Our study discusses the advantages of tandem transplantation for high-risk patients with R/R cHL.

A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China.

Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited. We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021. A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%). Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Impact of autologous stem cell transplantation (ASCT) on progression free survival (PFS) in newly diagnosed multiple myeloma patients (NDMM) with high risk cytogenetic abnormalities.

ASCT has been considered the standard of care for younger patients with NDMM, however, not all the studies published so far have uniformly demonstrated the complete superiority of ASCT over chemotherapy at standard doses. A systematic review and meta-analysis of randomized studies has shown a significant benefit with single ASCT in terms of prolonged progression-free survival (PFS), but not of overall survival (OS). In our retrospective analysis we investigated the impact of high dose (HD) chemotherapy followed by ASCT in special population of patients with high risk cytogenetic profile on the PFS and treatment outcome. Retrospective analysis of NDMM patients eligible for HD chemotherapy followed by upfront ASCT in the era of novel agents, who underwent the ASCT in the Department of hematology and oncohematology LF UPJŠ and UNLP Košice in the timeframe of 54 months (from 01/JAN/2019 to 30/JUN/2023). Patients were stratified according to their cytogenetic profile. PFS was defined by the time from ASCT to the disease progression. The OS was defined as the time from the the start of treatment to the death from disease progression. The high risk cytogenetic abnormalities (HRCA) were defined as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperploidy, gain (1q). Inclusion criteria were met by 65 patients with NDMM who received HD chemotherpy followed by ASCT. We identified 22 (33.8 %) patients with HRCA and 43 (66.2 %) patients with standard cytogenetic risk. During the monitored period we recorded 4 deaths due to disease progression, all of them in the HCRA subgroup. The response was enhanced by the ASCT in both subgroups. The very good partial response (VGPR) increased from 42 % to 46 % and complete remission (CR) increased from 23 % to 45 % after the ASCT. The number of patients achieving only partial response (PR) decreased from 35 % to 9 % after ASCT. In the subgroup of patients with HRCA the median PFS after ASCT was lower compared to the patients with standard cytogenetic risk (17 vs 38 months). The average PFS in both subgroups was 22.9 months. The median OS in both subgroups was not reached, however the only deaths due to disease progression were recorded in the HRCA subgroup. At the time of analysis, 100 % (43) of patients are alive in the standard cytogenetic subgroup versus 72 % (18) of patients in HRCA subgroup. HD chemotherapy followed by ASCT remains the standard of care for NDMM eligible for high dose chemotherapy. Our results confirm the benefit of ASCT even in the presence of HRCA. Lower PFS in the HRCA subgroup might indicate the need for more intensive treatment, which may be achieved by tandem ASCT defined as two ASCT performed within a period of no more than six months. Additionally, as three- and four-drug induction therapies are becoming increasingly available and effective, resulting in high minimal residual disease (MRD) negative rates, it is important to continue discussing and further personalizing upfront ASCT to avoid overtreatment and possible toxicities especially in the non-high-risk patient population (Tab. 5, Fig. 2, Ref. 9).