Upfront Autologous Stem Cell Transplantation Research Articles

Real-World Outcomes of Upfront Autologous Hematopoietic Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma with Deletion 17p

BackgroundDespite tremendous advancements in multiple myeloma (MM) therapeutics, outcomes remain heterogeneous, heavily influenced by clinical and cytogenetic factors. Among these, deletion of the short arm of chromosome 17 (del(17p)) is a strong predictor of poor prognosis. ObjectiveThe aim of this study was to evaluate real-world outcomes in patients with newly-diagnosed multiple myeloma (NDMM) with del(17p) undergoing upfront auto-HCT. Study DesignWe conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-HCT at MD Anderson Cancer Center between 2008 and 2018. Primary endpoints were progression-free survival (PFS) and overall survival (OS), with secondary endpoints being hematological response and minimal residual disease (MRD) status post-auto-HCT. MRD status in the bone marrow biopsy was evaluated using 8-color next-generation flow cytometry with a sensitivity of 1/10-5 cells. ResultsOne hundred and fifteen patients were included (55% male). Median age at auto-HCT was 62 years (range 34-83). The median del(17p) clone size was 20%, with 51 (53%) patients having clone sizes >20% and 15 (15%) patients having clone sizes >55%. Additional high-risk cytogenetic abnormalities included t(4;14) in 15 (13%) patients, t(14;16) in 8 (7%) patients, and 1q21+ in 25 (22%) patients. After induction, 10% of patients achieved ≥ CR and 50% achieved ≥ VGPR, with 25% having MRD-negative ≥ VGPR. Post-transplant, 42% achieved ≥ CR and 83% achieved ≥ VGPR as best response, with 55% (48/87) having MRD-negative ≥ VGPR. With a median follow-up of 31.4 months (range 3.1–199.1), median PFS and OS for the entire cohort were 19.9 and 71.5 months, respectively, and 5-year OS was 53%. Concurrent del(17p) and t(4;14) were associated with significantly worse outcomes, with median PFS and OS of 11.5 and 22.4 months, respectively. For the subset of patients with del(17p) and t(4;14), median PFS and OS were 11.5 months and 22.4 months, respectively. In multivariable analysis (MVA), female sex was associated with worse PFS (HR [95% CI] 2.87 [1.75-4.72], p<0.001), while MRD negative CR post-transplant (0.35 [0.18-0.68], p=0.002) and maintenance therapy (0.46 [0.27-0.77], p=0.003) were associated with better PFS. In MVA for OS, female sex (2.22 [1.18-4.17], p=0.013) and the presence of t(4;14)(2.55 [1.09-5.95], p=0.030) were associated with worse OS, whereas Karnofsky Performance Status of ≥90 (0.47 [0.23-0.94], p=0.034) was associated with better OS. ConclusionThis study affirms del(17p) as a high-risk abnormality with unfavourable outcomes despite modern therapies. The co-occurrence of del(17p) and t(4;14) was associated with particularly poor outcomes. Novel approaches are needed for this high-risk subgroup.

Variation in immunoglobulin use and impact on survival in myeloma.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p=0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Effect of dose-adjusted melphalan on MRD-negativity to full dose melphalan in patients with multiple myeloma post-autologous stem cell transplant.

