Autologous Stem Cell Transplantation For Multiple Myeloma Research Articles

Outcomes of Patients Treated at First Transplant Center in Dubai, UAE

Introduction: Autologous stem cell transplant (ASCT) is a well-known treatment modality for decades with curative potential in the field of hematological malignancies such as lymphoma (Relapsed Hodgkin's Lymphoma) and multiple myeloma (MM), but access in the Middle East, specifically in the metropolitan city of Dubai, United Arab Emirates (UAE) has been limited. This is despite the fact that UAE is a high-income country according to the Gross national income (GNI) and has a population of approximately 9.5 million. In 2021, we developed the first and only ASCT unit in Dubai, United Arab Emirates (UAE). This was a milestone achievement to offer ASCT to residents. This service was available since approval by Dubai Health Authority (DHA) in September 2021 and capacity for 2 ASCT at a time. The unit comprises 2 positive pressure isolation rooms, with in-house apheresis, stem cell storage facilities. This is the first report of the safety and efficacy outcomes of patients (pts) who were transplanted to date at our center. Despite the modest volume, this data will serve as a resource for policymakers, healthcare professionals and is important for the ASCT community as we advance care of ASCT recipients in regions with previously limited access. Methods: This is a single-center retrospective study performed at American Hospital Dubai, UAE. We identified and included pts who received ASCT for lymphoma and MM between September 2021-June 2023. Per institutional protocols, mobilization was done with granulocyte colony-stimulating factor (GCSF). The stem cells were collected via Optia®spectra apharesis system. MM pts collected for 2 ASCT while those with relapsed HL collected for 1 ASCT. Conditioning chemotherapy administration was outpatient for melphalan (for MM) and inpatient for rHL with BEAM. Monitoring was per institutional standards. Descriptive analysis is reported. Results: There have been 17 ASCTs performed with at least one month follow-up. The most common indication was MM (9) followed by Relapsed lymphoma (8) and 1 case of multiply relapsed Ewing's Sarcoma. (Table 1) Mobilization:100% pts received granulocyte colony-stimulating factor (GCSF) mobilization with one patient required plerixafor in addition. The median days of collection was 1 (Range 1-2 days). All pts collected successfully. Neutropenic Events: Almost all patients (95%) had expected neutropenic fever by day +8.Median time to onset of Grade 4 neutropenia (absolute neutrophil count <500) was 6 days (3-8); Median time to onset of neutropenic fever was 7 days (3-10). Causative organisms were identified in 2 (11%) (Both bacterial infections). Antibiotic of choice was meropenem. ICU Admissions: Only one (6%) patient was admitted in ICU for neutropenic typhilitis on Day +3. That pt spent 20 days in ICU and total of 45 days in hospital with recovery to baseline. Resource Utilization: ASCT for MM was 100% outpatient chemotherapy and cell infusions. The patients were admitted on Day 6 post-transplant for neutropenic care, except 1 patient who presented at the emergency department with febrile neutropenia and diarrhea on day +3. The patients planned for ASCT for rHL were admitted for conditioning chemotherapy, stem cell infusion and neutropenic care until count recovery. Median duration of hospital stay was 17 days (8-45 days). The median days of GCSF post-cell infusion per patient was 8 days (6-15). Efficacy Outcomes: Of the 9 MM pts, all achieved complete response (CR). With a median follow up of 21 months, 100% continued to be on maintenance. For the rHL cohort, response rate was 100%, all CR, and continue to have ongoing responses. The patient with relapsed refractory Ewing's sarcoma has progression-free survival (PFS) of 5 months after ASCT. Overall survival (OS) was 100% for all diseases post-transplant. Conclusion: Our study describes promising outcomes of pts treated at our center, which is the first and only center offering ASCT in Dubai, UAE. This demonstrates that with available infrastructure and expertise, ASCT programs in countries similar to UAE are feasible and increase access to this therapy. Continued efforts at monitoring outcomes, education of the local population, and outreach partnerships with colleagues are essential to increase access to patients in the region.

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<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<.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.

Assessing the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Risk-Stratifying Multiple Myeloma Patients for Autologous Stem Cell Transplantation

Background: Hematopoietic stem cell transplant (SCT) is a high-intensity treatment that can cause psychological distress. Pre-transplant psychosocial screening is commonly used to assess mental health, social support, compliance, and health behaviors in HCT centers. However, the optimal standardized approach to psychosocial screening is still being defined. Some studies have shown that pre-transplant psychosocial assessments can predict overall survival (OS) after SCT, while others have found associations with non-relapse mortality (NRM) but not with OS. Single-institution reports consistently indicate that pre-HCT psychosocial assessments are associated with the length of SCT hospitalization and readmission rate. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is an established tool in the solid organ transplant field that can be used to assess and quantify psychosocial risk, that can help in patient selection and pre-transplant preparation. Objective: This study aimed to validate the SIPAT as a standardized psychological assessment in patients with multiple myeloma (MM) undergoing autologous SCT (ASCT). The primary goal was to analyze the impact of psychosocial risk, as measured by the SIPAT score, on the length of hospital stay and readmission rates within 100 days post-discharge. Secondary outcomes included the risk of infections, progression-free survival (PFS), and overall survival (OS). Methods: This retrospective, single-center study included 87 patients with MM who underwent ASCT between 2019 and 2022 at University Hospitals Seidman Cancer Center. Patient and disease characteristics were collected, and SIPAT scores were recorded for all patients. Patients were grouped based on their SIPAT scores as “Excellent” (score ≤ 6) or “Good” (score > 6). Hospitalization duration during transplant, readmissions, and infections within the first 100 days after ASCT were used as indicators of treatment-related toxicity. Results: 30 patients had an “Excellent” SIPAT score (mean score: 3.47, SD 1.81), while 57 had a “Good” score (mean score: 11.81, SD 5.92). Both groups exhibited similar sex and race distribution, BMI, and KPS scores. The “Excellent” SIPAT group had more patients with HCT-CI scores of 0-2. Both groups had comparable ISS staging and high-risk cytogenetics, along with similar prior lines of treatment and disease status at the time of transplant. Patients in the “Good” SIPAT score group had a higher number of CD34+ cells infused per kg. No significant differences were observed between the groups in terms of engraftment time, hospitalization duration, or rates of hospitalizations and infections within the first 100 days after transplant. Univariate analysis of risk of readmissions showed that BMI had a significant effect (HR 1.09, 95% CI 1.02-1.16, p=0.009) for each unit increase and HCT-CI had a significant effect (HR 5.56, 95% CI 1.39-22.24, p=0.015) for HCT-CI score 3+ compared to 0-2. However, in the multivariable model, these effects did not persist. Conclusions: Although the SIPAT tool is widely used for evaluating different organ transplants, including HCT, a high SIPAT score alone may not be sufficient to risk-stratify candidates for ASCT in MM. Further research and evaluation are warranted to better understand the true predictive value of pre-transplant psychosocial assessments.

