Initial Autologous Stem Cell Transplantation Research Articles

Identifying Candidates for Effective Utilization of Stored Autologous PBSCs in Salvage Transplantation for Multiple Myeloma: Who Benefits Most?

Background/Objectives: High-dose chemotherapy (HD-CHT) followed by autologous stem cell transplantation (ASCT) remains the gold standard for eligible multiple myeloma (MM) patients, even amidst evolving therapeutic options. Clinical trials have demonstrated ASCT's efficacy in MM, including its potential as salvage therapy after prolonged remission. Peripheral blood stem cells (PBSCs) are now the primary source of hematopoietic stem cells for ASCT. Collecting additional PBSCs post-initial myeloablative conditioning is challenging, leading many centers to adopt the practice of collecting and storing excess PBSCs during initial therapy to support tandem transplants or salvage treatments. The use of salvage ASCT may diminish in the face of novel, highly effective treatments like bispecific antibodies and cellular therapies for relapsed/refractory MM (RRMM). Despite available stored PBSC grafts, salvage ASCTs are underutilized due to various factors, including declining performance status and therapy-related comorbidities. A cost utilization analysis from 2013 revealed that roughly 70% of patients had unused PBSC products in prolonged cryopreservation, costing a significant portion of total ASCT expenses. The average cost for collecting, cryopreserving, and storing PBSCs exceeded $20,000 per person, with more than $6700 spent on unused PBSCs for a second ASCT. A more recent analysis from 2016 underscored the declining need for salvage ASCT, with less than 10% of patients using stored PBSC grafts over a decade. Methods: To address the dilemma of whether backup stem cells remain necessary for myeloma patients, the study investigated strategies to reduce the financial burden of PBSC collection, processing, and storage. It evaluated MM patients undergoing frontline ASCT from January 2012 to June 2022, excluding those with planned tandem transplants and those who had a single ASCT with no stored cells. Discussion: Among the 240 patients studied, the median age at PBSC collection was 61. Notably, only 7% underwent salvage ASCT, with nearly 90% of salvage ASCT recipients being ≤ 61 years old at the time of initial ASCT. The study revealed a decreasing trend in salvage ASCT use with increasing age, suggesting that PBSC collection for a single transplant among elderly patients (>60 years old) could be a cost-effective alternative. Most transplant centers aimed to collect 10 × 106 CD34 + cells/kg, with patients over 65 often requiring multiple collection days. Shifting towards single-transplant collections among the elderly could reduce costs and resource requirements. Additionally, the study recommended implementing strategies for excess PBSC disposal or repurposing on the collection day to avoid additional storage costs. In summary, the decreasing utilization of salvage ASCT in MM, alongside financial considerations, underscores the need for revised stem cell collection policies. Conclusions: The study advocates considering single-transplant PBSC collections for elderly patients and efficient management of excess PBSCs to optimize resource utilization.

Salvage Autologous Peripheral Blood Stem Cell Transplantation after the Development of tMDS or AML in Multiple Myeloma Patients

Multiple Myeloma (MM) patients are often treated with high-dose chemotherapy and autologous stem cell transplantation (ASCT) for disease control. Lenalidomide is typically used as maintenance but results in an estimated 3.3% chance of developing a therapy-related myeloid neoplasm (TMN) typically myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). This complication is often devastating with a median survival for those with a TMN of just 13 months. Over the past 6 years, 4 patients with multiple myeloma who developed a TMN were treated with a salvage ASCT using banked stem cells collected prior to their initial ASCT and before lenalidomide maintenance. None of these patients qualified for an allogeneic transplant. Melphalan 140 - 200 mg/m2 was used as conditioning prior to infusion of the peripheral blood stem cells, resulting in successful MDS/AML disease control. Case 1 = 61-year-old man with MM initially treated with CyBorD then transplanted in 2010. Post transplant treatment included lenalidomide maintenance, followed by a variety of salvage regimens over the next 7 years including thalidomide, carfilzomib, daratumumab and pomalidomide. He developed cytopenias evaluated by bone marrow biopsy in May 2017. This showed tMDS (Karyotype 47-48, XY, der (5)t(5:20)(q11.1;q11.1), +19, der(21:22)(q10:q10),+2~3mar[cp11]/46-48,idem,-der(5),+20[cp5]/46,XY[4]. FISH confirmed deletion 5q in 76% and loss of chromosome 5 in 6.5% of cells. NGS showed a frame shift mutation of TP53 at a variant allele frequency of 92.5%. He underwent a second ASCT in Aug 2017 and recovered normal hematopoiesis within three weeks. Unfortunately, he developed an aggressive relapse of his multiple myeloma 9 months later and succumbed from refractory multiple myeloma 14 months after the salvage transplant, without evidence of MDS. Case 2 = 72-year-old man with MM initially treated with CyBorD then an ASCT in May 2015. Lenalidomide maintenance was continued until October 2017 when he developed severe thrombocytopenia and circulating blasts. A bone marrow biopsy showed tMDS EB-1. Cytogenetics 46, XY t(3:21) (q26.2,q22) [18]/46, XY[2]. He received a second ASCT after melphalan 140 mg/m2 in Oct 2017 followed by recovery of normal blood counts. Bone marrow biopsy showed complete remission. He remains in remission from both the multiple myeloma and MDS almost 6 years later without any further therapy. Case 3 = 65-year-old man with MM treated with bortezomib + dexamethasone followed by ASCT in Aug 2012. He received maintenance lenalidomide for 4 years but then progressed. In Jan 2018 he developed pancytopenia and bone marrow biopsy demonstrated MDS with ringed sideroblasts. Cytogenetics were normal but NGS showed mutations of ASXL1, RUNX1, SF3B1, SETBP1 and DNMT3A. He underwent a second ASCT using his banked stem cells after melphalan 140 mg/m2 in Jan 2018 followed by full hematopoietic recovery. A repeat bone marrow biopsy in March 2022 showed persistent MDS harboring ASXL1, SF3B1, and DNMT3A mutations, but no detectable RUNX1 or SETBP1 abnormalities. His multiple myeloma remains in remission >5 years later. He receives only intermittent erythropoietin to maintain a Hgb of 11. Case 4 = 58-year-old man with MM initially treated with CyBorD followed by an ASCT in May 2014. He received lenalidomide maintenance but relapsed multiple times after 4 years ultimately complicated by renal failure requiring permanent dialysis. In March 2022 he developed pancytopenia. Bone marrow biopsy showed 15% blasts harboring del(5q), del(17p) and trisomy 8 by FISH. NGS demonstrated a mutation of ASXL1, and a copy number loss of TP53. Six months of decitabine did not improve his blood counts. In Dec 2022 he underwent a second ASCT after melphalan 140 mg/m2. A repeat bone marrow biopsy in Feb 2023 showed a complete morphological remission with a normal NGS. He is off all treatment 8 months post-transplant other than erythropoeitic support due to ongoing dialysis-dependent renal failure. The development of TMN is an uncommon but devastating event in patients with multiple myeloma after ASCT and lenalidomide maintenance. These patients responded well to a salvage ASCT using banked stem cells. This approach was well tolerated and provided durable hematopoietic recovery. Second ASCT using banked autologous stem cells should be considered in such patients who are not otherwise candidates for allogeneic transplantation.

