Late Autologous Stem Cell Transplant Research Articles

Early Versus Late Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the IFM 2009 Trial

Early Versus Late Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the IFM 2009 Trial

The Effect of Autologous Stem Cell Transplant (ASCT) on Survival in Californians with Multiple Myeloma (MM) in the Era of Modern Treatment

Background: The use and timing of ASCT on survival after MM in the era of modern therapy remain topics of debate. Using population based data, we evaluated factors associated with the receipt of ASCT and the effect of ASCT on overall survival (OS).Methods: Patients diagnosed with MM during 2000 - 2012 were identified in the California Cancer Registry (CCR) (n=12,714). CCR data were linked to the California Patient Discharge Database (PDD). Logistic regression estimated the odds ratio (OR) of having an early (< 1 year from diagnosis) or late (> 1 year) ASCT (vs. no ASCT). OS was calculated using the Kaplan-Meier (KM) method. To determine the effect of ASCT on OS from diagnosis date, Cox regression models estimated adjusted hazard ratios (aHR) of death treating ASCT as a time dependent covariate. OS time was compared after matching ASCT to no ASCT patients on age, sex, race/ethnicity, neighborhood socioeconomic status (SES), comorbidity at diagnosis, year of diagnosis, and accounting for time to transplant.Results: The majority of MM patients were male (54%) and of non-Hispanic white (58%) race/ethnicity; 19% Hispanic, 12% African American, and 9% Asian. Median age at diagnosis was 67 (range 18 - 104). African Americans and Hispanics were younger than non-Hispanic whites (median age 64 and 65 vs 69). Comorbidity data from the PDD was available in 59% of the patients in the 2 years prior to MM diagnosis: 7.5% had 0, 21% had 1-2, and 31% had ≥3 comorbidities.A total of 2136 (17%) patients underwent ASCT: 1347 < 1 year from and 789 ≥1 year after diagnosis. Time to ASCT did not change over time: among patients diagnosed 2000 - 2003 median time to transplant was 9.2 mo, 10 mo among those diagnosed 2004 - 2007 and 9.7 in those diagnosed 2008 - 2012. Patients who underwent ASCT were younger than those who did not (median age 56 vs 70 respectively). African Americans were less likely to undergo early ASCT (OR 0.7, P<0.001), but not late ASCT (OR 0.8, P=0.07). Patients with ≥3 comorbidities (vs. 0) at diagnosis were less likely to have ASCT (OR 0.42 P<0.001 and OR 0.28 P<0.001 for early and late, respectively), while patients with 1-2 comorbidities were less likely to have late ASCT (OR 0.59 P<0.001). The lowest 2 quintiles of SES was associated with less use of early ASCT (OR 0.62 p<0.001 and 0.65 p<0.001 respectively), but not late ASCT (OR 0.89 p=0.4 and 0.96 p=0.7 respectively). The likelihood of receiving ASCT increased over time: compared to 2000-2003, the ORs for patients diagnosed in 2004 - 2007 were 1.36 for early (P<0.001) and 1.64 (P<0.001) for late ASCT and were 2.64 (P<0.001) for early and 1.80 (P<0.001) for late for those diagnosed in 2008-2012.The median follow-up was 32 months. Median OS from diagnosis for the entire cohort, unadjusted for age, comorbidities, and SES was 37 months. Adjusting for sex, race/ethnicity, age at diagnosis, SES, comorbidities, insurance status and year of diagnosis, OS improved over time: compared to patients diagnosed in 2008 - 2012, aHR of death of those diagnosed 2000-2003 was 1.58 (P<0.001), and 1.35 (P<0.001) for those diagnosed 2004-2007. ASCT at any point was associated with a 23% reduction in the risk of death from all causes (aHR 0.77 P<0.001). Patients who received early ASCT had a 27% reduction (aHR 0.73 P<0.001), while those receiving late ASCT had an 11% decrease (aHR 0.89 P<0.001) in risk of all cause death. In the matched analysis, the median OS from date of transplant, or matched date in the no ASCT cohort, were: no ASCT = 49 mo, early ASCT = 83 mo, and late ASCT 65 mo (P<0.001 Figure 1). The effect of aSCT on OS differed by date of diagnosis (P for interaction <0.001). Improvements in OS due to ASCT were more pronounced in later time periods: aHR for early and late ASCT in 2000-2003 were 0.9 (P = 0.12) and 0.98 (P 0.86) compared with those in 2004-2007 (0.63 P<0.001 and 0.85 P = 0.06) and in 2008-2012 (0.55 P<0.001 and 0.74 P=0.08).Conclusions :ASCT was utilized in 17% of Californians with MM during 2000-2012, and its use increased over time. The use of ASCT, whether within a year of diagnosis or later in the disease course, is associated with improved OS and this effect may be more pronounced in the era of novel agents. Despite the inherent limitations of analyses of administrative databases, the large number of patients and established robust nature of CCR and PDD data makes accurate depiction of results in the community probable. These data support the continued role of ASCT in the management of patients with MM. [Display omitted] DisclosuresJonas:Celgene: Honoraria; Incyte: Honoraria; Onyx: Honoraria; GlycoMimetics: Consultancy.