Impact of Diabetes Mellitus in Hospital Outcomes Among Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A NIS 2016 to 2020 Database Study

Impact of Diabetes Mellitus in Hospital Outcomes among Patients with Multiple Myeloma undergoing stem cell transplantation: A NIS 2016 to 2020 database Study. Background. Diabetes Mellitus (DM) is one of the comorbidities included in the Hematopoietic Cell Transplant-Specific Comorbidity Index (HCT-CI), which predicts the risk of non-relapse mortality (NRM) and overall mortality (OM) after transplantation. Therefore, they refrained from getting an Autologous stem cell transplant (ASCT) due to the concern of higher toxicity. However, limited data exist to assess this association. In this analysis, we intend to find the impact of DM on hospital outcomes in MM undergoing ASCT. Methods: A retrospective analysis of the NIS database was conducted using International Classification of Diseases (ICD-10) codes to identify hospitalization with ASCT for multiple myeloma and obesity with BMI > 30 kg/m2. STATA version MP14.2 was used for analysis. We used Fischer's exact test to compare proportions, the student's t-test to compare continuous variables, and multivariate regression analysis to calculate the adjusted odds ratio after controlling age, gender, primary payer, and CCI. Transplant complication includes (transplant rejection, transplant failure, and transplant infection). Results: Among 31,390 hospitalizations, 5475 (17.44%) were Diabetic. The mean age to get ASCT was 63 vs. 61, P < 0.001) with DM and without DM. Both groups had male predominance, with Caucasians being the most common race. The mean Charlson comorbidity index (CCI) in DM was 3 vs. 2.32 without DM. After Multivariate analysis, we found ICU admission (AOR: 0.28, 95% CI: 0.14-0.54, P <0.001), length of hospital stay (16.53 vs. 16.79, P <0.001) and acute kidney injury (AOR: 0.70, 95% CI: 0.56-0.87, P = 0.02) was significantly decreased with DM. However, there was no significant difference in the rate of blood transfusion (AOR: 0.87, 95% CI: 0.68-1.11, P = 0.87), transplant complication (AOR: 0.66, 95% CI: 0.42-1.01, P = 0.06), hospital mortality (AOR: 0.45, 95% CI: 0.19-1.03, P = 0.06). The only increase in the patient with DM was Mean hospital charges ($206,796.4 vs. $200,878.3, P = 0.013). Conclusion: This analysis shows that while some complications were decreased, blood transfusion rate and hospital mortality were not significantly affected. The study highlights the potential implications of DM in this patient population and warrants further investigation to individualize and optimize transplant outcomes.

Immunogenicity of Covid-19 Vaccine Among Multiple Myeloma Patients Post Autologous Stem Cell Transplant

Background: mRNA vaccines against SARS-CoV-2 have proven to be safe and effective and have been widely administered. Multiple myeloma (MM) is a disease of plasma cells and is known to weaken the host immunity leading to ineffective vaccine response there by increasing the risk of contracting severe disease. Anti-MM therapy can further suppress the immune system and consequently worsen vaccine response. Autologous stem cell transplant (ASCT) is the standard of care for fit MM patients and leads to prolonged immunosuppression. The effect of ASCT on vaccine response has not been well studied. In an effort to elucidate optimal timing and number of vaccines post ASCT we investigated the seroconversion rate among MM patients who received at least one vaccination post ASCT Methods: We conducted a single center retrospective analysis in patients at the University of Arkansas Medical Center (UAMS) who underwent ASCT for MM and subsequently received at least one dose of either available mRNA vaccine (Pfizer or Moderna). Antibody titers against SARS-CoV-2 spike glycoprotein were checked at various timelines post vaccination. Testing was performed using Roche Elecsys Anti SARS CoV-2 reagent assay from Roche diagnostics. We categorized the patients into two groups: complete responders with titers levels more than 250 U/ml and partial responders/non-responders with titers levels less than 250 U/ml. Covariates used were age, sex, race, MM isotypes, vaccine count, time from last transplant to first dose of vaccine and maintenance therapy post ASCT. Welch's t-test and Wilcoxon rank-sum test were used for continuous variables, while Fisher's exact test was used for categorical variables. Results: A total of 64 patients were analyzed. The mean age was 62.5 years (Range:35-81), with 39.1% (25/69) being female. The most common isotype was IgG and the most common free light chain was kappa, comprising 73.1% (38/53) and 68.8% (44/64) respectively. All patients initiated maintenance after ASCT consisting of daratumumab (30/64, 47.6%), proteosome inhibitors (47/64, 74.6%), immunomodulators (50/64, 78.7%) and steroids (58/64, 92.1%). The first vaccine dose was given at a minimum of 70 days after ASCT and for vaccinations that were given during the maintenance period, treatments were held one week prior and after each vaccine dose. The median follow up duration in days from 1st transplant to last follow-up was [Median, Inter quartile range (IQR)]: 152.0 (68.8, 254.3). At time point of data collection 25/64 (39.1%) had received at least 3 vaccines prior to titer assessment. Of those, 18/25 (72%) were complete responders compared to 7/25 (18%) partial/non-responders, p=0.02. In total, we observed 53.1% of subjects in the entire cohort mounted a complete response (>250 U/ml). Within the complete responders, there were significantly more patients who had received at least 3 vaccines post ASCT having higher chances of a complete response compared to those who received less vaccines, regardless of how many vaccines were given prior to ASCT, 76.5% vs 23.5%, p=0.03. There was a trend towards more time from transplant to first vaccine being associated with a complete antibody response (median days of 171 for complete responders vs 128 days for non/partial responders), albeit that was not significant, p=0.3. Factors that adversely impacted antibody response were higher age (>65), p=0.02 and daratumumab containing maintenance, p=0.04. Intriguingly, we observed significantly better antibody response in patients with IgA MM isotype compared to IgG Isotype, p=0.03, albeit the numbers were small for this analysis (IgA n=14/65). No significant difference was noted between complete and partial/non responders in regard to sex, race, light chain type, IVIG administration and other maintenance regimens. At the time point of data collection, a total of three patients developed symptomatic Covid infections, all of which were in the non-responders/partial responders' group; none of them required hospitalization. Conclusion: The administration of at least 3 mRNA Covid vaccines post ASCT leads to significantly improved antibody titers and should be the minimum standard in this patient population. Higher age (>65 years), IgG subtype and daratumumab based maintenance were associated with suboptimal response to Covid vaccine among post ASCT and those MM patients should have high priority to receive additional prophylactic measures.

