Salvage Autologous Stem Cell Transplantation Research Articles

Cost Analysis of Stored Autologous Peripheral Blood Stem Cells for a Second Autologous Transplantation in Multiple Myeloma Patients: A Markov Model

Background: Autologous stem cell transplantation (ASCT) is a standard part of first-line therapy for pts <70 years of age with multiple myeloma. If remission length is ≥ 2 years, our policy is to offer a salvage transplant upon relapse if the patient is eligible. Many centers, including ours, collect adequate CD34+ cells for two transplantations, as there is concern for poor mobilization post-therapy, including lenalidomide. However, no good data truly quantifies this rate, given plerixafor availability. The advent of novel therapies has reduced the use of second salvage ASCT (ASCT2), and the prolonged storage of cryopreserved stem cells imposes a significant economic burden. We performed a cost analysis to compare the cost of mobilizing and storing stem cells for ASCT2 in all patients versus remobilizing and collecting for ASCT2 upon relapse in eligible patients.Methods: We developed a Markov decision-analytic model to compare the two strategies in a hypothetical cohort of 60 year old patients newly-diagnosed with multiple myeloma. The model simulates the clinical course of 10,000 patients over a 10 year time horizon, with the end point of costs per patient per strategy. Baseline probabilities were derived from published studies as well as analysis of multiple myeloma patients who underwent ASCT1 at Princess Margaret Cancer Centre between January 2003 and December 2012. Key health states include probability of progression (pPD) and death in the 1st 2 years post-ASCT1, pPD >2 years post-transplantation, probability of having an ASCT2 upon relapse vs. a non-ASCT approach. Direct costs were collected from a Canadian public health payer’s perspective. Costs were obtained from hospital and provincial databases, as well as the literature and presented in 2016 Canadian dollars. Key costs collected were the cost of mobilization for 2 transplants vs. 1, the cost of remobilization and the cost of stem cell storage. Costs were discounted at 3%. All patients were assumed ASCT2 eligible at relapse. In the re-mobilization arm, all patients were successfully remobilized, with an assumed >50% rate of plerixafor use.Results: 938 patients underwent ASCT1 at Princess Margaret Cancer Centre during this time period, with stem cells stored for a salvage transplant. The mean age of transplanted patients at ASCT1 was 58.4 yrs. The mean number of aphaeresis days required to collect enough cells for 2 stem cell transplants was 1.53 days. The calculated mean aphaeresis days required to collect for 1 transplant was 1.15 days. The median number of bags processed for 2 ASCT was 4, as such, after ASCT1, the median number of bags stored per person was 2. 74 patients (7.9%) underwent ASCT2 over the 10 year period. Most (73%) occurred early, 2-5 yrs post-ASCT1, with only 27% beyond this time period. Over the 10 yr horizon, the total mobilization and storage cost of the stored stem cells strategy was C$9702, versus C$7229 for the re-mobilization strategy, thus storing stem cells for a potential ASCT2 costs an extra C$2473 per patient. Our centre collects such stem cells in >100 pts/yr, at a cost of approximately $250,000. The model was robust to one-way sensitivity analyses of all variables. Storing stem cells only becomes the less costly strategy if the storage costs are less than C$125/6mo or C$10/bag/month (figure 1).Conclusions: The use of salvage ASCT for patients who sustain at least a 2 yr remission with their first is low (less than 10%), and it is associated with significant costs to the system unless the costs of stem cell storage are minimal. With the availability of plerixafor, the cost savings would justify a re-mobilization approach for the minority of patients that are eligible for a salvage ASCT. [Display omitted] DisclosuresPrica:Janssen: Honoraria; Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding. Reece:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria; Oncoethix: Research Funding. Tiedemann:Takeda Oncology: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; BMS Canada: Honoraria. Kukreti:Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria.

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.

Pilot Study of Anti-CD19 Chimeric Antigen Receptor T Cells (CTL019) in Conjunction with Salvage Autologous Stem Cell Transplantation for Advanced Multiple Myeloma