7557 Background: Despite significant therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. Autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients, with high-dose melphalan (MEL200) as the preferred conditioning regimen. Reduced-dose melphalan (MEL140) is used for older or less fit patients. However, this was not prospectively studied and there has been ongoing debate about the efficacy of reduced dosing. This study aimed to investigate the impact of melphalan dose on minimal residual disease (MRD) negativity rates in MM patients undergoing upfront ASCT. Methods: We conducted a retrospective, single-center study involving 74 MM patients who underwent ASCT between 2018 and 2022 at UHCMC, Cleveland, OH and had MRD testing done after transplant. MRD testing was performed using the ClonoSEQ next generation sequencing platform. Results: Median age was higher in the MEL140 group compared to MEL200 (70.3 vs 59.8 years), both groups were similar in terms of sex and race distribution, BMI and KPS scores. Both groups have comparable ISS staging and high-risk cytogenetics. Similar numbers of lines of treatment prior to transplant were seen, with approximately 64% having only one line. First-line induction therapy included triplet therapy (Lenalidomide, Bortezomib, and Dexamethasone) in 73% of patients. Depth of remission at transplant was comparable between groups. MRD negativity rates at 10-5 and 10-6 were comparable between MEL140 and MEL200 groups (64% and 39% in MEL140; 61% and 41% in MEL200; p=0.8 and 0.7 respectively). Sustained MRD negativity at 10-5 over at least 12 months was also comparable (43% in MEL140; 50% in MEL200, p=0.8). After a median follow-up of 37 months, PFS was not reached for either group (p=0.69). Patients achieving MRD negativity at levels of 10-5 had a not reached median PFS, while those not achieving MRD negativity had a median PFS of 41 months (95%CI 23-NR; p=0.024). There was no significant difference in hospital stay duration, time to neutrophil engraftment, readmission rate, or infections within 100 days post-transplant between the MEL140 and MEL200 groups. Conclusions: Our real-world analysis demonstrates that MEL140 yields similar deep post-transplant remissions as MEL200, translating to improved PFS for patients achieving MRD negativity, regardless of the dose used. This is the first report to our knowledge of MRD negativity rate in patients receiving MEL140. [Table: see text]

Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma.

There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Long-term remission after upfront autologous hematopoietic stem cell transplant for CD5+ diffuse large-B cell lymphoma

CD5+ diffuse large B-cell lymphoma (DLBCL) is a rare subtype characterized by an inferior outcome. While dose-dense therapy shows promising activity, the optimal management remains to be determined. To evaluate the benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT), we retrospectively reviewed the medical records of 47 consecutive patients with newly diagnosed de novo CD5+ DLBCL. Of 19 patients ≤ 70 of age with age-adjusted International Prognostic Index 2–3, eight underwent upfront ASCT, and nine did not, despite preserved organ function and response after induction therapy. The remaining two, ineligible for ASCT due to early progression or comorbidities, had a dismal clinical course. Among younger 17 high-risk patients eligible for ASCT, ASCT was associated with better overall (p = 0.0327) and progression-free survival (p = 0.0184). Younger patients without ASCT demonstrated similar outcomes to older patients with similar risk profiles. ASCT could be considered for high-risk CD5+ DLBCL with a response after induction therapy.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016–2021)

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4–72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6–93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0–64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post–ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08–3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53–4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31–0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32–0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05–4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03–7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45–34.59), post–ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09–28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23–6.17) experienced shorter OS. In contrast, post–ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17–0.79) and post–ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24–0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post–ASCT outcome prediction beyond clinical trials.

Impact of revised International Staging System 2 risk stratification on outcomes of patients with multiple myeloma receiving autologous haematopoietic stem cell transplantation.

The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 and 24.8 months, (p < 0.001) and the median OS was 130.8, 128.5, 94.2 and 61.4 months (p < 0.001) for patients with R2-ISS stages I, II, III and IV respectively. On multivariable analysis (MVA) for PFS, using R2-ISS stage I as reference, R2-ISS stages III (hazard ratio [95% confidence interval], 1.55 [1.05-2.29]; p = 0.028) and IV (2.04 [1.24-3.36]; p = 0.005) were associated with significantly inferior PFS. In the MVA of OS, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS (2.43 [1.18-5.01]; p = 0.017). Overall, we found that R2-ISS is a reliable prognostic tool for NDMM patients undergoing up-front auto-HCT.