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

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

Regulatory T Cell Depletion during Stem Cell Mobilization Enhances Anti-Myeloma Immunity after Experimental Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) with G-CSF/plerixafor mobilized peripheral blood stem cells (PBSC) remains the standard of care for newly diagnosed eligible multiple myeloma (MM) patients and prolongs progression-free survival. However, most patients eventually progress and require additional therapy. We have previously demonstrated that experimental ASCT can enhance myeloma-specific immunity and limits disease progression characterized by immunological escape. Here we explored the ability of stem cell mobilization (SCM) to mobilize putative myeloma-specific T cells from the bone marrow (BM) and concurrent effects of regulatory T cell depletion (Treg), hypothesizing that this may represent an opportunity to optimize myeloma-specific immunity prior to ASCT. In myeloma patients we noted increased proportions of subsets of effector memory CD8 T cells, including a CX3CR1/granzyme B (GzmB)+ subset in PBSC grafts relative to BM (P<0.01). TIGIT+ Treg were also significantly expanded in PBSC (P <0.01). To study the relevance of these effects, we transferred congenically marked BM T cells into syngeneic mice. We noted that BM-derived effector (CD44+) CD8 cells preferentially homed back to BM (vs. spleen/blood), consistent with T cell residency at this site. SCM subsequently promoted the migration of these resident effector CD8 T cells from BM (4-fold reduction, P <0.001) to blood (5-fold expansion, P <0.001), confirming that PBSC contain BM resident T cells. BM Foxp3+ Treg were also reduced in BM and increased in blood after SCM. Mobilized Treg were characterized by an immunosuppressive phenotype with high levels of CD73, Nrp-1, CTLA4 and TIGIT, and this represents a possible suppressive pathway invoked by SCM. We thus examined the role of BM Treg in limiting myeloma-specific immunity during SCM with Foxp3-GFP-DTR mice. Depletion of Treg with diphtheria toxin (DT) during SCM promoted the expansion of antigen experienced CD8 T cells that secreted IFNg, TNF and GzmB. We next hypothesized that expansion of these polyfunctional cells would enhance myeloma-specific immunity after ASCT. To test this, we treated Vk*MYC bearing Foxp3-GFP-DTR donor mice with DT (vs. saline) 1 week after tumor injection followed by SCM. CD8 T cells from mobilized grafts were transplanted with BM and CD4 T cells from naïve B6 into lethally irradiated Vk*MYC bearing recipients (Figure 1A). Recipients transplanted with CD8 T cells from Treg depleted donors had dramatically improved tumor control (Figure 1B) after ASCT compared to recipients of cells from Treg intact donors (survival 100 days post-ASCT; 100% for DT group vs 13% for saline group, P <0.0001). Rechallenge of mice surviving over 100 days after ASCT confirmed MM clone-specific immunity with complete elimination of the MM seen at initial ASCT, but not an unrelated clone. We next studied clinically relevant approaches to mimic this scenario. Administration of TIGIT, CTLA4, CD25 or LAG3 antibodies resulted in inadequate Treg depletion in BM to recapitulate this effect. In contrast, a synthetic IL-2/IL-15 mimetic NL-201 that selectively binds the beta and gamma chains of IL-2 receptor but not the high affinity IL-2Ra (CD25) reduced BM Treg (45.9% vs 18.6%, P <0.05) and expanded polyfunctional effector cells expressing IFNg+TNF+GzmB+ in SCM grafts. MM-bearing mice transplanted with NL-201 mobilized CD8 T cells were also protected against relapse after ASCT (survival 100 days post-ASCT; 87.5% for NL-201 group vs 25% for saline group, P <0.05). This protection was characterized by expansion of antigen experienced (CD38+) and cytokine secreting (TNF, IFNg) memory (CD44+) CD8 T cells in the BM 3 weeks after ASCT. BM CD8 T cells and Treg are efficiently mobilized after G-CSF/plerixafor. Depletion of Treg in donors during SCM dramatically increases myeloma specific T cells in stem cell grafts and enhances myeloma-specific immunity after ASCT. Stem cell mobilization in the presence of the synthetic IL-2/15 mimetic NL-201 is a promising clinically tractable approach to recapitulate these effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Parameters Influencing Count Recovery Post Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Introduction Autologous stem cell transplant (ASCT) following high-dose chemotherapy is an established treatment for patients with multiple myeloma (MM). Previous studies have aimed at identifying the minimum number of required stem cells to achieve CBC engraftment defined by an absolute neutrophil count (ANC) of >0.5 x 109/l x 3 days, hemoglobin (HGB) of >8 g/dL and platelets count (PLT) of >20 × 109/L free of transfusion requirements. However, for diseases like MM, where stem cell transplantation is followed by prolonged maintenance, adequate CBC recovery to near normal levels is crucial for successful initiation and continuation of completion of maintenance. Various studies have established the impact of the number of infused CD34+ stem cells as the strongest predictor of cell counts recovery, yet the ideal amount of infused stem cells and ideal time between ASCT and initiation of maintenance remain elusive and vary greatly between institutions. Current practice is to wait at least 100 days after ASCT, however this prolonged time interval could lead to regrowth of MM cells, particularly in aggressive disease. In an effort to determine which parameters influence count recovery post ASCT we investigated 780 MM patients at the University of Arkansas for Medical Sciences Methods We carried out a single center retrospective assessment on patients who received their initial ASCT following induction chemotherapy for newly diagnosed MM from 2015 to 2019. All patients had a bone marrow (BM) examination post ASCT, which typically precedes the immediate initiation of maintenance. The time point of BM assessment was used to determine count recovery and the time from ASCT to BM assessment was evaluated as an independent parameter. We further examined various factors that could potentially affect CBC recovery aside the total CD34+ cell dose infused. Covariates examined were age, race, gender, CD34+ cell dose, Karnofsky score and conditioning regimen received. Results A total of 780 patients were analyzed using a linear regression model. The median age was 62 years (range: 29-82). 44.2% (345/780) were female, 78.8% (615/780) identified as Caucasians and 17.7% (138/780) as African Americans. High dose melphalan was the conditioning regimen in 88% (687/780) patients followed by low dose melphalan in combination with Cisplatin, Adriamycin, Cyclophosphamide and Etoposide (PACE) in 8.4% (66/780) and BEAM conditioning in 3.7% (29/780). Median number of CD34+ stem cells infused was 5.6 x106/kg (0.9-13.4) and median time from ASCT to assessment of bone marrow examination and count recovery, was 60 days ( 14-365). Overall, infusing 5.0 x106/kg CD34 cells lead to a robust CBC 9 weeks post ASCT. Estimated ANC was 2.86 (CI95%: 2.70-3.01) with no significant changes with higher numbers of stem cells infused or longer time to assessment. Estimated HGB was 10.93 (CI95%: 10.81 - 11.04). An increase of 1 × 106 CD34 cells was expected to increase HGB by 0.10 (CI95%: 0.02 - 0.14) and waiting an additional week to assess count recovery was expected to increase hemoglobin by 0.03 (CI95%: 0.02 - 0.05). Estimated platelet count for a patient receiving 5 × 106 CD34 cells after 9 weeks of ASCT was 157 (CI95%: 151 - 163). An increase of 1 × 106 CD34 cells was expected to increase platelet counts by 6 (CI95%: 4 - 9). Males had HGB levels that were 0.6 (CI95%: 0.36 - 0.78) higher and ANC counts that were 0.3 (CI95%: 0.006 - 0.6) higher than females, while African Americans had HGB levels that were 0.5 (CI95%: 0.2 - 0.8) lower and PLT that were 18 (CI95%: 4 - 32) higher than Caucasians. A 10-point increase in Karnofsky performance scores corresponded to a 0.2 (CI95%: 0.1 - 0.4) increase in HGB and a 9 (CI95%: 3 - 15) increase in PLT. Interestingly, there were no significant alterations when accounting for age. More aggressive conditioning regimen, such as BEAM, were associated with lower PLT and ANC counts, albeit given the small number of patients receiving BEAM, this was not significant. Conclusion The infusion of at least 5 x106 CD 34+ stem cells leads to robust count recovery 9 weeks post ASCT in MM patients. These results suggest that initiation of maintenance could be considered at an earlier time point than the accepted 100 day mark. Earlier initiation of maintenance could be crucial especially for high risk patients with highly proliferative disease, where prolonging the time from transplant to maintenance can potentially lead to regrowth of aggressive clones.