PB1996: TREATMENT PATHWAYS AT FIRST RELAPSE POST-ASCT IN MULTIPLE MYELOMA: IMPACT OF MAINTENANCE THERAPY ON TREATMENT OPTIONS

Background: The introduction of new agents and treatment combinations has led to significant improvements in outcomes for multiple myeloma (MM) patients. In particular, lenalidomide maintenance therapy (LenM) following autologous stem cell transplant (ASCT) in younger/fitter MM patients has now become standard given the survival benefits associated with it. However, most MM patients will relapse post-ASCT and many effective relapse regimens have a lenalidomide backbone (e.g. KRD: carfilzomib, lenalidomide, dexamethasone, DRD: daratumumab-RD, IRD: ixazomib-RD) making choice of regimen at first relapse increasingly difficult in patients progressing during LenM therapy. Real world data reflecting these choices is needed to inform treatment decisions and consensus guidelines. Aims: We carried out an audit with an aim to: 1. Evaluate treatment and outcomes in MM patients undergoing ASCT from 2010-2020 2. Assess the impact of LenM post-ASCT and therapy choice after relapse. Methods: We carried out a retrospective audit of all patients with MM attending an Irish hospital who underwent ASCT from 2010-2020. Data was collected by chart/electronic record review. Endpoints included no. of ASCT/year and type of induction/maintenance therapy, relapse rates post-ASCT and choice of post-relapse therapy. Results: 71 patients at our centre underwent ASCT for MM between 2010-2020 (24 female,47 male) with median age of 67 and most common isotype IgG Kappa (n=33). The most frequently used induction was cyclophosphamide(C), bortezomib(V) and dexamethasone(D) (>60%, VCD). Use of maintenance therapy increased markedly over this decade, with 0% receiving maintenance in 2010, 44% in 2014 and 83% in 2020. LenM was most common, >75% (n=28).Other maintenance therapies included bortezomib n=4, daratumumab (dara)n=3 and lenalidomide + bortezomib (RV) combination n=4. First relapse treatment data was available for 36 patients. Regimens included carfilzomib/dexamethasone (KD) n=16 +/- lenalidomide (KRD) n=1, pomalidomide (PD), n=1, ixazomib (ID) n=1, dara (n=3) and dara combinations, including daraVD, n=1, and daraPD, n=1. 26 patients did not receive maintenance containing lenalidomide and the majority of these patients received ASCT pre-2015. There were n=13 relapses in this group: n=4 received lenalidomide regimens (RVD/VCD) at relapse. KD n=4, dara n=1, and ID n=1 were also used. First relapse therapy for 17 patients who progressed during LenM included: KD(n=11) 64.7%, dara(n=2) 11.7%, pomalidomide(n=1) 5.8%, and RV(n=2) 11.7% and VCD(n=1) 5.8%. Overall, carfilzomib-based therapy (without lenalidomide) was the most commonly prescribed therapy on first relapse. We observed a clear increase in its use from 2015-2020, in parallel with increased use of LenM. We also noted reducing rates of lenalidomide-based relapse therapies in later years, correlating with increased LenM. Importantly, neither DRD or PVD combinations were reimbursed for prescription in Irish healthcare during the period of audit and are notable absences from the relapse treatment regimens used. Summary/Conclusion: This audit highlights the treatment pathway and outcomes for all patients with MM undergoing ASCT over 10 years in our centre. We have noted significant changes in choice of therapy upon relapse, with carfilzomib prescription rates increasing and lenalidomide-based regimen use decreasing. Our real world data provides direct insight into the effect of widespread LenM therapy on choice of agent upon relapse and highlights the need for consensus treatment guidelines to reflect this evolution in treatment for MM patients.

P1443: AUTOLOGOUS NK CELLS AS CONSOLIDATION AFTER FRONT-LINE STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA: A LONG-TERM FOLLOW-UP

Background: Immunotherapies have shown great anti-tumour effect in a variety of malignancies. In multiple myeloma (MM) antibodies, including bispecific T cell engagers, antibody-drug conjugates, and more recently, CAR T cells have reported exciting clinical results and many of them have been incorporated in the treatment armamentarium. Less is reported for NK cells, in particular autologous NK cells. Initial results from our first-in-human trial ACP-001 with autologous NK cells given as consolidation after front-line autologous stem cell transplantation (ASCT) were recently reported (Nahi et al., 2022, Cell Reports Medicine 3, 100508 February 15, 2022). It showed that the concept was feasible with good safety, including no SAEs, and promising efficacy. We here report the long-term clinical follow-up. Aims: The aim of this report was to investigate long-term safety, disease progression, second-line therapy and survival after autologous NK cell treatment. Methods: This first-in-human trial included six patients with newly diagnosed MM eligible for ASCT at the Karolinska University Hospital Huddinge in Sweden. After standard induction treatment (bortezomib, cyclophosphamide and dexamethasone (VCD) at the time) and ASCT with melphalan 200 mg/m2 (MEL200) the patients received three escalating doses of autologous activated and expanded NK cells. Clinical data on long-term safety, disease progression, second-line therapy and survival were captured from the patients’ electronical charts. Results: No subject were lost to follow-up or had withdrawn from the study. With a median follow-up from study inclusion of 6.9 (6.1-7.2) yrs, and 6.2 (5.4-6.7) yrs from the first NK cell infusion, there are no new reported AE related to the NK cell infusions. All six patients are alive with one subject still in first remission 6.8 yrs after inclusion. Five patients had disease progression 13-51 months after study inclusion and four of them underwent reinduction (VRD (n=2), KRD (n=1), KRD+dara (n=1)) followed by a second ASCT with MEL200. The fifth patient progressed within the first yr after ASCT and received VRD+dara. All five patients responded to second line treatment with PR (n=2), VGPR (n=2) and MRD negative (n=1) but subsequently progressed with a PFS2 ranging from 11.5 to 26.3 months. Summary/Conclusion: This long-term follow-up confirms the safety and feasibility of autologous NK cell therapy as consolidation after front line ASCT in MM. Autologous NK cell treatment in first line did not negatively impact the possibility to administer, or the outcome, of later treatments which is important with all new treatment options for patients with advanced MM.

Digital Life Coaching During Stem Cell Transplantation: Development and Usability Study.