Prognostic factors in 448 newly diagnosed multiple myeloma receiving bortezomib-based induction: impact of ASCT, transplant refusal and high-risk MM

In Hong Kong, newly diagnosed multiple myeloma (NDMM) receives bortezomib-based triplet induction. Upfront autologous stem cell transplant (ASCT) is offered to transplant eligible (TE) patients (NDMM ≤ 65 years of age), unless medically unfit (TE-unfit) or refused (TE-refused). Data was retrieved for 448 patients to assess outcomes. For the entire cohort, multivariate analysis showed that male gender (p = 0.006), international staging system (ISS) 3 (p = 0.003), high lactate dehydrogenase (LDH) (p = 7.6 × 10−7) were adverse predictors for overall survival (OS), while complete response/ near complete response (CR/nCR) post-induction (p = 2.7 × 10−5) and ASCT (p = 4.8 × 10−4) were favorable factors for OS. In TE group, upfront ASCT was conducted in 252 (76.1%). Failure to undergo ASCT in TE patients rendered an inferior OS (TE-unfit p = 1.06 × 10−8, TE-refused p = 0.002) and event free survival (EFS) (TE-unfit p = 0.00013, TE-refused p = 0.002). Among TE patients with ASCT, multivariate analysis showed that age ≥ 60 (p = 8.9 × 10−4), ISS 3 (p = 0.019) and high LDH (p = 2.6 × 10−4) were adverse factors for OS. In those with high-risk features (HR cytogenetics, ISS 3, R-ISS 3), ASCT appeared to mitigate their adverse impact. Our data reaffirmed the importance of ASCT. The poor survival inherent with refusal of ASCT should be recognized by clinicians. Finally, improved outcome with ASCT in those with high-risk features warrant further studies.

Clinical significance of bone marrow involvement by immunoglobulin gene rearrangement in de novo diffuse large B-cell lymphoma: a multicenter retrospective study.

Bone marrow (BM) involvement is an indicator of a poor prognosis in diffuse large B-cell lymphoma (DLBCL); however, few studies have evaluated the role of immunoglobulin gene rearrangement (IgR) in detecting BM involvement. We evaluated the clinical characteristics and treatment outcomes of patients with DLBCL based on histological BM involvement or positive BM IgR using polymerase chain reaction or next-generation sequencing. We also investigated the role of consolidative upfront autologous hematopoietic stem cell transplantation (ASCT) in patients with DLBCL and BM involvement. Among 624 patients, 123 (19.7%) with histological BM involvement and 88 (17.5%) with positive IgR in histologically negative BM had more advanced disease characteristics. Overall (OS) and progression-free (PFS) survival was better for patients with negative BM histology and negative IgR than that in patients with histological BM involvement (P = 0.050 and P < 0.001, respectively) and positive IgR with negative BM histology (P = 0.001 and P = 0.005, respectively). Survival rates did not differ among 82 (13.1%) patients who were treated with upfront ASCT and had histological BM involvement or positive IgR with negative BM histology. The survival outcomes were worse for patients who were not treated with upfront ASCT and for those with histological BM involvement or positive IgR, than for those with negative BM histology and negative IgR. Patients diagnosed with DLBCL and BM involvement based on histology or IgR had aggressive clinical features and poor survival. Upfront ASCT mitigated poor prognosis due to BM involvement.

Treatment Pattern and Outcome of Newly Diagnosed Multiple Myeloma Patients in a Resource-Limited Setting.

Multiple myeloma is the third most common hematologic malignancy in Malaysia. The introduction of novel agents over the past decades has improved patient outcome and survival substantially. However, these agents incur significant economic burden, thus leading to limited use in less developed countries. This study aims to report on the real-world treatment pattern and outcome of newly diagnosed multiple myeloma (NDMM) patients from a resource-constraint setting. This is a retrospective study on NDMM patients diagnosed between 1 January 2008 and 31 December 2022 in a single academic center. Patients' demographic and treatment details were included for analysis of progression free survival (PFS) and overall survival (OS). One hundred and thirty-six NDMM patients with a median age of 64.0 years (ranged from 38 to 87 years old) were included. Bortezomib-containing regimens were the most commonly used induction agent, followed by thalidomide. Almost half of the patients (47.1%) achieved very good partial response (VGPR) or complete remission (CR), while 31.6% achieved partial response (PR). Bortezomib containing regimen was associated with significantly deeper and more rapid response, (p=0.001 and p=0.017, respectively) when compared to other agents. Only 22.8% of these patients proceeded to upfront autologous haematopoietic stem cell transplantation. The median OS and PFS were 60.0 months and 25.0 months, respectively. Best initial response and upfront autologous stem cell transplantation (ASCT) were significantly associated with better PFS. Achieving at least a VGPR significantly associated with better outcome in NDMM patients. In a resource constrain country, we recommend incorporating bortezomib in the induction therapy followed with an upfront ASCT.