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib-Based Induction: An Analysis of Real World Data

IntroductionMultiple myeloma (MM) represents an incurable plasma cell malignancy. Success in the management of this disease requires a focus on prolonging disease control to positively impact survival. This is the rationale behind maintenance chemotherapy after frontline autologous stem cell transplant (ASCT). Recent large-scale phase 3 randomized trials have shown daily low dose lenalidomide, an oral immunomodulator (IMID), has led to markedly improved progression free survival (PFS) and an evolving benefit on overall survival (OS). We sought to evaluate the effect of lenalidomide maintenance in patients with MM undergoing bortezomib-based induction chemotherapy and ASCT in a real world setting.MethodsRetrospective review of patients with MM undergoing initial bortezomib-based induction chemotherapy and ASCT was completed in patients at our institution. Patients who began therapy up until June 30th, 2015 were included to ensure a minimum of 2-yrs follow-up. Patients were analyzed on an intention-to-treat basis. Maintenance chemotherapy included those on lenalidomide alone or lenalidomide plus bortezomib, the latter being a treatment option at our centre for high-risk patients. OS was measured from the time induction therapy was started until death or last follow-up. PFS was measured from the time of induction therapy initiation to relapse, death or last follow-up. Maximal response to treatment was assessed according to the IMWG consensus criteria although an additional endpoint of near CR (nCR) was included to account for patients where the monoclonal protein on electrophoresis disappeared and light chains normalized but where CR was not confirmed with immunofixation and a bone marrow biopsy was not done.Results198 patients were included in the analysis. 121 received lenalidomide based maintenance and 77 received no maintenance between December 2004 to June 30th, 2015. Median ISS score was 2 in both groups without significant difference between them (p=0.98) . In the maintenance and no maintenance groups respectively 32% and 36% had ISS stage 3 disease. The mean number of maintenance cycles received was 25 cycles (0.5 - 84). Sixty percent of patients required dose reductions or discontinuation due to adverse effects excluding relapse. Most commonly this was due to cytopenias (29.8%), rash (10.7%), infection (9.1%) and fatigue (5.8%). 15% discontinued therapy before relapse occurred. Though venous thromboembolism and second primary malignancies (SPMs) are a worry in patients treated long term with IMIDs these were only seen in 3.3% and 1.7% of patients respectively. Median follow-up in the maintenance group was 44 months and 60 months in the no maintenance group. Survival data is shown in figure 1. The median OS was not reached in the maintenance cohort and was 89 months in the no maintenance group (p = 0.01). Estimated 3-year OS was superior in the maintenance group at 88.4% versus 80.5% in the no maintenance cohort. A statistically significant difference in median PFS was also noted favouring the lenalidomide maintenance (55.0 months versus 32.9 months, p=0.002). Of patients treated with lenalidomide-based maintenance 95.0% achieved ≥ VGPR (53.7% ≥ nCR) while 77.9% (29.1% ≥ nCR) of those who did not receive maintenance therapy achieved these endpoints (p=0.03). Further characterization of therapy for relapsed disease as well as PFS after 1st relapse (2nd PFS) and time to second relapse (PFS2) will be presented at the meeting.ConclusionsOur retrospective analysis of lenalidomide maintenance therapy in MM patients treated with bortezomib-based induction chemotherapy and ASCT illustrates the positive impact lenalidomide has had on both PFS and OS. Patients treated with lenalidomide at our centre experienced a more prolonged and profound remission of their disease. The treatment was well tolerated with no unexpected adverse effects. Rates of thromboembolic disease and SPMs were low. Most importantly, the superior OS in the maintenance arm suggests that second line therapy for those not receiving maintenance could not overcome the negative impact of an earlier relapse. This data supports our ongoing approach incorporating lenalidomide-based maintenance continued until progression for all patients who have undergone an ASCT. Importantly, these real world results validate the phase 3 trial experience, helping to further establish this approach as a standard of care. [Display omitted] DisclosuresBelch:Amgen, Celgene, Takeda: Honoraria.

Assessing Outcomes, Healthcare Resource Utilisation and Costs across Europe in Newly Diagnosed Multiple Myeloma (NDMM) Patients Post Autologous Stem Cell Transplant (ASCT)

BACKGROUNDRecently introduced treatment options, including the introduction of maintenance therapy (MT) post ASCT, have significantly improved outcomes and life expectancy of MM patients. To date, the impact these treatment options have on healthcare resource utilisation (HCRU) has not been assessed.AIMSThe aim of the analysis was to determine current management of post-ASCT NDMM patients in terms of outcomes, HCRU and the associated costs in Europe for patients receiving either MT or no MT.METHODSA retrospective chart review was conducted in France, Germany, Italy, Spain and the UK in Q1 2017. Physicians provided data on consecutive patients with MM who had undergone an ASCT as part of first-line (1L) treatment on or after 1st January 2014; HCRU data was collected post initial ASCT until the end of follow-up. Mean follow-up time for patients was 18.2 months (21.2 vs 18.0 months for patients receiving and not receiving MT post initial ASCT, respectively).Data collected pertained to patient characteristics, treatment patterns, duration of treatment and outcomes (including time to progression [TTP] estimated based on Kaplan-Meier method), HCRU post initial ASCT including: supportive drugs, other supportive treatments (blood transfusions and dialysis), hospitalisations, healthcare professional (HCP) visits and monitoring tests conducted, but excluded cancer drug costs.Costs were applied to the relevant resources consumed. Tariffs from a single-country health service (the United Kingdom) were applied; an exchange rate of £1 to €1.1365 was used (correct as of 1st July 2017). Cost for hospitalisations, HCP visits, supportive treatments and monitoring tests were obtained from the NHS Schedule of Reference Costs (2015-2016), and supportive drug costs were obtained from MIMS 2017. The costs have been applied to data collected from the healthcare system perspective, thus allowing for a broad overview to assess the impact of MT on HCRU across treatment lines post 1L ASCT. Monthly resource use was calculated for the duration of the follow-up time for patients.RESULTSFifty-one physicians completed record forms for 337 patients. Fifty-seven percent of patients were male; mean age at diagnosis was 58.7 years (± 7.7 SD). Mean duration from diagnosis to receiving an ASCT was 9.8 months (± 13.2 SD). Of the patients included in the study, 61%, 27% and 9% had received up to 1L, second-line (2L) and third-line (3L) therapy, respectively; 3% of patients also went onto receive ≥ 4 lines. In the 1L setting, 93% of patients did not receive any MT post ASCT; 7% received MT. Of the patients who did not receive MT, 40% and 12% went on to receive 2L and 3L therapy respectively, whereas only 20% of patients who received MT went on to 2L and none on to 3L. The most frequently prescribed regimens at 1L MT were lenalidomide (88%), bortezomib (8%), and thalidomide (4%).The mean TTP from start of 1L therapy was 30.0 months (95% CI: 27-32 months; n = 312) for patients not receiving MT and 39.0 months (95% CI: 31- months; n = 24) for patients receiving MT.Of the 337 patients, 91 had complete resource use data across their treatment pathway. The total cost of HCRU post 1L ASCT per patient was €945.80 per month; patients receiving MT (n = 14) had an associated HCRU cost of €638.14 per month, whereas patients not receiving MT (n = 77) cost €1001.74 per patient per month. Over the course of the treatment pathway, the level of HCRU consumption varied depending on the type of resource (Table 1). Patients receiving MT required a higher level of supportive drugs (€442.52 vs €250.15 per patient, respectively) and other supportive treatments (€55.12 vs €22.18, respectively). However, the utilisation of other resource data captured was higher for no-MT patients vs MT patients (hospitalisations: €243.12 vs €59.78; HCP visits: €498.58 vs €181.11; monitoring tests: €198.48 vs €84.20 per patient, respectively).CONCLUSIONThe patient sample observed within this real-world study is reflective of the patient demographics data reported in Raab et al. 2016. The TTP data for patients not receiving MT post ASCT at 1L is comparable to recently published pooled PFS data from large RCTs. The data presented indicates that the use of MT therapy at 1L defers future treatment lines, therefore reducing the overall monthly HCRU cost relating to hospitalisations, HCP visits and monitoring over a patient's MM treatment pathway. [Display omitted] DisclosuresAshcroft:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Dhanasiri:Celgene Corporation: Employment, Equity Ownership.