BackgroundFor patients with multiple myeloma receiving high-dose chemotherapy followed by autologous stem cell transplantation (SCT), acute life disruptions and symptom burden may lead to worsened quality of life (QOL) and increased emotional distress. Digital life coaching (DLC), whereby trained coaches deliver personalized well-being–related support via phone calls and SMS text messaging, has been shown to improve QOL among SCT survivors. However, DLC has not been investigated during the acute peri-SCT period, which is generally characterized by symptomatic exacerbations and 2-week hospitalizations.ObjectiveWe launched a single-arm pilot study to investigate the feasibility of patient engagement with DLC during this intensive period.MethodsWe approached English-speaking adult patients with multiple myeloma undergoing autologous SCT at our center. Enrolled patients received 16 weeks of virtual access to a life coach beginning on day −5 before SCT. Coaches used structured frameworks to help patients identify and overcome personal barriers to well-being. Patients chose the coaching topics and preferred communication styles. Our primary endpoint was ongoing DLC engagement, defined as bidirectional conversations occurring at least once every 4 weeks during the study period. Secondary endpoints were electronic patient-reported outcome assessments of QOL, distress, and sleep disturbances.ResultsOf the 20 patients who were screened, 17 (85%) chose to enroll and 15 (75%) underwent SCT as planned. Of these 15 patients (median age 65 years, range 50-81 years), 11 (73%) demonstrated ongoing DLC engagement. The median frequency of bidirectional conversations during the 3-month study period was once every 6.2 days (range 3.9-28 days). During index hospitalizations with median lengths of stay of 16 days (range 14-31 days), the median frequency of conversations was once every 5.3 days (range 2.7-15 days). Electronic patient-reported outcome assessments (94% adherence) demonstrated an expected QOL nadir during the second week after SCT. The prevalence of elevated distress was highest immediately before and after SCT, with 69% of patients exhibiting elevated distress on day −5 and on day +2.ConclusionsDLC may be feasible for older patients during intensive hospital-based cancer treatments such as autologous SCT for multiple myeloma. The limitations of our study include small sample size, selection bias among enrolled patients, and heterogeneity in DLC use. Based on the positive results of this pilot study, a larger phase 2 randomized study of DLC during SCT is underway to investigate the efficacy of DLC with regard to patient well-being.Trial RegistrationClinicalTrials.gov NCT04432818; https://clinicaltrials.gov/ct2/show/NCT04432818.

Trends in autologous stem cell transplantation for newly diagnosed multiple myeloma: Changing demographics and outcomes in European Society for Blood and Marrow Transplantation centres from 1995 to 2019.

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61years, and the percentage of patients aged >65years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm.

Unique Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (trALL) Following Therapy for Multiple Myeloma (MM)

Unique Characteristics and Outcomes of Therapy-Related Acute Lymphoblastic Leukemia (trALL) Following Therapy for Multiple Myeloma (MM)

Interval Progression Serves As a Predictor of Adverse Outcomes in Patients with Multiple Myeloma

Background: Multiple myeloma (MM) remains an incurable disease, but deep, lasting remission can be achieved with induction therapy and autologous stem cell transplant (ASCT). The current ASCT treatment timeline includes a gap between the end of induction and the day of ASCT to permit correct mobilization and collection of stem cells. During this interval, some patients experience increases in their MM markers. We specifically evaluated if patients with interval progression (IP) have different outcomes post-ASCT compared to patients without IP.Methods: We completed a retrospective analysis of 482 patients who underwent ASCT at The Ohio State University Wexner Medical Center between 2011 and 2016. MM labs, including protein electrophoresis with immunofixation and free light chains, were obtained at day of diagnosis, end of induction, and day of ASCT. A 20% increase in the index protein between the end of induction and the day of ASCT was defined as IP. The primary outcomes evaluated were time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS). TTP was defined as time from ASCT to disease progression, treating death without progression as a competing risk. PFS was defined as the time from ASCT until either disease progression or death, while OS was defined as the time from ASCT until death or last follow-up. Poisson regression models with robust variance were used to evaluate the associations between patients' characteristics and IP, while competing risk regression models were used for TTP analysis, and Cox regression models for OS and PFS analysis.Results: 482 patients who underwent ASCT for MM between 2011 and 2016 were studied. The patient population was primarily male (n = 296, 61.4%), Caucasian (n = 420, 87.1%), and had IgG disease (n = 269, 55.8%). MM stage at diagnosis was equally represented. Cytogenetic analysis showed 108 (22.4%) patients with 1q21 amplification, 60 (12.4%) patients with t(11;14) translocation, 33 (6.8%) patients with t(4;14) translocation, and 40 (8.3%) patients with 17p deletion. More than 80% of patients underwent maintenance therapy following ASCT.One hundred and fifty-six (32.3%) patients were defined as having IP. Patients in the IP group were significant more likely to have LC disease (p = 0.0018), but no other patient characteristics varied significantly between the two groups. LC disease (relative risk (RR adj) = 2.12, 95% CI 1.37-3.30, p = 0.001) and deletion 17p (RR adj = 1.62, 95% CI 1.08-2.42, p = 0.02) were associated with increased risk of IP on multivariate analysis (MVA).Five-year PFS rates were 47.2% and 36.8% in the non-IP and IP groups, respectively. Five-year cumulative progression rates were 49.0% in the non-IP group and 57.8% in the IP group. Five-year OS rates were 76.8% in the non-IP group and 69.6% in the IP group. On univariate analysis (UVA), IP correlated with inferior outcomes in both TTP (hazard ratio (HR) = 1.39, p = 0.01) and OS (HR = 1.39, p = 0.04). In agreement with previous literature, other factors independently correlated with inferior TTP and OS outcomes, including MM stage, cytogenetics (amp1q, t(4;14), and del(17p)), and absence of maintenance therapy post-ASCT. On MVA, IP was no longer significantly associated with a shorter TTP (HR = 1.16, p = 0.35), but approached statistical significance in conferring inferior OS (HR = 1.40, p = 0.07). Notably, once deletion 17p was removed from the MVA, the presence of IP once again conferred significantly lower OS (HR = 1.45, 95% CI 1.01-2.07, p = 0.04), suggesting that deletion 17p, which is a significant risk factor for both IP and OS, may mediate the effect of IP. Combined, all data suggest that uncontrolled disease prior to ASCT trends towards worse long-term outcomes.Conclusion: In this study, we report the first data regarding patients who experienced rapid disease progression in the interval between induction therapy and ASCT. These patients have inferior TTP, PFS, and OS, likely due to the presence of LC disease or deletion 17p. IP may provide a valuable predictor of robustness of response to ASCT and prompt the need for additional induction cycles or alternative regimens. This is especially relevant for patients with deletion 17p. Indeed, these data support a prospective study of concepts to improve outcomes for patients with IP prior to ASCT. DisclosuresBumma: Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Motixafortide (BL-8040) and G-CSF Versus Placebo and G-CSF to Mobilize Hematopoietic Stem Cells for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: The Genesis Trial

Motixafortide (BL-8040) and G-CSF Versus Placebo and G-CSF to Mobilize Hematopoietic Stem Cells for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: The Genesis Trial