Long-Term Responders after Upfront Autologous Hematopoietic Stem Cell Transplant for Multiple Myeloma

Long-Term Responders after Upfront Autologous Hematopoietic Stem Cell Transplant for Multiple Myeloma

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

Upfront Autologous Stem Cell Transplant at First Complete Remission in Patients with Advanced-Stage Extra-Nodal NK/T Cell Lymphoma: A Multicenter Retrospective Study

Objective: Treatment outcome of patients with advanced-stage extranodal NK/T cell lymphoma (NKTCL) remains unsatisfactory. The role of consolidation therapy with autologous stem cell transplantation (ASCT) at first complete remission (CR1) in these patients is controversial. This study aimed to investigate the effect of upfront ASCT on the prognosis of patients with advanced-stage NKTCL achieving CR1 to frontline therapy. Methods:This is a multicenter retrospective study. Data were collected from patients diagnosed with NKTCL between 2006 and 2021 in the China Lymphoma Collaborative Group (CLCG) database. The inclusion criteria were as follows: pathologically confirmed diagnosis of NKTCL, age≤65 years at diagnosis, stage III or IV disease, and achievement of CR1 at the completion of frontline induction therapy. Clinical characteristics, treatment including the use of ASCT, and follow-up information were reviewed. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 99 patients from 14 medical centers in China were included in this study. The median age was 38 years (range: 6-64 years). Sixteen patients (16%) had an ECOG-PS≥2 at diagnosis, and 26 patients (26%) presented with primary extra-nasal disease. The baseline Prognostic Index for NK-cell lymphoma (PINK) was≥2 in 63 patients (64%). Regarding first-line treatment, 85 patients (86%) received non-anthracycline-based chemotherapy, and the remaining patients received anthracyline-based chemotherapy. At the time of CR1, 32 patients (32%) received upfront ASCT consolidation and 67 patients did not. Baseline clinical characteristics were comparable between the ASCT group and non-ASCT group. With a median follow-up time of 33 months, median PFS was not reached in the ASCT group versus 46 months in the non-ASCT group (3-year PFS: 76.6% versus 54.9%, P=0.012). OS was not significantly different between the ASCT group and the non-ASCT group (3-year OS: 85.2% versus 69.4%, P=0.098). In multivariate analyses, upfront ASCT was independently associated with better PFS (HR=0.40, 95%CI 0.17-0.94, P=0.037) after adjusting for baseline PINK score and types of first-line chemotherapy (anthracyline-based versus non-anthracyline-based). Only non-anthracyline-based first-line chemotherapy (HR=0.32, 95%CI 0.11-0.88, P=0.028) was associated with better OS in multivariate analysis. Conclusions: In this multicenter real-world study, upfront ASCT improves PFS of patients with advanced stage NKTCL achieving CR1 to front-line chemotherapy, but the effect of upfront ASCT on OS in the era of non-anthracycline-based chemotherapy remains uncertain. The specific subgroups of patients most likely to gain a survival benefit from upfront ASCT need to be further investigated.