Real-World Use of Maintenance Therapy and Associated Outcomes Following Autologous Stem Cell Transplant in US Patients with Newly Diagnosed Multiple Myeloma

Background: In patients with newly-diagnosed multiple myeloma (NDMM) who receive frontline autologous stem cell transplantation (ASCT), maintenance therapy (MT) following ASCT has been shown to delay disease progression and death. Current National Comprehensive Cancer Network (NCCN) guidelines also recommend MT for patients with MM, including the use of lenalidomide, bortezomib-based regimens, or ixazomib. However, there is limited evidence on the use and outcomes associated with MT in contemporary real-world patients. The present study assessed MT treatment patterns and clinical outcomes in a real-world US cohort of patients with NDMM following ASCT. Methods: This retrospective, observational cohort study included NDMM patients initially diagnosed from 2011-2018 who received frontline ASCT. Patients were selected from the US Flatiron Health (FH) deidentified electronic health record (EHR)-derived database, which includes longitudinal patient-level data from over 265 community-based and academic cancer clinics across the US. To ensure capture of post-ASCT consolidation and MT, the study sample was restricted to patients who resumed contact within the FH network within 60 days following ASCT. Patients were excluded if they received treatment within the context of a clinical trial or had a second transplant within 180 days of their initial ASCT. Patients were classified as receiving MT if (during the 180-day post-transplant period) they initiated treatment with an NCCN-recommended MT regimen or continued to receive a subset of the antimyeloma agents used as induction regimen following ASCT and consolidation (if any). Key measures included baseline demographic and clinical characteristics, antimyeloma treatments (frontline induction, consolidation, and MT, if any), and clinical outcomes (time to next myeloma treatment [TTNT] and overall survival [OS]). Treatment duration and clinical outcomes were analyzed using Kaplan-Meier estimators and Cox regression to account for right-censoring. For TTNT and OS, follow-up began on the earlier of the ASCT date + 90 days or start of MT and continued through the dataset cut-off date (May 30, 2020) or loss to follow-up; TTNT and OS were estimated for patients receiving lenalidomide maintenance [R-MT], bortezomib maintenance [V-MT], or no MT, but was not estimated for other MT regimens due to sample size considerations. Results: 528 NDMM patients (median age 61 years, interquartile range [IQR]: 55, 68; 45.3% female) underwent ASCT and met study inclusion criteria. The most common induction regimens were bortezomib-lenalidomide-dexamethasone (VRd; 60.0%), lenalidomide-dexamethasone (Rd; 16.3%), and cyclophosphamide-bortezomib-dexamethasone (CyBorD; 10.2%). Following ASCT, 7.2% of patients received consolidation therapy and 74.2% received MT (lenalidomide monotherapy [R-MT]: 58.7%; bortezomib monotherapy [V-MT]: 7.6%; other MT: 7.8%). Median duration of MT was 18.0 months (IQR: 8.7, 29.1), and was similar for R-MT and V-MT (median 18.9 and 18.6 months, respectively). MT use increased from 69.3% to 79.0% from 2011-2013 to 2017-2018 (P=0.04); in addition, patients were more likely to have received VRd as induction across different MT (Table 1). R-MT and V-MT were both associated with longer TTNT relative to no MT (unadjusted hazard ratios [HRs]: 0.29 [95% CI: 0.22, 0.38] and 0.39 [95% CI: 0.25, 0.61], respectively) (Figure 1A). Improvements in OS were marginally significant with R-MT (HR: 0.58 [95% CI: 0.33, 1.00]) and nonsignificant with V-MT (HR: 0.86 [95% CI: 0.35, 2.11]) relative to no MT (Figure 1B); however, the OS estimates are characterized by low precision due to the relatively small number of events observed. Limitations included lack of documentation of reasons for treatment in the FH database, and use of consolidation and MT were inferred from observed treatment patterns; therefore, misclassification of MT was possible. Conclusions: This analysis demonstrates that MT use following ASCT has increased in routine clinical practice in the US since 2011-2013, with R-MT being the most common regimen followed by V-MT. However, a substantial proportion of patients did not receive MT. MT use in real-world settings was associated with longer TTNT and a trend toward longer OS. Exploration of additional maintenance regimens to improve clinical outcomes is warranted in this patient population. Disclosures Ammann: Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Tang:Janssen: Current Employment. Kampfenkel:Janssen: Current Employment. Sharma:Mu Sigma: Current Employment; Janssen: Other: Contractor. Lee:Janssen: Current Employment. Kaila:Janssen Scientific Affairs: Current Employment. Fu:Janssen: Current Employment. Gray:Janssen: Current Employment. He:Janssen: Current Employment.

The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear.Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results.Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID).The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1.Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months.Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT.Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance.At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed.In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002).Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. [Display omitted] DisclosuresSchroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Significance of Salvage Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma: A Nationwide Retrospective Study in Japan

Autologous stem cell transplantation (ASCT) has been employed for patients with relapsed multiple myeloma (MM) after up-front ASCT. The present retrospective study aimed to examine the survival benefit from salvage ASCT. Among 446 patients with relapsed MM after up-front single ASCT, 70 patients received salvage ASCT, the employment of which reduced the risk of mortality after relapse (p = 0.041). Using the parameters before initial ASCT, the advantage of salvage ASCT compared to standard therapy was confirmed in the subgroup with an international staging system stage of I or II (p = 0.040), good performance status (PS; p = 0.043), or no/mild renal comorbidity (p = 0.029). The advantage of salvage ASCT was also confirmed in the subgroup excluding those with early relapse within 7 months after initial ASCT (p = 0.026). Among patients who received salvage ASCT, a favorable prognosis is apparent for those with a time to relapse after initial ASCT of longer than 24 months. The overall survival after salvage ASCT was favorable excluding patients with the following factors: early relapse, poor PS, moderate/severe renal comorbidity, and progressive disease (p < 0.001). In conclusion, our results reinforced the evidence for encouraging salvage ASCT for eligible patients.