Background: Though CD19 is expressed only rarely on multiple myeloma (MM) plasma cells (PC), rare CD19+ B cells can be identified in MM patients that are clonally related to the MM PC. These clonotypic B cells may exhibit properties of cancer stem cells (enhanced MM-propagating properties and drug resistance compared to MM PC) and thus be a potential therapeutic target in conjunction with therapies that target MM PC. CTL019 consists of autologous T cells transduced via lentiviral vector with an anti-CD19 scFv coupled to CD3-zeta and 4-1BB signaling domains and expanded ex vivo with anti-CD3/CD28-conjugated beads. To target both clonotypic B cells and MM PC, we conducted a pilot clinical trial of CTL019 administered after high-dose melphalan and autologous stem cell transplantation (ASCT) in relapsed/refractory MM patients who had previously undergone first-line ASCT with short progression-free survival (PFS).Methods: Subjects were required to be medically fit for ASCT and have progressed within 1 year of a prior ASCT performed as part of first-line therapy. Study therapy consisted of ASCT with melphalan 140-200 mg/m2 followed by 1-5x107 CTL019 cells 12-14 days later. The primary endpoint was safety and feasibility of CTL019 manufacturing and administration in this clinical setting. Secondary endpoints included assessments of CTL019 in vivo persistence and activity against normal B cells, plasma cell immunophenotype as a response biomarker, and PFS after ASCT + CTL019 in comparison to PFS after initial ASCT.Results: Twelve subjects enrolled, and 10 received study therapy; autologous T cells failed to expand ex vivo in one enrolled subject, and one enrolled subject elected to pursue off-study therapy. Median age was 61 (range 48-68). Median prior lines of therapy was 6 (range 2-10). Poor-prognosis features were present in 8/10 subjects (6/10 with poor-prognosis cytogenetics, 2/10 with BRAF V600E mutations, 1/10 with secondary plasma cell leukemia). Median PFS after first-line ASCT was 258 days (range 100-342). In pre-ASCT bone marrow (BM), the dominant MM PC population was CD19-negative by flow cytometry in 9/9 evaluable subjects, though 7/9 exhibited rare CD19+ subsets comprising 0.05-1.5% of MM PC. Melphalan dose was 140 (N=7) or 200 (N=3) mg/m2. All subjects infused received the maximum target dose of 5x107 CTL019 cells. Adverse events (AE) consisted mostly of expected ASCT toxicities. Grade ³3 AE that were at least possibly related to CTL019 included grade 3 autologous GVHD (N=1, resolved with corticosteroids) and oral mucositis (N=1). Grade 1 cytokine release syndrome occurred in 1 subject. There was no ASCT-related mortality. After infusion, CTL019 cells were detectable in peripheral blood (PB) of all subjects and persisted for median of 44 days (range 14-156). Presence of PB CTL019 cells was associated with absence of PB B cells. Notably, CTL019 cells were detected in BM in 9/10 subjects at day 42 and/or 100 post-ASCT. Median PFS after ASCT + CTL019 was 185 days (range 42-479); all subjects have progressed. The peak BM CTL019 frequency correlated significantly with favorable PFS (SpearmanÕs rho=0.77, P=0.009). There was no association between PFS and peak frequency of CTL019 or duration of CTL019 persistence in PB. In 3/10 subjects, PFS after ASCT + CTL019 met or exceeded PFS after first-line ASCT (Figure). For comparison, in a historical cohort of 18 patients who received first-line and salvage ASCT at our institution since 2008, no patients exhibited longer PFS after salvage ASCT.Conclusion: CTL019 manufacturing and administration post-ASCT is safe and feasible in patients with advanced MM. Correlation of PFS with CTL019 frequency in BM and prolonged PFS in 3 subjects is suggestive of clinical efficacy. A phase-two study of CTL019 using a 10-fold higher dose after first-line ASCT in high-risk MM patients is ongoing. [Display omitted] DisclosuresGarfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Teva: Consultancy; Celgene: Consultancy. Maus:Novartis: Patents & Royalties: related to CTL019, Research Funding. Hwang:Novartis: Research Funding. Vogl:Takeda: Consultancy, Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Constellation: Research Funding; Celgene: Consultancy; Acetylon: Research Funding; Karyopharm: Consultancy. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Weiss:Novartis: Consultancy. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Frey:Novartis: Research Funding; Amgen: Consultancy. Milone:Novartis: Patents & Royalties, Research Funding. Mangan:Novartis: Speakers Bureau. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Ambrose:Novartis: Research Funding. Chen:Novartis: Research Funding. Kulikovskaya:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Johnson & Johnson: Honoraria; Tmunity Therapeutics: Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Immune Design: Consultancy, Equity Ownership; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Honoraria.