Up-Front ASCT Overcomes the Survival Benefit Provided By HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort

Introduction: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high-doses of cytarabine (HDAC) remains controversial in the management of ASCT-eligible patients. Based on this premise, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. Methods: This retrospective, observational, and single-center study involved 165 MCL patients, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2010 to December 2022. Endpoints included overall survival (OS), event-free survival (EFS), and progression of disease within 24 months (POD-24) from up-front treatment. Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI), and a p-value ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 65 years (38-89) and 73.9% (122/165) were male. More than 90% of cases (150/165) had a classic nodal variant (cnMCL), 76.4% (120/157) had bone marrow infiltration, and 56.4% (93/165) presented splenomegaly. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and advanced-stage III/IV were observed in 32.7% (54/165), 64.8% (107/165), 32.1% (53/165), and 95.8% (158/165), respectively [ Table 1]. Sixty-four percent of patients (106/165) were categorized as high-risk according to MIPI score. Table 2 summarizes the main therapeutic modalities applied to the whole cohort. With a median follow-up of 71.1 months (95% CI: 61.8-80.4) the estimated 2-year OS and EFS were 64.1% (95% CI: 56.2-71.9%) and 31.8% (95% CI: 23.0-40.6%), respectively. The ORR for the whole cohort was 64.7% (95% CI: 57.1-71.7%), with CR achieved in 41.5% (95% CI: 34.1-49.1%). POD-24 was observed in 46.7% (95% CI: 39.1-54.3%), and the overall mortality rate (OMR) during all follow-up was 58.2% (95% CI: 50.6-65.5%), with disease progression being the main cause of death. Patients treated with R-HDAC-based regimens (43.4%-66/152) had higher ORR (85.9% vs 65.7%, p=0.007) compared to those receiving R-CHOP (46.0%-70/152), as well as lower POD-24 rates (61.9% vs 80.4%, p=0.043) and lower mortality (43.9% vs 68.6%, p=0.004). However, intensified induction regimens using R-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (N=41) (2-year OS: 88.7% for R-HDAC plus ASCT vs 78.8% for R-CHOP plus ASCT, p=0.289), as summarized in Figure 1. Furthermore, up-front ASCT was independently associated with increased OS (p&amp;lt;0.001), EFS (p=0.005), and lower POD-24 rates (p&amp;lt;0.001) in MCL. Additionally, CNS involvement (HR: 3.12, 95% CI: 1.45-6.73, p=0.004), tumor lysis syndrome (HR: 2.79, 95% CI: 1.13-6.86, p=0.026), albumin &amp;lt; 3.5 g/dL (HR: 2.69, 95% CI: 1.61-4.50, p&amp;lt;0.001), and failure to achieve remission after induction therapy (HR: 3.71, 95% CI: 2.07-6.67, p&amp;lt; 0.001) were predictors of poor OS. Conclusion: In the largest Latin American cohort of MCL reported to date, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young anf fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS, it was associated with higher ORR and lower rates of early-relapses.

Racial Disparities in Autologous Stem Cell Transplant Utilization in Multiple Myeloma Persist Despite Referral to a Transplant Center