Immunophenotypic and Single-Cell Transcriptional Profiling of CD34+ Hematopoietic Stem and Progenitor Cells Mobilized with Motixafortide (BL-8040) and G-CSF Versus Plerixafor and G-CSF Versus Placebo and G-CSF: A Correlative Study of the Genesis Trial

▪Background: CD34 expression remains the most common immunophenotypic cell surface marker defining human hematopoietic stem and progenitor cells (HSPCs). Recently, use of multicolor fluorescence-activated cell sorting (mFACS) and single-cell RNA sequencing (scRNA seq) has illustrated the heterogenous nature of CD34+ HSPCs, with immunophenotypically and transcriptionally distinct subsets ranging from primitive hematopoietic stem cells (HSCs) capable of long-term multilineage potential to differentiated, lineage-committed progenitors. Meanwhile, the addition of CXCR4 inhibitors (CXCR4i) to G-CSF (G) has increased mobilization of CD34+ HSPCs for stem cell transplantation (SCT). Yet, the effect of CXCR4i +/- G on mobilization of specific immunophenotypic and transcriptional CD34+ HSPC subsets is not well-characterized. Motixafortide (M) is a novel cyclic peptide CXCR4i with a low receptor off rate and extended in vivo action vs plerixafor (Px). M was recently evaluated in the phase 3, double blind, placebo controlled GENESIS Trial as an HSPC mobilizer prior to autologous SCT (ASCT) in multiple myeloma (MM).Methods: GENESIS Trial patients were prospectively randomized (2:1) to receive either M+G or placebo (P)+G for HSPC mobilization. Demographically similar patients undergoing mobilization with Px+G prior to ASCT for MM were prospectively enrolled on a parallel tissue banking protocol. All patients received G (10 mcg/kg) on days 1-5 (and 6-8 if needed). Patients also received either M (1.25 mg/kg) or P on day 4 (and 6 if needed); or Px (0.24 mg/kg) on day 4 (and 5-7 if needed). Apheresis began day 5 (and 6-8 if needed). HSPCs were purified from apheresis product on day 5 via CD34+ immunomagnetic selection. CD34+ HSPC subset profiling was performed via mFACS and scRNA seq. CXCR4 expression and receptor occupancy was evaluated by antibody binding capacity of 12G5 and 1D9 clones.Results: Demographics were similar between the M+G (n=24), P+G (n=13) and Px+G (n=14) cohorts. By mFACS, M+G mobilized a 5.5 fold higher absolute number (#) of HSCs, multipotent progenitors (MPP) and common myeloid progenitors (CMP) vs P+G (p<0.0001); and a 2.6 fold higher # of these subsets vs Px+G (p=0.0327) (Figure 1A). M+G mobilized a 10.5 fold higher absolute # of primitive HSCs vs P+G (p<0.0001) and a 1.1 fold higher # vs Px+G (p=0.7876) (Figure 1B). M+G and Px+G mobilized a 7-8 fold higher # of plasmacytoid dendritic cell precursors vs P+G (p-values >0.05). 1D9 binding to CXCR4 on CD34+ HSPCs was similar between all 3 arms (p-values 0.45-0.75). 12G5 binding (which competes with CXCR4i's for binding to CXCR4) was significantly lower with M+G (MFI:11) vs P+G (MFI:74; p<0.0001) and Px+G (MFI:271; p<0.0001).By scRNA seq, UMAP clustering identified 3 transcriptionally similar HSC sub-clusters (HSC-I, -II and -III) mobilized by all 3 regimens; and 1 distinct HSC-PL cluster mobilized by P+G expressing heat shock protein genes (HSPA1 A/B) (Figure 1C). Differentially expressed genes (DEGs) of HSCs I-III included CD52, FTH1, HLA-E, KLF2 and LMNA. AVP was unique to HSC-I while EGR1, JUN and ZFP36 were unique to HSC-III. MPPs clustered into 3 sub-clusters (MPP-I, -II and -III). MPP-I clustered closely to HSC-II/III with low expression of genes of differentiation. MPP-II expressed DEGs (PLEK) on a continuum toward megakaryocyte-erythroid progenitors (MEP-I/II), which expressed DEGs of erythroid differentiation (HBD/HBB). MPP-I and -II contained cells from all 3 regimens. However, MPP-III was specific to M+G with DEGs (MT-ATP8, HIST1H1) associated with monocyte, lymphocyte and NK cell differentiation.Conclusions: Extended CXCR4i with M+G mobilized significantly higher #s of combined CD34+ HSCs, MPPs and CMPs vs Px+G and P+G (p-values <0.05). Additionally, M+G mobilized a 10.5 fold higher # of immunophenotypically primitive CD34+ HSCs capable of broad multilineage hematopoietic reconstitution vs P+G (p<0.0001) and similar #s vs Px+G. CXCR4 expression on CD34+ HSPCs by 1D9 binding was similar across all arms. Whereas, 12G5 binding was much lower with M+G vs P+G and Px+G, consistent with extended CXCR4 receptor occupancy by M. All regimens mobilized transcriptionally similar HSC-I-III subsets. However, lack of CXCR4i (M or Px) resulted in mobilization of more-differentiated HSCs (HSC-PL subset). Whereas extended CXCR4i with M+G (but not Px+G) mobilized a unique MPP-III subset with DEGs related to leukocyte differentiation. [Display omitted] DisclosuresCrees: BioLineRx Ltd.: Research Funding. Retting: BioLineRx Ltd.: Research Funding. Jayasinghe: WUGEN: Consultancy; MMRF: Consultancy. Vainstein: BioLineRx LTD: Current Employment. Sorani: BioLineRx LTD: Current Employment. Ickowicz: BioLineRx Ltd.: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Kadosh: BioLineRx Ltd.: Current Employment.