The efficacy of Salvage Autologous Stem Cell Transplant for Patients With Multiple Myeloma Who Received Maintenance Therapy Post an Initial Transplant

Background: For patients relapsing after initial autologous stem cell transplantation (ASCT), a second ASCT is a potential, although infrequently used, salvage option. Until recently, the benefits of second ASCT were unclear but recent prospective studies have shown second ASCT to improve PFS and OS compared to conventional salvage therapy. However, these studies have included few patients who received maintenance therapy following initial ASCT as maintenance therapy is a relatively recent innovation and is not standard of care in many EU countries where these studies where these studies were completed. Therefore, it is not currently clear if these patients benefit similarly from second ASCT. Methods: We performed retrospective chart review of patients with multiple myeloma that received two ASCTs, one for initial treatment and one for salvage at time of relapse, between 2008 and 2016 at our institution. We identified 30 who received maintenance therapy following initial therapy; 2 patients were excluded as they experienced treatment related mortality prior to disease assessment post-ASCT, leaving 28 for the analysis. Results: The median age of the study population was 59 years (range 48-69) at second ASCT. 64% (n = 18) were males, 36% (n = 10) females. Prior to initial ASCT, the median number of induction cycles was 4 (range 2-11). 86% (n = 24) of patients received bortezomib during induction, 39% (n = 11) lenalidomide, 7% (n = 2) cyclophosphamide, and 11% (n = 3) received another agent. All patients received melphalan conditioning for initial ASCT. Maintenance therapy consisted mostly of lenalidomide (93%, n = 26); 7% (n = 2) had bortezomib maintenance due to lenalidomide intolerance. The overall response rate (ORR) was 100% (n = 28); the complete response rate was 39% (n =11). The median progression-free survival (PFS) post-ASCT was 31 months (range 9-57), the median interval between initial and salvage ASCT was 38 months (range 22-63). At relapse, 93% (n =26) received reinduction chemotherapy while 7% (n = 2) went directly to salvage ASCT. The median number of reinduction cycles was 4 (range 2-28). 54% (n = 15) of patients received carfilzomib during reinduction, 46% (n = 13) bortezomib, 32% (n = 9) cyclophosphamide, 29% (n = 8) lenalidomide, 14% (n = 4) pomalidomide, and 7% (n = 2) received another agent. Prior to second ASCT, 79% (n =22) received melphalan conditioning, while 21% (n = 6) received BEAM. 79% (n = 22) received maintenance therapy post transplantation; 39% (n = 11) received bortezomib, 21% (n = 6) pomalidomide, 11% (n = 3) lenalidomide, 7% (n =2) carfilzomib, 18% (n = 5) were observed off maintenance, and 4% (n = 1) had frank progression post-ASCT prior to starting maintenance. The overall response rate (partial response or better) was 86% (n = 24); the complete response rate was 21% (n = 6). The median estimated PFS was 12 months (95% CI 10-15). The median duration of follow-up was 16 months; the estimated 2 year overall survival was 49%. Conclusion: In patients who relapse post-ASCT with maintenance therapy, the PFS following salvage ASCT is ~40% that of the initial ASCT. Strategies to improve outcomes using novel reinduction, conditioning, and post-transplant maintenance regimens are needed for these patients. Disclosures Wildes:Carevive Systems: Consultancy. Vij:Shire: Consultancy; Jazz: Consultancy; Karyopharma: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Outcome of Third Salvage Autologous Stem Cell Transplantation in Multiple Myeloma

Background. Autologous stem cell transplantation (ASCT) remains a gold standard treatment for younger patients with multiple myeloma (MM). With the aid of new drugs, the patients live longer and third salvage ASCT is an increasingly used option. However, the outcome of third salvage ASCT has not yet been analyzed. Methods. Between 1997 and 2010, 1288 MM patients who had received at least 3 ASCT were registered in the EBMT database. We excluded patients older than 75 years, those with a time from diagnosis to first ASCT of more than 10 years, patients transplanted with bone marrow, those with a time between relapse and ASCT of less than one month and those with an uncertain relapse date. Planned tandem ASCT was considered to be performed within a 6 month interval and at least 1 month apart. The conditioning regimen for the third transplant was high dosemelphalan alone or in combination withbusulfan orbortezomib. We could distinguish two main groups: 417 patients who received tandem ASCT and then a third ASCT after single relapse (AARA group) and 72 patients who received one ASCT, a second ASCT after first relapse, and a third ASCT after second relapse (ARARA group). A third group, who received tandem ASCT after relapsing following single ASCT comprised only 25 patients and was not studied. Results. We compared the two groups AARA vs ARARA. A third ASCT was performed in the AARA group in more recent years (p=0.047). There were more males than females (65% vs 72%) in both groups (p=NS). The main myeloma isotype was IgG (56% vs 58%). The ISS stage at diagnosis was similar (stage III in 70% vs 72% of cases). The time interval between diagnosis and first ASCT tended to be shorter in the AARA group (p=0.089), being within the first 6 months in 50% vs 38% of patients. The status at third ASCT was different: CR, 5% vs 4%: VGPR or PR, 45% vs 19%: MR or stable disease, 12% vs 15%: primary refractory/progressive disease, 38% vs 62% (p 70% at third ASCT was reported in 91% vs 90% of cases. The conditioning regimen at third ASCT was different between the two groups: melphalan 200 mg/m2, 42% vs 18%: melphalan 140 mg/m2, 6%vs 12%: other 52%vs 70% (p=0.018). The median age at third ASCT was 59vs 61 years. There was a trend to a longer time between first ASCT and first relapse (27vs 22 months (p=0.056)) in the AARA group while the interval between first ASCT and third ASCT was much shorter (44vs 64 months (p The median follow-up was similar (70vs73 months (p=0.9)). Engraftment was similar (96%vs93% (p=0.35)).The best response achieved after the third ASCT was superior in the AARA group: CR, 32%vs12%: VGPR or PR, 60%vs71% :MRor SD, 4%vs14%: progression, 4%vs3% (p Conclusions.A third ASCT is feasible in MM with more than 80% of patients achieving at least PR although with increased non relapse mortality. This treatment is mostly used in one of two scenarios: tandem ASCT followed by relapse and a third ASCT, or less commonly a first ASCT followed by a first relapse, a second ASCT, a second relapse and subsequently a third ASCT. The first scenario gives much better results, partly due to a better remission status at the third ASCT with no sign of increased SPM. In this AARA group, if relapse occurred more than 3 years after the initial tandem ASCT, the median OS after third ASCT was more than 4 years. These results should be compared with those obtained with the new drugs, especially in combination. Disclosures Garderet:Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy. Dreger:Janssen: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Leleu:TEVA: Membership on an entity9s Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Peschel:MophoSys: Honoraria. Meuleman:Bristol-Myers-Squibb: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Ciceri:MolMed SpA: Consultancy. Schonland:Janssen, Prothena, GSK: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel, accommations, Patents & Royalties, Research Funding, Speakers Bureau. Kroger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

The Efficacy of Salvage Autologous Stem Cell Transplant for Patients with Multiple Myeloma Who Received Maintenance Therapy Following Initial Transplant