Introduction: Although the role of upfront autologous stem cell transplantation (ASCT) as an effective therapy for multiple myeloma (MM) is established in multiple clinical trials, it is well documented that non-Hispanic Black (NHB) and Hispanic individuals are less likely to receive ASCT for MM compared with age- and sex- matched non-Hispanic white (NHW) individuals. Methods: We conducted an institutional review of new patient consultations for MM at the Froedtert and Medical College of Wisconsin Cancer Center from 1/1/2012 to 12/31/2022, a tertiary medical center in the state of Wisconsin. We looked at the ASCT utilization rate by race and studied factors related to patients undergoing ASCT, including univariate and multivariate analyses. We utilized a logistic regression model to examine the likelihood of receiving ASCT. We considered the following covariates in the model building process: age, race, sex, cytogenetics, ISS stage, renal co-morbidity, year of consult, time from diagnosis to consult. A significance level of 0.1 was used for entry into the model. Race was self-reported by patients in the medical record. Results: We identified 1,221 MM consults from 2012 to 2022, of which 1,019 were NHW, 158 were NHB, and 44 were other minorities (“Other”) (Table 1). Median age at consult was 63, 66.1, and 61.8 years for NHBs, NHWs, and Other (p&amp;lt;0.1). All groups had similar cytogenetic risk, ISS staging, myeloma subtype, and time of diagnosis to consult. NHBs had longer median time from diagnosis to ASCT when compared to NHWs and Other, 6.4, 5.8, and 5.5 months, respectively (p=0.03). Median time from consult to ASCT was 4.3, 3.6, and 4.2 months for NHBs, NHWs, and Other (p=0.06). However, when comparing NHBs to NHWs, the difference between median time from consult to ASCT was significant (p=0.02). ASCT utilization rate was lowest in NHBs at 67.7% compared to Other at 72.7% and highest at 78.3% in NHWs (p=0.01) with trends over time shown in Figure 1. Multivariate analysis showed that NHWs were more likely to proceed to ASCT than NHBs (OR=2.698, 95% CI: 1.788-4.071, p=0.0021) while those with age ≥75 (OR=0.063, 95% CI: 0.044-0.09, p&amp;lt;.0001) and those with renal co-morbidity were less likely to proceed to ASCT (OR=0.523, 95% Cl: 0.36-0.761, p=0.0007). Conclusion: Consistent with prior studies, NHBs were younger at the time of their MM transplant consultation and had a longer median time from diagnosis and consultation to ASCT when compared to NHWs. Despite referral to a transplant center, NHBs still had lower ASCT utilization than NHW, indicating that simply access to a transplant center is not the only barrier driving ASCT utilization differences between NHBs and NHWs. Age ≥75 years and renal comorbidity were also associated with lower ASCT utilization per multivariate analysis. Future plans to further understand the role of social determinants of health and the underlying role of structural racism on access to ASCT in multiple myeloma will help identify targets for interventions to eliminate these barriers.

Impact of Revised International Staging System 2 (R2-ISS) Risk Stratification on Outcomes of Patients with Multiple Myeloma Receiving Autologous Hematopoietic Stem Cell Transplantation

Background: The second revision of the International Staging System (R2-ISS) is a new and simple tool to risk stratify newly diagnosed multiple myeloma (NDMM) patients. Our aim in this study was to evaluate the utility of R2-ISS in NDMM patients who received upfront autologous hematopoietic stem cell transplantation (auto-HCT). Methods: We conducted a retrospective analysis of all NDMM patients who underwent upfront auto-HCT between 1988 and 2021 at MD Anderson Cancer Center and had available data for calculation of R2-ISS, including albumin, β-2 microglobulin, LDH, and fluorescence in-situ hybridization (FISH) analysis at diagnosis. High-risk cytogenetic abnormalities (HRCA) were t(4;14), del(17p), and 1q21 gain or amplification, as detected by FISH. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was hematological response after auto-HCT. Results: A total of 1291 patients were included, with a median age of 62 years (range 29 - 83) and 60% were male. Four hundred-and-nineteen patients (32%) had HRCA. Most patients received either bortezomib, lenalidomide, and dexamethasone (VRD) (34%) or carfilzomib, lenalidomide, and dexamethasone (KRD) (25%) induction regimens, and most patients (95%) received melphalan based conditioning. The distribution of R2-ISS stages in our cohort was as follows: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III, and 131 (10%) stage IV. A total of 1027 (80%) patients received post auto-HCT maintenance, mostly lenalidomide with or without dexamethasone (n = 785, 61%) (Table 1). With a median follow-up of 42.2 months (range 0.3 - 181.0) for the entire cohort, the median PFS was 73.0, 65.2, 44.0, and 24.8 months ( P &amp;lt; .001) and the median OS was 130.8, 128.5, 94.2, and 61.4 months ( P &amp;lt; .001) for patients with R2-ISS stages I, II, III, and IV, respectively (Figure 1). On multivariable analysis (MVA) for PFS, using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (hazard ratio [95% CI], 1.11 [0.76-1.63]; P = .59), but there was a significant worsening in PFS for R2-ISS stage III (1.55 [1.05-2.29]; P = .028) and R2-ISS stage IV (2.04 [1.24-3.36]; P = .005). On MVA for OS, again using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (1.33 [0.74-2.40]; P = .34) or R2-ISS stage III (1.75 [0.97-3.17]; P = .06), but there was a significant worsening in OS for R2-ISS stage IV (2.43 [1.18-5.01]; P = .017). On MVA, other measures significantly associated with worsening PFS were year of auto-HCT &amp;lt; 2010, lambda light chain disease subtype, presence of HRCA, prior MRD/response other than negative/≥CR, and not achieving MRD negative/≥ CR post auto-HCT. For OS, other measures significantly associated with worsening survival on MVA were presence of HRCA, HCT-CI &amp;gt; 3, having at least one bone lesion, not achieving CR at best response, and not receiving post auto-HCT maintenance therapy. Conclusion: Our study demonstrates that R2-ISS is a reliable prognostic tool for NDMM in a large cohort of patients who received standard anti-myeloma treatment, including modern induction regimens, upfront auto-HCT, and post-transplant maintenance.