A Markov Model of Phase I Clinical Trials before or after Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma

Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT), performed either at the time of initial diagnosis or at relapse, is considered the standard of care for younger patients (<70 years of age) with multiple myeloma (MM). Currently, the optimal timing of ASCT, i.e., early transplantation versus transplant upon relapse, is under investigation (clinical trial NCT01208662). In addition, there has been an unprecedented pace of anti-myeloma compound discovery tested through phase I trials (i.e., 500% increase) during the last decade, and its timing in relation to ASCT is not clear. Further, the current perception of low therapeutic benefit from participation in phase I trials is the main obstacle for patient recruitment and makes the phase I trial a "last resort" in the overall therapeutic plan (Meropol et al. 2003). Here, we present a landscape of therapeutic benefit and toxicity of all MM phase I trials over the past decade. Also, in order to determine the optimal timing of ASCT and phase I trial we constructed a Markov model to examine two different approaches: early ASCT and subsequent phase I trial recruitment (early ASCT) vs. phase I trial recruitment before ASCT (late ASCT).Methods: The primary decision examined in this study is the timing of ASCT in relation to a phase I trial. We systematically reviewed the outcome of all MM phase I trials between 2004-2014 to build a comparable cohort for decision analysis. Response rate, adverse effects and mortality from single agents, as well as the combination of the experimental agents with immunomodulators (IMiDs) and proteasome inhibitors (PIs) are reported. Two strategies were tested through Markov modeling: early ASCT vs. late ASCT (Figure-1). The model was built using the commercially available DecisionMaker software. An annual discount rate of 3% was used for all clinical outcomes. Quality of life (QOL) information for post-ASCT and phase I trials were extracted from similar research papers.Results:Phase I systematic review: A total of 43 phase I clinical trials with 946 patients (530 males and 416 females) were included. The precipitants' median age was 60 years old. 21 trials tested single agents and the remainder were done using combination therapies (i.e., with an IMiD or PI). Median overall response rate (ORR) was 34% for all trials, 16% with single agents and 42% with combination therapy (Figure-2). 89% of trials were completed in less than a year. The therapeutic benefit of single vs. combination therapy phase I clinical trials does not show an increasing trend during the last decade (Figure-3). Patients who participated in combination therapy phase I trials had more grade III-IV toxicity than single agents (HR: 1.35, p-value: 0.04). There were only 4 patients (less than 1% of all participants) who experienced therapy-related death. Although, time from diagnosis was a predictor of response in univariate analysis, but it was not statistically correlated with response by multivariate analysis. Also, ORR was not affected by the number of prior therapies.Markov model: The discounted life expectancies for two strategies were calculated; fixed-time intervals of 6, 12, 18 and 24 months were chosen for analysis. The gains in life expectancy were the same in patients undergoing combination therapy phase I trials in early or late ASCT strategies (6.76 and 6.64, respectively; p-value: 0.21). Importantly, for patients undergoing single agent phase I therapy, early ASCT was associated with a higher life expectancy than was the strategy of delayed ASCT (7.96 vs. 6.86, respectively; p-value: 0.036).Conclusions: Taken together, our study indicates that phase I trials demonstrate a higher ORR than reported response rates from traditional chemotherapy phase I trials, i.e. 5%, Horstmann et al. 2005, even with single agents. We conclude that phase I participation should not be viewed as the "last resort". Our decision-making analysis shows that combination therapy phase I trials can be offered irrespective of ASCT. However, single agent phase I trials should be offered after ASCT for transplant-eligible patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresOff Label Use: Panobinostat and Ixazomib combined in myeloma.

Cost-effectiveness analysis of early vs. late autologous stem cell transplantation in multiple myeloma.