Background: For patients relapsing after initial autologous stem cell transplantation (ASCT), a second ASCT is a potential, although infrequently used, salvage option. Until recently, the benefits of second ASCT were unclear but recent prospective studies have shown second ASCT to improve PFS and OS compared to conventional salvage therapy. However, these studies have included few patients who received maintenance therapy following initial ASCT as maintenance therapy is a relatively recent innovation and is not standard of care in many EU countries where these studies where these studies were completed. Therefore, it is not currently clear if these patients benefit similarly from second ASCT.Methods: We performed retrospective chart review of patients with multiple myeloma that received two ASCTs, one for initial treatment and one for salvage at time of relapse, between 2008 and 2016 at our institution. We identified 30 who received maintenance therapy following initial therapy; 2 patients were excluded as they experienced treatment related mortality prior to disease assessment post-ASCT, leaving 28 for the analysis.Results: The median age of the study population was 59 years (range 48-69) at second ASCT. 64% (n = 18) were males, 36% (n = 10) females.Prior to initial ASCT, the median number of induction cycles was 4 (range 2-11). 86% (n = 24) of patients received bortezomib during induction, 39% (n = 11) lenalidomide, 7% (n = 2) cyclophosphamide, and 11% (n = 3) received another agent. All patients received melphalan conditioning for initial ASCT. Maintenance therapy consisted mostly of lenalidomide (93%, n = 26); 7% (n = 2) had bortezomib maintenance due to lenalidomide intolerance. The overall response rate (ORR) was 100% (n = 28); the complete response rate was 39% (n =11). The median progression-free survival (PFS) post-ASCT was 31 months (range 9-57), the median interval between initial and salvage ASCT was 38 months (range 22-63).At relapse, 93% (n =26) received reinduction chemotherapy while 7% (n = 2) went directly to salvage ASCT. The median number of reinduction cycles was 4 (range 2-28). 54% (n = 15) of patients received carfilzomib during reinduction, 46% (n = 13) bortezomib, 32% (n = 9) cyclophosphamide, 29% (n = 8) lenalidomide, 14% (n = 4) pomalidomide, and 7% (n = 2) received another agent.Prior to second ASCT, 79% (n =22) received melphalan conditioning, while 21% (n = 6) received BEAM. 79% (n = 22) received maintenance therapy post transplantation; 39% (n = 11) received bortezomib, 21% (n = 6) pomalidomide, 11% (n = 3) lenalidomide, 7% (n =2) carfilzomib, 18% (n = 5) were observed off maintenance, and 4% (n = 1) had frank progression post-ASCT prior to starting maintenance. The overall response rate (partial response or better) was 86% (n = 24); the complete response rate was 21% (n = 6). The median estimated PFS was 12 months (95% CI 10-15). The median duration of follow-up was 16 months; the estimated 2 year overall survival was 49%.Conclusion: In patients who relapse post-ASCT with maintenance therapy, the PFS following salvage ASCT is ~40% that of the initial ASCT. Strategies to improve outcomes using novel reinduction, conditioning, and post-transplant maintenance regimens are needed for these patients. [Display omitted] DisclosuresWildes:Carevive Systems: Consultancy. Vij:Shire: Consultancy; Jazz: Consultancy; Karyopharma: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Outcome of Third Salvage Autologous Stem Cell Transplantation in Multiple Myeloma

Background. Autologous stem cell transplantation (ASCT) remains a gold standard treatment for younger patients with multiple myeloma (MM). With the aid of new drugs, the patients live longer and third salvage ASCT is an increasingly used option. However, the outcome of third salvage ASCT has not yet been analyzed. Methods. Between 1997 and 2010, 1288 MM patients who had received at least 3 ASCT were registered in the EBMT database. We excluded patients older than 75 years, those with a time from diagnosis to first ASCT of more than 10 years, patients transplanted with bone marrow, those with a time between relapse and ASCT of less than one month and those with an uncertain relapse date. Planned tandem ASCT was considered to be performed within a 6 month interval and at least 1 month apart. The conditioning regimen for the third transplant was high dosemelphalan alone or in combination withbusulfan orbortezomib. We could distinguish two main groups: 417 patients who received tandem ASCT and then a third ASCT after single relapse (AARA group) and 72 patients who received one ASCT, a second ASCT after first relapse, and a third ASCT after second relapse (ARARA group). A third group, who received tandem ASCT after relapsing following single ASCT comprised only 25 patients and was not studied. Results. We compared the two groups AARA vs ARARA. A third ASCT was performed in the AARA group in more recent years (p=0.047). There were more males than females (65% vs 72%) in both groups (p=NS). The main myeloma isotype was IgG (56% vs 58%). The ISS stage at diagnosis was similar (stage III in 70% vs 72% of cases). The time interval between diagnosis and first ASCT tended to be shorter in the AARA group (p=0.089), being within the first 6 months in 50% vs 38% of patients. The status at third ASCT was different: CR, 5% vs 4%: VGPR or PR, 45% vs 19%: MR or stable disease, 12% vs 15%: primary refractory/progressive disease, 38% vs 62% (p 70% at third ASCT was reported in 91% vs 90% of cases. The conditioning regimen at third ASCT was different between the two groups: melphalan 200 mg/m2, 42% vs 18%: melphalan 140 mg/m2, 6%vs 12%: other 52%vs 70% (p=0.018). The median age at third ASCT was 59vs 61 years. There was a trend to a longer time between first ASCT and first relapse (27vs 22 months (p=0.056)) in the AARA group while the interval between first ASCT and third ASCT was much shorter (44vs 64 months (p The median follow-up was similar (70vs73 months (p=0.9)). Engraftment was similar (96%vs93% (p=0.35)).The best response achieved after the third ASCT was superior in the AARA group: CR, 32%vs12%: VGPR or PR, 60%vs71% :MRor SD, 4%vs14%: progression, 4%vs3% (p Conclusions.A third ASCT is feasible in MM with more than 80% of patients achieving at least PR although with increased non relapse mortality. This treatment is mostly used in one of two scenarios: tandem ASCT followed by relapse and a third ASCT, or less commonly a first ASCT followed by a first relapse, a second ASCT, a second relapse and subsequently a third ASCT. The first scenario gives much better results, partly due to a better remission status at the third ASCT with no sign of increased SPM. In this AARA group, if relapse occurred more than 3 years after the initial tandem ASCT, the median OS after third ASCT was more than 4 years. These results should be compared with those obtained with the new drugs, especially in combination. Disclosures Garderet:Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy. Dreger:Janssen: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Leleu:TEVA: Membership on an entity9s Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Peschel:MophoSys: Honoraria. Meuleman:Bristol-Myers-Squibb: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Ciceri:MolMed SpA: Consultancy. Schonland:Janssen, Prothena, GSK: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel, accommations, Patents & Royalties, Research Funding, Speakers Bureau. Kroger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Tandem Autologous Stem Cell Transplantation for Multiple Myeloma Patients Based on Response to Their First Transplant-A Prospective Phase II Study.