Daratumumab-Based Maintenance in Patients with Relapsed Multiple Myeloma after Salvage Autologous Hematopoietic Stem Cell Transplantation

Introduction: Maintenance therapy is considered standard of care after upfront autologous hematopoietic stem cell transplantation (auto-HCT) for patients with newly diagnosed multiple myeloma (MM). However, there is paucity of data on the use of maintenance after a salvage auto-HCT, whether first or second. Aim: We designed a clinical trial for relapsed MM patients who underwent salvage auto-HCT after disease relapse to receive post-transplant maintenance with daratumumab (dara), with the addition of pomalidomide (pom) in a later amendment. Methods: We hypothesized that maintenance therapy with dara +/- pom will improve the progression-free survival (PFS) after a salvage auto-HCT. Patients with prior exposure to dara or pom were included, but patients refractory to either drug were excluded. The trial was planned to enroll a total of 56 patients. Patients received dara SQ weekly for weeks 1-8, every 2 weeks for weeks 9-24, and monthly from week 25 until progression. Pom was given at 2 mg PO from day 1-21 every 28 days. Patients received herpes zoster prophylaxis for the duration of the trial. The primary endpoint of this phase II trial was PFS. Disease response was assessed according to the International Myeloma Working Group (IMWG) uniform response criteria. Minimal residual disease (MRD) was measured by multiparametric flow cytometry (10 -5) in the bone marrow at day 90-180 after transplant. Results: The trial was terminated due to poor accrual after 13/56 patients were enrolled between May 2019 and August 2022. Median age at salvage auto-HCT was 64 (range: 43-76) years, and 7 patients (54%) were male. Median prior lines of treatment was 2 (range: 2-4). Six patients (46%) had a prior auto-HCT, and 7 (54%) had a hematopoietic stem cell comorbidity index (HCT-CI) of &amp;gt;3. Median time from diagnosis to salvage auto-HCT was 58.3 (range 7.6-132) months. Five patients (38%) had high-risk cytogenetic abnormalities (1q+ in all 5). Eight (61%) patients received melphalan alone, 4 (31%) received busulfan/melphalan, and 1 (8%) received gemcitabine/busulfan/melphalan/panobinostat as their conditioning regimen (Table 1). Three patients (23%) started maintenance with dara alone, while the remaining 10 (77%) patients received dara + pom. At study entry, 6 patients (46%) had a complete response (CR), 4 (31%) in very good partial response (VGPR), 2 (15%) in partial response (PR), and 1 (8%) had stable disease (SD). At day 100 post maintenance, 9 (69%) were in CR, while 1 (8%) each had VGPR, PR, SD and progressive disease (PD), respectively. For the 12 patients that did not progress at day 100, best response to dara +/- pom maintenance was CR in 10 (83%), and VGPR and SD in 1 (8%) each. With a median follow up of 26.1 months (range: 14.2-37.7) from the start of maintenance, 3 patients had progressed but there are no deaths so far. Median PFS from the date of auto-HCT was not reached, and from start of maintenance 28.5 (95% CI 26.3-NA) months. 2-year PFS was 92% (Figure 1). Most common adverse events were neutropenia (n=11, 84%; none grade&amp;gt;3), grade 1-2 fatigue (n=6, 46%), and grade ≤3 bacterial infection, grade ≤3 viral infection, grade 1-2 diarrhea and grade 1 thrombocytopenia (n=5, 38% each). Conclusion: Maintenance therapy with dara, with or without pom, is safe and feasible after a salvage auto-HCT for MM, with 83% achieving a CR. After a median follow up exceeding 2 years, the median PFS was 28.5 months. The trial was terminated due to poor accrual.