Single Centre Experience in Treating Newly Diagnosed t(4;14) Multiple Myeloma with and without Planned Front-Line Autologous Stem Cell Transplant

Introduction: The optimal management of multiple myeloma (MM) patients (pts) with t(4;14) is not certain. Before the introduction of novel agents, the progression-free (PFS) and overall survival (OS) outcomes with autologous stem cell transplant (ASCT) were disappointing (median PFS 9.9 months [mos]; Chang H, et al. Bone Marrow Transplant 2005;36:793). Subsequently, early experience with bortezomib (btz) in relapsed myeloma showed its efficacy in t(4;14) disease, and led to the prospective Canadian trial of 12 cycles of btz-based therapy (DBD = Doxorubicin + btz + dexamethasone) x 4, followed by CyBor-P (Cyclophosphamide + btz + prednisone) x 8 and then dexamethasone maintenance, without planned ASCT, in newly diagnosed pts with this cytogenetic abnormality by FISH (Reece D, et al; Blood 2010;116: abstract 1968). After completion of this trial, particularly with the absence of provincial funding for long-term upfront btz, we adopted a standard approach of btz-based induction followed by ASCT. We now report the results of newly diagnosed t(4;14) pts treated at our centre with these 2 approaches. Methods: We analysed consecutive patients with newly diagnosed MM harbouring t(4;14), who were transplant-eligible and treated at Princess Margaret Cancer Centre with btz-based therapy between July 1, 2006 and June 30, 2014. Patients lost to follow-up (F/U) before completion of front-line treatment or transferred to another centre after first-line treatment were excluded. Statistical analyses were performed using IBM SPSS version 20. Results: A total of 58 patients were analysed with a median F/U of 41.5 mos. The median age at diagnosis was 56.5 years, and 62.1% were male. Concomitant del(17p) was noted in 10.3% of the patients. Thirty-two of these pts (Group A) were enrolled onto the prospective phase II study described above; the other 26 pts (Group B) received the subsequent standard of care, which involved btz-based induction (usually CyBor-D) for 4-6 months, followed by planned ASCT. Amongst these 26 patients, 11 received single ASCT, 13 received tandem ASCT and 2 failed to respond to btz-based induction. The only significant difference in pt characteristics between these 2 groups was a higher median haemoglobin level in group A (116 g/L vs 106 g/L; p=0.003). The median OS was 54.7 months for Group A and 47.6 months in Group B (HR = 1.095, p = 0.817). Median PFS for Group A was 24.2 months and was 30.0 months for Group B (HR = 0.874, p = 0.680). No difference in OS and PFS was noted between those who received single and tandem ASCT as planned front-line treatment (OS HR = 1.105, p = 0.895; PFS HR = 1.723, p = 0.317). Amongst those in Group A, 25 patients have relapsed to date. Eight received single ASCT, 6 received tandem ASCT, and 11 received chemotherapy only as salvage therapy. In Group B, 15 patients have relapsed, and 11 of these went on to receive lenalidomide-based salvage treatment. The PFS and OS from the time of first relapse in this group of relapsed patients in Group A was similar between those who received ASCT as front-line treatment in Group B (median PFS 12.5 vs 11.1 months, p = 0.842; median OS 27.5 vs 21.6 months, p = 0.985). Amongst those who relapsed in Group A, those who received salvage ASCT had a better PFS and OS from the time of relapse than those who did not received salvage ASCT (median PFS 22.4 vs 1.7 months, p Conclusions: Newly diagnosed MM pts with t(4;14) treated with btz-based therapy with or without ASCT as part of first-line therapy have a median OS in the range of 4-4.5 years; 2) the use of ASCT at some time point in the course of t(4;14) disease is likely beneficial; 3) however, there was no obvious benefit for tandem ASCT as part of initial or salvage therapy in this analysis, although we cannot exclude an effect of pt bias in the ability to perform 1 or 2 ASCT; 4) the integration of an IMiD, particularly lenalidomide, in more pts either in combination with btz or as maintenance therapy, may have improved the outcome but was not available for all pts in this analysis; 5) as observed in other centres, the co-existence of del 17p and t(4;14) identifies a particularly high risk group of MM pts. Disclosures Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kukreti:Amgen: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria. Prica:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:Celgene: Honoraria; Janssen: Honoraria; BMS Canada: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda Oncology: Honoraria. Trudel:Celgene: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding; Novartis: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days −4 and −1 before transplantation with melphalan 200 mg/m2 given on day −2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial

The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial. BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up. Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2). Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse. Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.

Improved survival with salvage autologous stem-cell transplantation in myeloma

Improved survival with salvage autologous stem-cell transplantation in myeloma

Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity.

The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.