Risk Factors for Catheter-Related Thrombosis in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

Background and Objectives: Cancer associated thrombosis (CAT) is a common complication of neoplasms. Multiple myeloma (MM) carries one of the highest risks of CAT, especially in the early phases of treatment. Autologous stem cell transplantation (ASCT) as the standard of care in transplant-eligible patients with MM carries a risk of catheter-related thrombosis (CRT). The aim of this study was identification of the risk factors of CRT in MM patients undergoing ASCT in 2009–2019. Materials and Methods: We retrospectively analyzed patients with MM undergoing ASCT. Each patient had central venous catheter (CVC) insertion before the procedure. The clinical symptoms of CRT (edema, redness, pain in the CVC insertion area) were confirmed with Doppler ultrasound examination. We examined the impacts of four groups of factors on CRT development: (1) patient-related: age, gender, Body Mass Index (BMI), obesity, Charlson comorbidity index, hematopoietic stem cell transplantation comorbidity index, renal insufficiency, and previous thrombotic history; (2) disease-related: monoclonal protein type, stage of the disease according to Salmon–Durie and International Staging System, number of prior therapy lines, and MM response before ASCT; (3) treatment-related: melphalan dose, transplant-related complications, and duration of post-ASCT neutropenia; (4) CVC-related: location, time from placement to removal. Results: Symptomatic CRT was present in 2.5% (7/276) of patients. Univariate analysis showed an increased risk of CRT in patients with a catheter-related infection (OR 2.4, 95% CI; 1.109–5.19, p = 0.026), previous thrombotic episode (OR 2.49, 95% CI; 1.15–5.39, p = 0.021), previous thrombotic episode on initial myeloma treatment (OR 2.75, 95% CI; 1.15–6.53, p = 0.022), and gastrointestinal complications of ASCT such as vomiting and diarrhea (OR 3.87, 95% CI; 1.57–9.53, p = 0.003). In multivariate analysis, noninfectious complications were associated with higher CRT incidence (OR 2.75, 95% CI; 1.10–6.19, p = 0.031). Conclusions: The incidence of symptomatic CRT in ASCT in MM was relatively low. Previous thrombotic events, especially during the induction of myeloma treatment, increased CRT risk during ASCT. Dehydration following gastrointestinal complications may predispose to higher CRT incidence.

Costs and in-Hospital Mortality Rates in Autologous Stem Cell Transplant for Multiple Myeloma: An Analysis of the Nationwide Inpatient Sample (NIS) Database

Background: Multiple myeloma (MM) treatment facility volume, an indirect measure of treating physician experience with the disease, has been shown to affect mortality (Go et al, JCO 2016). Since MM is commonly treated with autologous stem cell transplantation (AUTO-SCT), we set out to explore if annual facility volume of AUTO-SCT had an impact on survival outcomes. We additionally explored if hospital volume or public/private hospital type had an effect on hospitalization cost among this patient population.Methods: The Nationwide Inpatient Sample (NIS) is a validated database of discharges from a representative sampling of U.S. hospitals excluding rehab facilities and federal hospitals. Using the NIS, we identified adult patients hospitalized with ICD-9 codes for AUTO-SCT and MM from 2005 to 2014. Hospitals were divided into four similar sized groups based on the number of patients who received AUTO-SCT for multiple myeloma per year: low-volume (L) <=3; low-intermediate volume LV = 4-7; high-intermediate volume (HV) = 8 - 14; and high volume (H) >14). Public (non-federal government) hospitals and Private, non-profit and for-profit hospitals were assessed separately. We used trend analysis to evaluate hospitalization mortality and hospitalization cost over the study period. We used logistic regression to determine associations between mortality and hospital volume or public/private hospital type among patients with MM, adjusting for year of admission, demographics (gender, race, age), socioeconomic variables (income, insurance), geography (facility location), institution type (facility ownership, teaching hospital status), and comorbidity (Charlson comorbid score). We used multivariate regression to determine volume to cost and public/private hospital to cost associations adjusted for the same variables and also for inflation rate and length of stay.Results: We identified 8183 patients in the NIS database, which was equal to an estimated 39,971 nationwide admissions for AUTO-SCT for MM from 2005 to 2014. The median age for all admitted patients was 58.9 years and 57.1% were men. The median hospital volume was 12.94 patients per year. In-hospital mortality decreased to < 1% from >3% over the study period (Figure 1, p=0.002). The distribution of patients according to hospital volume was L: 4.45%, LV: 9.31%, HV: 17.34% and H: 68.3%. The unadjusted mortality was: L: 2.52%, LV: 0.37%, HV: 0.51%, and H: 1.79%. No crude length of stay difference was observed between low-volume hospitals and higher-volume hospitals. Patients who received autologous stem cell transplantation in higher-volume hospitals had lower in-hospital mortality (odds ratio: 0.27 [95% CI, 0.11-0.26]). We further looked into each individual group and found that patients treated at higher-volume hospitals all had a lower risk of death (Table 1). When compared to public hospitals, mortality risk for MM patients who received AUTO-SCT was lower at private non-profit hospitals (OR: 0.30 [95% CI, 0.16 to 0.56], p<0.001) and not significantly different in private for-profit hospitals (OR: 0.43 [95% CI, 0.16 to 1.12], p=0.08). The overall hospitalization cost of AUTO-SCT corrected for inflation decreased during the study period (p=0.03). No cost differences were found between low-volume hospitals and higher-volume hospitals. Costs at both private non-profit and for-profit hospitals were lower compared to public hospitals (p<0.001 and p=0.003, respectively).Conclusion: Mortality and inflation-adjusted costs for AUTO-SCT for MM have gone down over the past decade. Patients who receive AUTO-SCT for MM at low-volume or public hospitals face a higher risk of mortality compared to those at higher-volume hospitals or private non-profit hospitals. Hospitalization costs at private hospitals are lower than public hospitals. Analysis of the NIS database reveals significant nationwide differences in costs and mortality risk for MM patients undergoing AUTO-SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

US Regional Difference in Hospitalization Cost for Autologous Stem Cell Transplantation in Multiple Myeloma Patients: A Nationwide 10-Year Analysis from 2005 to 2014

Background: Tremendous improvement of multiple myeloma (MM) care has been made in the past 10 years. However, limited real-word data is available regarding regional difference of hospitalization cost for autologous stem cell transplantation (AUTO-SCT) in MM.Methods: The Nationwide Inpatient Sample (NIS) is a validated database of discharges from a representative sampling of U.S. hospitals excluding rehab facilities and federal hospitals. Using the NIS, we identified adult patients hospitalized with ICD-9 codes for AUTO-SCT and MM from 2005 to 2014. We used trend analysis to evaluate hospitalization cost over the study period. All US hospitals in the NIS database were divided by 4 regions: Northeast(NE), Midwest(MW), South (S) and West (W). We used multivariate regression to determine associations between hospitalization cost and hospital region among patients with MM undergoing AUTO-SCT, adjusting year of admission, demographics (gender, race, age), socioeconomic variables (income, insurance), geography (facility location), institution type (facility ownership, teaching hospital status), comorbidity (Charlson comorbid score), inflation rate and length of hospitalization. We used logistic regression to determine associations between hospitalization mortality and hospital region, adjusting the same factors as above excluding length of hospitalization and inflation rate.Results: We identified 8183 patients in the NIS database, which was equal to an estimated 39,971 nationwide admissions for AUTO-SCT for MM from 2005 to 2014. Patients admitted to hospitals in South region were more likely to have an annual household income less than 39,000 (p<0.01). Patients admitted to hospitals in West region were more likely to be insured (p<0.01). Otherwise, no statistical difference was found among the hospitals from the four regions in terms of age, gender, race, comorbidity, length of stay and crude mortality. Using trend analysis, we found that the overall hospitalization cost of AUTO-SCT corrected for inflation decreased during the study period (Figure 1). When compared with hospitals in Northeast, Midwest and West region individually, hospitals in South region are associated with significantly lower hospitalization cost (P<0.001 for all three comparisons). No other significant association was found among hospitals in other regions. No statistically significant association between hospitalization mortality and hospital region was identified.Conclusion: Nationwide, inflation-adjusted costs for AUTO-SCT for MM have decreased over the past decade. However, significant regional cost differences do exist. US hospitals in South region cost significantly less during hospitalization of AUTO-SCT for MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cyclophosphamide Based Regimens Compared to Plerixafor-Based Regimens for Stem Cell Mobilization in Patients with Multiple Myeloma Result in Higher CD34+ Cell Yield, Lower Cost and Similar Outcome Post Autologous Transplantation