Identification of Clinical-Biological Features of Newly Diagnosed Early Relapse Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation

Despite many therapeutics advances, Multiple Myeloma (MM) remains an incurable hematological malignancy with a cohort of patients who relapse early or does not respond to first-line therapy, including autologous stem cell transplantation (ASCT). The proportion of patients with early relapse is stable over time at about 30% and they have a median Overall Survival (OS) less than 3 years. Consequently, clinical and/or biological features that identify patient at high risk for early relapse at diagnosis represent a critical unmet medical need. With the aim of identify possible factors of early relapse (ER), we conducted a retrospective, observational, single center study on a cohort of 74 MM patients who received an upfront ASCT between 2011 and 2021 after a novel agent-based induction at the Hematological and BMT Unit of the University Hospital of Parma (Italy). The primary end point of the study was the assessment of possible predictive markers for ER, defined as progressive disease that occurred within 18 months from the time of ASCT. Clinical, biochemical and cytogenetics features of the cohort of MM patients were evaluated (Table 1). Definitions of response and progression were used according to the International Myeloma Working Group (IMWG) response criteria. All statistical analyses were done by SPSS Statistics. The characteristics of cohorts were summarized using the median value for continuous variates and the frequency for categorical ones. The Pearson chi-square test and Student t-test were used to identify differences between groups for categorical and continuous variables, respectively. Kaplan-Meier Curve with log-rank test were used to analyze survival data. The bivariate logistic analysis was conducted to recognize independent factors predicting ER, subsequently Cox regression analysis was performed to confirm the validity of multivariate analysis for survival data. The cohort characteristics were summarized in table 1. Among the 74 MM patients included in the study, a total of 19 patients (25.5) experienced ER, with mean time to relapse of 15.6 (18.0) months. Univariate statistical analysis identified as possible predictive markers for early relapse at diagnosis: IgA MM (p &amp;lt; 0.05), elevated serum LDH level (p &amp;lt; 0.05), C-CRAB criteria (p &amp;lt; 0.05), high risk cytogenetic aberrations (p &amp;lt; 0.05), stage R-ISS III (p &amp;lt; 0.001) and stage R2-ISS III or IV (p &amp;lt; 0.001). Multivariate statistical analysis confirmed IgA isotype (p &amp;lt; 0.05) and higher stage according to R2-ISS (p &amp;lt; 0.001) as effectively independent predictive risk factors for ER. Time-to-event analysis displayed a mean progression free survival (PFS) from transplant of 24.7 (16.0) months and 32.5 (19.0) months for those with IgA MM and stage R2-ISS III or IV, respectively. In the group of patients with IgA isotype the mean OS from transplant was 49.5 (30.0) months, while the mean OS from diagnosis was 58.0 (35.0) months without statistically significant differences compared to counterpart. In the group of patients with stage R2-ISS III or IV the mean OS from transplant was 48.2 (41.0) months, while the mean OS from diagnosis was 56.5 (49.0) months. Finally, in ER cohort the mean OS from diagnosis was 47.1 (35.0) in comparison with the 75.0 (71.0) months of non-ER cohort. In conclusion, this retrospective study was able to identify the main features of newly diagnosed early relapsed MM patients eligible to ASCT identifying the IgA isotype and the R2-ISS score system as the main predictive prognostic factors for early relapse in this cohort of patients.