In this prospective phase II clinical trial, multiple myeloma (MM) patients were randomized to receive a second (tandem) autologous stem cell transplantation (ASCT) based on whether they achieved a partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who achieved a very good partial response or better (≥VGPR) had salvage ASCT at relapse. Seventy-five patients received conditioning therapy and ASCT1. A total of 44 patients (59%) achieved ≥VGPR, whereas 31 patients entered ≤PR and were offered tandem ASCT. In all, 20 patients agreed to tandem ASCT. Demographic and clinical characteristics were similar between the two cohorts except for median lactate dehydrogenase (LDH) (P = 0.0141) and percentage of marrow plasma cells before ASCT1 (P = 0.0047), both lower in the ≥VGPR group. Intent to treat analysis showed that patients who achieved ≥VGPR to ASCT1 had a trend toward improved progression-free survival (PFS) (37 vs. 26 months, P = 0.078) and superior overall survival (OS) (not reached vs. 50 months, P = 0.0073). Patients with ≤PR who declined tandem transplantation had shortened PFS (20 vs. 28 months, P = 0.05) but similar OS (53 vs. 57.5 months, P = 0.29) compared to those who received it. Thus, a favorable clinical response to ASCT1 identifies a low-risk group with superior long-term prognosis despite similar PFS.

Cost and Utilization Of Stored Autologous PBSC To Support Tandem ASCT In MM Patients In The Era Of Novel Agent Therapy

Introduction Historically, autologous stem cell transplantation (ASCT) for multiple myeloma (MM) improves overall survival (OS) compared to conventional chemotherapy alone. Before the introduction of novel agent therapy, tandem ASCT, defined as a second ASCT within 180 days of the first, was an important option for suboptimal responses after an initial ASCT and thus collecting adequate peripheral blood stem cells (PBSCs) for 2 transplants has been considered standard of care. However, the role of tandem transplants is being challenged by novel agent maintenance strategies. Considering this changing landscape of MM therapy, we sought to evaluate the current PBSC collection and storage practices that set the CD34+ cell dose goal to be sufficient for 2 transplants. Methods We obtained clinical, PBSC collection and storage data on MM patients who underwent ASCT from 1993 to 2011 from the Autologous Transplant and Cellular Therapy Laboratory databases at the Fred Hutchinson Cancer Research Center. We determined frequencies and trends of all second ASCTs, including tandem, costs involved in PBSC collection, storage, and utilization of the product that remained cryopreserved for a second ASCT. Cell dose target at our center is 5 x 106 CD34+ cells/kg/transplant. To analyze trends over time, we divided the sample into groups of 3 or 4 year periods. Collection and cryopreservation costs for second ASCT were calculated by first determining the number of days required to collect sufficient PBSC for one ASCT, then the number of additional days to complete the actual collection, and the cumulative costs of long-term storage in our facility. Cost was estimated per July 2012 charges: 1 day PBSC collection $3,016, 1 day processing for cryopreservation $5,955, 1 year storage fees $408 ($34/month). The cost of mobilization chemotherapy and growth factors were not included. Results From May 1993 to June 2011, 889 MM patients underwent PBSC collection and ASCT (111 of 1000 excluded due to incomplete records). Median total PBSC collection days was 2 (range 1 – 10) with median yield of 13.18 x 106/kg CD34+ cells. Median days to collect sufficient cells for one ASCT was 1 day (1 – 9) and 383 patients collected adequate cells for 2 ASCTs after 1 apheresis procedure. Of 889 patients, 135 underwent a second ASCT within a median 14 months (2.5 – 113) of the first. Number of second ASCTs per time period: 1993 to 1995 – 9 of 39 MM patients undergoing ASCT (23%), 1996 to 1999 – 18 of 100 (18%), 2000 to 2003 – 15 of 162 (9%), 2004 to 2007 – 62 of 251 (25%), 2008 to 2011 – 31 of 337 (9%). Fifty patients underwent tandem ASCTs and these accounted for 89%, 72%, 7%, 24%, and 42% of all second ASCTs during the respective periods; the other 85 occurred &gt; 6 months after the first. Number of additional days and associated costs to collect and store PBSC for a second ASCT: 5 days ($44,855), n=1 patient; 4 days ($35,844), n=2; 3 days ($26,913), n=10; 2 days ($17,942), n=41; and 1 day ($8,971), n=211. 637 patients had unused PBSC that remained in storage for ≥ 1 year, with a rising trend over time: 1993 to 1995 – 7 (1%), 1996 to 1999 – 65 (10%), 2000 to 2003 – 77 (12%), 2004 to 2007 – 185 (29%), 2008 to 2011 – 303 (48%). Duration of storage was &lt; 2 years for 34, 2 to 5 years for 346, and &gt; 5 years for 257 patients. Median PBSC storage time was 40 months. PBSC products from 260 patients were discarded (or sent to repository), after a median storage of 54 months, for the following reasons: 5 had allogeneic transplant, 74 were alive and possibly concerned about costs and/or the unlikely need for a second ASCT, 3 had cell viability issues, and 178 patients had died. From January 2009, some patients received plerixafor to achieve the collection goal for 1 ASCT. Its cost was not considered additional. Estimated average cost for PBSC collection, cryopreservation and storage was at least $20,065.96/person and at least $6718.11/person was spent to collect and store PBSC for a tandem ASCT that was never performed. Conclusions Approximately 70% of patients had PBSC products that remained unused and in prolonged cryopreservation after the first ASCT. Estimated cost for collection and storage of PBSC beyond that needed for a single ASCT accounted for roughly 1/3 of total costs. This conventional practice should be reconsidered in view of rising treatment costs, the evolving role of novel agents in maintenance therapy, and the deeper responses achievable with novel agents prior to first ASCT, thus reducing the need for tandem ASCT. Disclosures: No relevant conflicts of interest to declare.

Incidence and Kinetics Of Full Donor Chimerism and The Impact Of Minimal Residual Disease Status Following Outpatient Non-Myeloablative Allogeneic Stem Cell Transplantation For Myeloma