Background: Autologous stem cell transplantation (ASCT) is standard therapy for patients with multiple myeloma (MM). Stem cell mobilization for peripheral blood stem cell collection prior to ASCT is most commonly achieved with cyclophosphamide based chemotherapy regimens and GCSF (Cy-G) or with plerixafor and GCSF (Pler-G). Using a chemotherapy based mobilization regimen for patients with lymphoma has been shown to result in higher CD34+ cell yield and lower cost than plerixafor based regimens (Dhakal, et al. 2016). The question remains if stem cell mobilization regimens impact stem cell collection and ASCT outcomes in patients with MM.Methods: We reviewed 496 patients who received 596 ASCT for MM between January 2005 and December 2015. Data analyzed included stem cell mobilization regimen, number of CD34+ cells collected, number of apheresis procedures, CD34+ cells infused and survival. Univariate and Multivariate Cox Proportional Regression Models were utilized. The purpose of the review was to determine outcome differences between the use of Cy-G for stem cell mobilization vs Pler-G.Results: The median age at transplantation was 61 years (range 39-84) and 59% were male. Cy-G was used for stem cell mobilization for 438 patients (91%) vs 44 patients (9%) who received Pler-G. Significantly greater numbers of CD34+ cells were collected using Cy-G, with a median of 16.17 x 10e6/kg vs a median of 12.47 x 10e6/kg with Pler-G (p=0.0012). Median days of collection were less for Cy-G, 2 vs 3 for Pler-G (p=0.292), although not significant. There was no statistical difference in the dose of CD34+ cells infused, with a median of 5.73 x 10e6/kg for Cy-G vs a median of 5.00 x 10e6/kg for Pler-G. Pre-ASCT therapy using immunomodulatory agents lenalidomide, bortezomib or carfilzomib had no impact on the number of CD34+ cells collected (p=0.3427), number of apheresis procedures (p=0.6336) or CD34+ cell dose infused (p=0.941).OS at 84 months was 58% for patients using Cy-G for stem cell mobilization vs 55% for patients using Pler-G (p=0.9168) indicating no difference. By multivariate analysis, there was no difference in OS between the 2 groups (p=0.488). There was no difference in PFS between the 2 stem cell mobilization regimens by univariate or multivariate analysis (p=0.2737 and p=0.4226). There was no statistical difference (p=0.424) in the incidence of engraftment syndrome based on the stem cell mobilization regimen.Conclusion: For patients with MM, using a Cy-G regimen results in a higher CD34+ cell yield compared to Pler-G. Higher CD 34+ cell yield may be advantageous for patients considering tandem autologous transplantation. Pre-transplant therapy with immunomodulatory agents had no significant impact on CD34+ cell yield or apheresis days. There was no difference in OS or PFS between the 2 groups and no difference in the incidence of engraftment syndrome. The medication cost at our institution for a 70 kg patient receiving cyclophosphamide, dexamethasone and etoposide with GCSF is $8,846.64 compared to $24,846.09 for Pler-G. Cyclophosphamide based regimens for stem cell mobilization results in a higher cell yield with lower cost and equal survival compared to Pler-G in patients with MM. [Display omitted] DisclosuresMcKiernan:Novartis: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Gilead: Speakers Bureau. Biran:Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Richter:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Goy:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Pereiras:Portola Pharmaceutical: Other: stock holder; TEVA: Consultancy.

Outcomes of Autologous Stem Cell Transplantation in Very Elderly Patients with Multiple Myeloma

Background: Autologous stem cell transplantation (ASCT) is considered standard of care for patients with multiple myeloma (MM). The majority of patients with MM are diagnosed over the age of 65 and 37% are over the age of 75 (Van de Donk and Sonneveld, 2014). As treatment outcomes and survival improve across age groups for patients with MM (Libby, et al. 2013), more elderly patients are potential candidates for ASCT. Elderly patients have been defined as greater than age 65 in many studies of ASCT, but as referral age for transplantation continues to increase, the ASCT outcomes of patients 75 years and older need to be elucidated.Methods: Between January 2005 and December 2015, 24 patients age 75 or older received ASCT for MM. High-risk disease (HRD) was defined as t(14;16), t(14;20), del 17p, t(4;14) or 1q gain by FISH, del 13q, monosomy 13 or hypodiploidy by standard cytogenetics, or high risk signature gene expression profiling. Patients were mobilized for peripheral blood stem cell collection with either a cyclophosphamide-based mobilization chemotherapy regimen with GSCF (Cy-G), plerixafor and GCSF (Pler-G), or with GCSF alone. Conditioning regimens were melphalan based, with patients receiving either 140 mg/m2 (Mel 140) or 200 mg/m2 (Mel 200). Response criteria was based on the International Working Group Diagnostic Criteria for MM. Outcomes reported included disease response, progression free survival (PFS), overall survival (OS) and cause of death.Results: The ages ranged from 75 to 84 years and 71% were male. HRD at diagnosis was reported for 8 patients (33%). Twenty patients (83%) were in a partial response (PR) or better at time of transplantation, with 1 patient in a complete response (CR), 10 patients (42%) in a very good partial response (VGPR), and 9 patients (37%) in a PR. No patient had progressive disease at the time of ASCT and 4 patients (17%) had stable disease (SD). Twelve patients (50%) received Cy-G for stem cell mobilization, 11 (49%) received Pler-G, and 1 patient received GCSF alone. Five patients received Mel 140 and 19 patients received Mel 200, 21% and 79% respectively. Best response post ASCT was CR in 10 patients (42%), VGPR in 5 patients (21%), PR in 4 patients (17%) and 2 patients (8%) had SD. There were 2 early deaths prior to day 100 post ASCT. One patient died of a subdural hematoma at day +11 and the other patient died of a staphylococcus aureus sepsis at day +25. PFS was 40% at 5 years and OS was 56% at 5 years. There was no difference in OS (p=0.1511) for patients age 75 and older at the time of transplantation compared to patients younger than age 75 (n=472).Conclusions: ASCT for very elderly patients 75 years or older is feasible and can result in long-term survival. Elderly patients can tolerate chemotherapy for mobilization and doses of melphalan 200 mg/m2 for conditioning. Elderly patients with MM should not be denied ASCT based on age alone. [Display omitted] DisclosuresMcKiernan:Novartis: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Novartis: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau. Biran:Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Richter:BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Goy:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Phase II Study of a Novel Conditioning Regimen of Bendamustine and Melphalan Followed By Autologous Stem Cell Transplant for Patients with Multiple Myeloma