Autologous stem cell transplant (ASCT) is the current standard of care for most patients with multiple myeloma (MM) who are transplant eligible, yet the timing of ASCT is disputed due to a similar overall (OS) and progression-free survival with an early ASCT (eASCT) or a delayed ASCT (dASCT) approach. We developed a decision analytic model to perform cost-effectiveness analysis of the two commonly used treatment strategies for MM. Data on disease progression and treatment effectiveness came from 2001 to 2008 cohort treated at the Mayo Clinic and from published studies. Cost analysis was performed from a third-party payer perspective. The Consumer Price Index adjusted 2012 costs of eASCT and dASCT were $249236 and $262610, respectively. eASCT cohort had a benefit of 1.96 quality-adjusted life years (QALYs), 0.23 QALYs more than dASCT, implying that eASCT is preferred (dominant) over dASCT. The most critical variables in one-way sensitivity analysis were treatment-related mortality and OS associated with eASCT strategy. We conclude that eASCT could potentially be a relatively cost-effective treatment option for appropriate patients with MM, and these results would help patients, providers, and payers in decision making for timing of ASCT.

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Agents

Cost Effectiveness Decision Tree Analysis of Early Versus Late Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM) in the United States (US)

Cost Effectiveness Decision Tree Analysis of Early Versus Late Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM) in the United States (US)

Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma

Autologous stem cell transplant (ASCT) is an effective treatment for multiple myeloma (MM). However, the timing of ASCT in the era of novel agents (lenalidomide, thalidomide, bortezomib) is unknown. We retrospectively reviewed the outcome of patients with MM who received novel agent-based induction treatment and received first ASCT within 12 months of diagnosis (early ASCT, n = 102) or at a later date (late ASCT, n = 65). Median time to ASCT was 7.9 months vs. 17.7 months in early vs. late ASCT. The 3- and 5-year overall survival (OS) from diagnosis was 90 and 63% vs. 82 and 63% in early and late ASCT, respectively (p = 0.45). Forty-one and 36 patients in the early and late ASCT groups have relapsed or progressed, with median time to relapse of 28 and 23 months (p = 0.055). On multivariable analysis, factors predictive of increased risk for progression were International Scoring System (ISS) stage III (p = 0.007), and less than a very good partial response (< VGPR) post-ASCT (p < 0.001). A factor predictive of worst outcome for OS was being on hemodialysis (p = 0.037). No superiority of one agent was seen. In summary, early or late ASCT is a viable option for patients with MM receiving induction treatment with novel targeted therapies.

Cost Effectiveness Decision Tree Analysis of Early Versus Late Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM) in the United States (US)

AbstractAbstract 602Although, MM remains the most common indication for ASCT in the US, a controversy exists about the timing of ASCT. Since early ASCT (eASCT) versus delayed ASCT (dASCT) results in similar progression free survival (PFS) and overall survival (OS) in the novel agent era, economic assessment of one strategy over the other may help both clinicians and policy makers in establishing guidelines in the MM treatment paradigm. Here we designed a study to model a decision tree of both the strategies and estimate their cost-effectiveness.A decision tree was developed to compare the outcomes of ASCT in newly diagnosed transplant eligible MM patients after chemotherapy with novel drug lenalidomide which formed the base case. The survival data was obtained from our published data on eASCT versus dASCT in MM patients who underwent initial therapy with dexamethasone + immunomodulatory agents (IMiDs). The initial decision node on the decision tree model was dichotomized based on the cutoff of 12 months for eASCT versus dASCT. The probabilities of events during the length of follow up (60 months) period which formed our base case were: (a) eASCT cohort: Induction chemotherapy for median of 6 months - ASCT - median 30 months to relapse (drug free interval) followed by median therapy of 24 months for relapsed MM; (b) dASCT cohort: Median initial therapy for 36 months - ASCT - median 24 months to relapse (drug free interval).The cost analysis was done from a US third party payer perspective. The cost data for MM ASCT was obtained from the published data in which direct hospital costs were obtained from Nationwide Inpatient Sample and were converted to Medicare cost-to-charge ratio for urban hospitals. Chemotherapy cost consisted of actual drug costs that calculated based on average wholesale prices AWP (2008), costs of medical oncology visits, and the costs of managing adverse events. Post-ASCT maintenance costs were not included in the analysis. TreeAge Pro 2012 software was used to perform a static decision analysis.The outcomes were expressed in the units of health utility values obtained from phase III HOVON trial which measured quality of life (QoL) using EORTC QLQ-C30 & EuroQoL-5D. All scales and items were linearly transformed to range from 0 to 100. The utilities measured by the EuroQol-5D ranged from 0.40 before induction therapy to 0.70 after ASCT and translated to QALYs using area under the curve method. Using a Consumer Price Index (CPI), the costs of ASCT and chemotherapy were converted into 2012 US$. The robustness of the decision model was tested through univariate analyses and tornado diagram to identify those variables which if varied across clinically relevant measures may result in difference in outcomes. The expected cost of providing treatment to newly diagnosed MM patients for a period of 5 years when they undergo eASCT after induction with IMiDs was calculated to be $211,869. This was $52,454 less than the expected cost of undergoing dASCT. Patients who underwent eASCT had an expected benefit of 2.06 QALYs following treatment, which was 0.19 QALYs more than the patients who received dASCT. This implies that eASCT is preferred over (dominates) dASCT. One-way sensitivity analysis was undertaken to identify factors that were found to be most influential and included OS, overall response rate (ORR) and 1 year ASCT related mortality rate (TRM). Specifically, eASCT showed dominance even if the probability of OS was lowered to 52.1% from the actual case base of 65%, or the probability of ORR was lowered to ≥ 75.8% from the actual case base of 92%, or the probability of 1 year TRM was increased to 11.5% from actual case base of 2%, indicating the robustness of the model favoring cost effectiveness of eASCT.In absence of a survival benefit, the cost savings of early ASCT as measured by ICER would favor this approach, and it would help clinicians, patients, policy makers and third party payers in decision making. Future prospective studies in MM ASCT should incorporate economic and QOL components in the analysis and also focus on the added cost of post-ASCT maintenance therapies with respect to ICER and QALYs. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Early Versus Delayed Autologous Stem Cell Transplant In Patients Receiving Novel Therapies for Multiple Myeloma