BackgroundChimerism analysis is routinely performed following allogeneic haemopoietic stem cell transplantation (allo HSCT) as a means of monitoring donor engraftment and relapse risk, although its role in the management of allografted myeloma patients is controversial. Multiparameter flow cytometry (MFC) assessment of minimal residual disease has been demonstrated to predict outcome following myeloblative autologous stem cell transplantation (ASCT) in multiple myeloma (MM). Relapse and disease progression is the principle cause of allograft failure and the detection of minimal residual disease (MRD) following tandem autologous/non-myeloablative(NMA) allo HSCT may potentially identify patients at risk of early relapse and provide a platform for early post-allograft therapy designed to further cytoreduce or enhance alloreactive T cell function and graft versus myeloma effect. AimTo evaluate the impact of MRD assessment performed at 3 months post-allo HSCT on PFS and OS and document the incidence and kinetics of full donor chimerism (FDC) in a cohort of myeloma patients undergoing tandem ASCT/outpatient non-myeloablative (NMA) allogeneic HSCT for MM. MethodsRetrospective analysis of 33 MM patients referred to our centre for tandem ASCT/outpatient NMA HSCT between May 2008 and December 2012. Patients were transplanted as part of their front line management (upfront) (n=18) if they had one or more high risk disease features (poor prognosis cytogenetics/FISH abnormalities, elevated LDH, stage III disease or less than a PR following a novel agent-containing induction regimen) or as a ‘deferred' procedure (n=15), if relapsing/progressing after an initial ASCT and maintenance/consolidation. Allo HSCT was undertaken as an ambulatory procedure and conditioned with oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0 followed by donor stem cell infusion, with a target CD34 dose of 2 x 106/kg and T cell dose of 3 x 108/kg. Sequential peripheral blood monitoring of CD3+ and CD33+ donor-specific chimerism was performed on days 30, 60, 90, 180 and 365 following allo HSCT. Bone marrow samples were collected for MRD analysis using MFC incorporating a CD56/CD19/CD45 panel following CD38/CD138 gating on plasma cells. MRD assessment was performed every 3 months during the first 12 months, 6 monthly during the second year and annually thereafter. ResultsThe median age for the entire cohort (M 19, F 14) was 52 years (range 39-65) and the analysis performed after a median follow up of 719 days (50-1733). All patients were transplanted using matched sibling (20/33) or unrelated donors (13/33). Non-relapse mortality was 0% at 1 year and 6% overall. At the time of analysis, 26 (79%) patients were alive including 15 (45%) in CR. The median PFS for all patients was 2.8 years and although the median OS for the entire cohort has not been reached, the estimated probability of overall survival at 4 years is 67% (95% CI: 38-85%). 29/33 (88%) patients had MRD assessments performed at least once post-allo HSCT and 4 patients progressed within 3 months prior to MRD evaluation. At the first 3 month assessment, 11/29 (38%) were MRD +, 12/29 (41%) were MRD – , results were unavailable in 3/29 (10.5%) and 3 (10.5%) patients had morphological evidence of disease. Patients achieving MRD negativity at 3 months had superior PFS in comparison to those who remained MRD positive (median 2.81 years v 1.02 years; p=0.01) but this has yet to translate into an OS advantage. The MRD + patients transplanted as a deferred procedure (n=6) had a median PFS of less than 6 months (0.47 years), suggesting this subset of patients have a particularly poor outcome, although overall numbers are insufficient to directly compare outcome according to MRD status and transplant timing. 30 (91%) patients achieved FDC (16 and 14 in the upfront and deferred groups respectively) with 2 patients not assessed. The median time to FDC for the entire cohort was 180 days (range 30-730) and there was no significant difference according to transplant timing or relationship between FDC and MRD status, GVHD, PFS or PS. ConclusionThe majority of patients undergoing outpatient-based tandem ASCT/NMA allo HSCT for myeloma achieve FDC. MRD status as assessed by MFC at 3 months post-allo HSCT appears to predict PFS and may be a useful early trigger for additional post-allograft therapy, particularly in patients with high risk disease or those transplanted later in their disease course. Disclosures:Spencer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Phase II Study Of V-BEAM (Bortezomib, Carmustine, Etoposide, Cytarabine, and Melphalan) As Conditioning Regimen Prior To Second Autologous Stem Cell Transplantation For Multiple Myeloma

BackgroundHigh-dose melphalan (HDM) has been the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) for decades. Second ASCT is often offered as salvage therapy for patients who relapse after a first ASCT, but while response rates are similar, the progression free survival (PFS) is rarely comparable with that of the first ASCT when HDM conditioning is used for both. BEAM (carmustine, etoposide, cytarabine, and melphalan) is one of the most commonly used conditioning regimens for lymphoma patients undergoing ASCT and all of the components have been shown to be effective in refractory MM, but it has not been tested as a conditioning regimen for ASCT in MM. Bortezomib has been incorporated with HDM as a conditioning regimen for initial ASCT, with promising outcomes and limited toxicities. Based on these findings, we proposed a new conditioning regimen, V-BEAM (bortezomib-BEAM), administered prior to a second ASCT for relapsed/progressive MM, aiming to improve the response rates and PFS of the second ASCT. ObjectivesTo evaluate the safety and efficacy of a new conditioning regimen, V-BEAM, prior to a second ASCT in patients with relapsed/progressive MM after a first ASCT with HDM conditioning. Patient/MethodsPatients with relapsed/progressive MM after a previous ASCT with HDM conditioning were enrolled after 2 to 6 cycles of induction chemotherapy with a bortezomib or carfilzomib based regimen. Patients who had progressive disease on induction chemotherapy were excluded. V-BEAM was administered as the following: Bortezomib 1.3 mg/m2on days -6, -3, +1, and +4, carmustine 300 mg/m2on day -7, etoposide 100 mg/m2 and cytarabine 100 mg/m2 each twice daily on days -6 through -3, and melphalan 140 mg/m2on day -2. On day 0, autologous stem cells (> 2.0x106/kg) were infused. No maintenance or consolidation therapy was given post-transplant. ResultsA total of 10 patients were enrolled from October 2012 to May 2013 at the Siteman Cancer Center. The median age was 64.5 years old (range, 48-68) and 50% were male. Seventy percent of patients were Durie-Salmon stage IIIA at diagnosis, while the remaining 30% were stage IIA. The median time to progression following previous autologous stem cell transplant was 29 months (range, 17-97). The median number of prior therapies (including first ASCT) was 4 (range, 3-6).At the time of abstract submission, one patient has not reached day +100 and two patients expired within 30 days of transplant. For the remaining seven patients, the day +100 response rates include five complete responses (CR) and two very good partial responses (VGPR). To date, no patients have had subsequent disease progression after a median follow-up of 5.0 months (range, 2.3-9.3).Two patients suffered from treatment related mortality (one from neutropenic colitis [Day +18] and the other from sepsis [Day +2]). Serious complications included: neutropenic fevers (100%), diarrhea (grade 3-4, 100%), oral mucositis (all grade, 100%; grade 3-4, 20%), sepsis (30%), Clostridium difficile colitis (30%), and neutropenic colitis without Clostridium difficile (30%). Two patients (20%) had new or worsening peripheral neuropathy, both of which were grade 2 and easily controlled. The median duration of hospitalization was 23 days (range, 19-29). The median duration of neutrophil engraftment and platelet engraftment (>20x109/L) were 10 days (range, 9-11) and 22.5 days (range, 17-36), respectively. The median duration of intravenous antibiotics was 14 days (range, 2-23). Two patients were readmitted shortly following discharge for neutropenic fevers and candida esophagitis, respectively. In June 2013, eight months after study initiation, the decision was made to terminate the study due to excessive toxicity. ConclusionWhile the new conditioning regimen V-BEAM prior to a second ASCT produced promising response rates for relapsed/progressive MM, it resulted in unexpected treatment related mortality and should not be investigated further without modifications. Disclosures:Off Label Use: BEAM regimen as a conditioning regimen for relapsed multiple myeloma. Abboud:Ariad, Alexion, Novartis, Teva: Honoraria, Speakers Bureau. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau. Vij:Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau.

Continuous Infusion Cyclophosphamide and Low-Dose Total Body Irradiation Is a Safe and Effective Conditioning Regimen for Autologous Transplant in Multiple Myeloma

We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m2 over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m2 if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

Successful Treatment With Third Stem Cell Transplant From an Allogeneic Donor for a Patient With Relapsed Diffuse Large B-Cell Lymphoma

High-dose chemotherapy with autologous stem cell transplant is commonly used for diffuse large B-cell lymphoma that recurs after successful salvage chemotherapy. However, in patients in whom the disease recurs again, the prognosis is poor. A 40-year-old woman who underwent allogeneic stem cell transplant 4 years after autologous stem cell transplant developed recurrent diffuse large B-cell lymphoma 3 years after the initial autologous stem cell transplant. She then underwent reduced-intensity hematopoietic stem cell transplant from a human leukocyte antigen-matched, unrelated donor who was not the previous autologous stem cell transplant donor. She achieved a long survival (328 days after the reduced-intensity hematopoietic stem cell transplant and 1844 days after the first allogeneic transplant). A second allogenic transplant may provide survival benefits in a proportion of patients with malignant lymphoma recurring after allogeneic transplant, although careful consideration is required because of the high risk of treatment-related mortality with second allogenic transplant.