IntroductionHigh dose melphalan 200mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) is the standard of care for fit patients with Multiple Myeloma (MM). Bendamustine has been shown to induce responses in MM resistant to other alkylating agents. Our prior Phase I trial, adding bendamustine to MEL200, demonstrated no additional toxicity above that expected with MEL200 alone (Mark et. al. BBMT 2013). A phase 2 trial of bendamustine/MEL200 conditioning was conducted to evaluate treatment efficacy.Objective and MethodsThis single arm, open-label, phase II study was designed to establish the efficacy of Bendamustine (225 mg/m2) in combination with MEL200 in patients undergoing first ASCT for MM. Patients 18 to 75 years with confirmed MM, prior induction therapy, adequate mobilization (at least 2x106 of CD34+ hematopoietic stem cells), Karnofsky performance status >70% and life expectancy >12 weeks were eligible for screening. Major exclusion criteria included serious/uncontrolled medical conditions, or previous ASCT. Responses were determined according to the IMWG response criteria and adverse events (AEs) were reported per CTCAEv4.0. The primary endpoint was to evaluate the overall response rate (ORR) and CR or better at 6 months.ResultsA total of 35 patients were enrolled (Table 1). Median age was 61 (range 41 - 75). Intermediate or high-risk disease was present in 44.8% by R-ISS. All patients engrafted. Median time to neutrophil and platelet engraftment was 11 days (range 10-14) and 21 days (range 15 to 29) respectively. At day +180, the ORR was 91.4% and 51.4% of patients achieved a CR or sCR (Table 2). Only 1 patient progressed before day +100 (R-ISS 1 double-refractory to lenalidomide + bortezomib, achieved VGPR with second line therapy with VDT-PACE prior to transplant), and one additional patient progressed before Day +180 (R-ISS 2, with prior 4 lines of therapy, SD prior to transplant). Maintenance was initiated in 20 patients out of 32 patients (62.5%). Choice of maintenance was at the discretion of the treating physician and patient.After a median 33 months (range 3-73) of follow up post ASCT, 20 patients had progressed (57.1%), 4 of whom died from complications of MM progression (11.4%). Median progression free survival (PFS) was 40 months (14 months vs 48 months depending on maintenance therapy, p=0.024). The 3 year PFS was 64.5% (95%CI 44.7-78.8). The median overall survival (OS) was not reached. The 3 year OS was 91.2% (95%CI 75.1-97.1) (Figure 1). Baseline response, categorized as CR or better, VGPR, PR and SD or PD prior to transplant, was statistically significant for PFS (p=0.019). In a multivariable Cox proportional hazards model controlling for baseline response prior to transplant, maintenance therapy continued to be associated with improved PFS (HR 0.16, p=0.004). No variable had a statistically significant impact on OS. There was no transplant related mortality (TRM). The most common overall AEs were hypocalcemia (100%), nausea (94.3%), fatigue (94.3%), anorexia (91.4%), mucositis (57.1%), abdominal pain (51.4%), peripheral edema (48.6%) and constipation (34.7%). The most frequently observed grade 3 AEs were febrile neutropenia in 45.7% of patients, hypocalcaemia in 34.3%, hypokalemia in 20%, and hypophosphatemia in 14.3%. There was only one grade 4 AE, hyperbilirubinemia associated with a reaction to antibiotics.ConclusionWe confirmed that Bendamustine can safely be combined with standard dose MEL200 as a conditioning regimen for ASCT. This regimen shows promising efficacy, with median PFS of 48 months for patients who received maintenance. Further evaluation of this conditioning regimen in a Phase III comparison trial with single agent MEL200 is warranted in conjunction with newer induction approaches and standard maintenance therapies. (NCT00916058). [Display omitted] DisclosuresNiesvizky:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Rossi:Celgene: Consultancy; Thrassos: Consultancy.

Application of the Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Backgroud Busulfan isthe most commonly used drug in conditioning regimens for hematopoietic stem cell transplantation, and high-dose melphalan (HDM)is the standard conditioning regimen in autologous stem cell transplantation(ASCT)for multiple myeloma. Studies have shown that in ASCT for multiple myeloma, conditioning regimens containing busulfan is equally effective as HDM.Aims Evaluate the safety and efficacy of BUCY(busulfan and cyclophosphamide ) conditioning regimen for autologous hematopoietic stem cell transplantation(ASCT)in patients with multiple myeloma(MM).Methods We retrospectively analyzed the clinical data of 72 MM patients who received transplantation in the Hematology Department of the First People's Hospital of Soochow University from May 2012 to June 2015. Among them, 36 patients underwent BUCY regimen, while the others received HDM regimen. Those were compared between the two groups including the complication, the hematopoietic reconstitution and the post-transplantation efficacy.Results There were no significant differences in age, stage, induction therapy, mobilization method between the two groups. The transplantation-related adverse events were similar in both groups but the incidence of pulmonary infection and bloodstream infection were slightly higher in BUCY group .The median time to neutrophil engraftment in the BUCY and HDM groups were 10(8-17)days versus 10(9-13)days, taking the same time on average(P=0.046). On the other hand, the median time to platelet engraftment was 10(8-18)versus 11(9-47)days accordingly (P=0.017). The TRM in both group was 2.7%. The SCR/CR rates after ASCT (47.2% and 50.0%) were higher than those before it (38.9% and 26.6%) in both groups. In the BUCY group, the median follow-up was 12.5(0-26) months. Six patients (16.7%) underwent disease progression. The 2-year progression-free survival(PFS) rate was 68%. Correspondingly, in the HDM group, the median follow-up time was 23 (0-38) months. Fifteen patients (41.7%) developed disease progression and the 2-year PFS rate was 55%.Conclusion The BUCY regimen is a safe and effective therapy for ASCT in patients with multiple myeloma. Besides, BUCY regimen is not inferior to HDM regimen. In conclusion, BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.