AbstractAbstract 3564 Background:Autologous stem cell transplant (ASCT) with high-dose therapy (HDT) is an effective treatment modality for multiple myeloma (MM). MM is the leading indication for ASCT in North America. It was shown in a recent meta-analysis that a strategy of using ASCT early in the course of myeloma improves progression free survival (PFS) and quality of life. However, this study addressed only patients who had received conventional chemotherapy. Over the last decade, novel agents (thalidomide, bortezomib, and lenalidomide) have replaced conventional chemotherapy for induction in myeloma. These agents have demonstrated superior response rates when compared to conventional chemotherapy, and there is some indication that using novel therapies for induction before ASCT improves the duration of response and overall survival (OS). However, the question of whether early ASCT is the best strategy in the era of novel agents remains unanswered. We performed a retrospective analysis in order to compare the outcomes of patients with newly diagnosed MM treated with novel agents who received an early versus late ASCT. Methods:179 newly diagnosed MM patients were treated or referred to The Ohio State University for ASCT between October 2006 and December 2009. All patients in the analysis received either thalidomide, bortezomib, or lenalidomide as part of their induction regimen and went on to receive HDT and ASCT. We compared the outcomes of patients who received ASCT within 12 months of diagnosis (early group, N=134) to those who received ASCT at a later date (late group, N=45). All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to compare PFS and OS. Result:In our sample of 179 subjects there were no statistically significant differences in age, sex, race, performance status, comorbidity index score, disease stage at diagnosis, genetic risk and preparative regimen dose between the two groups. The median time from diagnosis to transplant was 7.2 months in the early group (N=134) and 17.7 months in the late group (N=45). In the early group, 81% of patients had received one line of treatment before transplant vs. 49% in the late group (p < 0.001). The overall response rate (ORR) prior to transplant was 90% (9% complete (CR), 31% very good (VGPR), 45% partial (PR)) in the early group, and 83% (9% CR, 22% VGPR, 47% PR) in the late group (p = 0.277). The ORR post transplant was 92% in the early group and 82% in the late group (p = 0.082), with a statistically significant proportion of patients in the early group obtaining CR (52% vs. 27%, p = 0.003). One year non-relapse mortality was 2% for both groups. At a median follow up of 22 months, 36% vs. 47% of patients had progressed (p = 0.29) and 7.5% vs. 24% had died due to disease progression (p = 0.005) in the early vs. late group. Median PFS was 30 months vs. 27 months with 1 year and 3 years PFS of 83% vs. 75% and 64% vs. 55% in the early vs. late group respectively (p = 0.851, Fig. 1). Of patients who had only one therapy pre transplant, results trended toward equivalent PFS in the two groups (p = 0.090), however more than 1 line of therapy and late transplant resulted in a progression hazard ratio of 2.43 (p = 0.050). OS was significantly better in the early group vs. the late group (p = 0.005, Fig. 2). On Cox regression analysis, a late ASCT resulted in a mortality hazard ratio of 3.30. [Display omitted] [Display omitted] Conclusion:An early ASCT in newly diagnosed MM patients receiving novel agents for induction resulted in an improved OS but not PFS. Patients who are responding well to their first line treatment may have equivalent PFS regardless of time to ASCT. Patients who have had ≥ 2 lines of treatment and underwent ASCT within 12 months had significantly improved PFS compared to those who received ≥ 2 lines of treatment but were transplanted later. Therefore, patients who have not responded to their first line regimen and are within 12 months of diagnosis may have the greatest benefit from ASCT. An extended analysis will be presented at the meeting. A multicenter randomized study comparing early vs. late transplant is underway. Disclosures:Phillips:NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.