A Salvage Autologous Stem Cell Transplant (ASCT2) Induces Superior Overall Survival Following Bortezomib-Containing Re-Induction Therapy for Relapsed Multiple Myeloma (MM): Results from the Myeloma X (Intensive) Trial

Introduction: Autologous transplantation (ASCT) in myeloma (MM) is standard consolidative therapy in first line therapy in eligible patients. We have shown definitely that a salvage ASCT in relapse setting can induce superior durability of responses (time-to-progression; TTP) over non-transplant consolidation with oral cyclophosphamide after a proteasome inhibitor-based re-induction schedule (ISRCTN601231201). The secondary end point of this multi-centre phase III randomised controlled trial was to evaluate the impact of salvage ASCT on the overall survival (OS_ of patients relapsing after a prior ASCT and delineate patient subgroups that may benefit the most. Patients and Methods: Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with Bortezomib, Doxorubicin and Dexamethasone (PAD) therapy delivered in 2-4 21-day cycles before 1:1 randomization to either a second ASCT (melphalan 200mg/m2 iv; ASCT2 supported by either stored or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (Non-Transplant Consolidation; NTC). Response was assessed (by IMWG criteria) after re-induction and 100 days post-randomization with TTP being determined as the primary end-point. Patients were stratified by β2microglobulin (β2M) at trial entry, ASCT1 TTP and response to re-induction, analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4;14), t(14;16) and del17p) with OS was a key secondary endpoint. Results: 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n=89, NTC n=85. Median age was 61 (range 38-75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4% with a 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher after ASCT2 (39.3% [95% CI 29.1,50.3] vs 22.4% [95% CI 14.0,32.7]; p=0a012). The median follow-up is 52 months (IQR range 41, 62) and the up-dated TTP demonstrates continued advantage in ASCT2 cohort compared to NTC (19 months [95% CI 16,26] vs 11 months [95% CI 9,12]; Log Rank p 24m (HR0.60, p=0.089), β2M level Conclusion: This long-term follow-up analysis demonstrates a clear advantage in terms of OS when salvage ASCT consolidates bortezomib-based re-induction therapy in patients with MM at first relapse. The delay of salvage ASCT to third line, though being suggestive of benefit over no salvage ASCT, does not confer the same degree of OS advantage as shown with a salvage transplant in second line. This data is key for patient-centered clinical decision-making. 1. G Cook, et al.. The Lancet Oncology, Vol. 15, No. 8, p874-885 Disclosures Cook:Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Sanofi: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Williams:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Snowden:MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Takeda: Honoraria; Autolous: Consultancy; Janssen: Honoraria; Novartis: Consultancy; BMS: Honoraria; Amgen: Honoraria. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Janssen: Other: Educational support; Celgene: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Heartin:Celgene: Speakers Bureau; Janssen: Consultancy. O9Connor:Celgene: Research Funding. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Bayer: Research Funding. Morris:Janssen: Other: Meeting support; Celgene: Other: Meeting support.

Patient-Reported Outcomes (PRO) in the Setting of Relapsed Myeloma: The Influence of Treatment Strategies and Genetic Variants Predict Quality of Life and Pain Experience

Patient-Reported Outcomes (PRO) in the Setting of Relapsed Myeloma: The Influence of Treatment Strategies and Genetic Variants Predict Quality of Life and Pain Experience

Outcomes Following Salvage Autologous Stem Cell Transplant (ASCT2) Vs Low Dose Alkylating Consolidation Therapy Following Bortezomib-Containing Re-Induction for Relapsed Multiple Myeloma (MM) May be Dependent on Age and Symptomatic Status Initiation of Re-Induction: Results from the Myeloma X (Intensive) Trial

Outcomes Following Salvage Autologous Stem Cell Transplant (ASCT2) Vs Low Dose Alkylating Consolidation Therapy Following Bortezomib-Containing Re-Induction for Relapsed Multiple Myeloma (MM) May be Dependent on Age and Symptomatic Status Initiation of Re-Induction: Results from the Myeloma X (Intensive) Trial

Case Report: Pomalidomide as Consolidation Therapy after Salvage Autologous Stem Cell Transplant

Over the past decade there have been many advances in the treatment of multiple myeloma (MM). In the first-line setting, induction treatment followed by high-dose chemotherapy plus autologous stem cell transplant (ASCT) is still considered the standard of care for eligible patients. Maintenance therapy has become a mainstay in MM treatment for both transplant-eligible and eineligible patients and, accordingly, a recent study showed that in both groups maintenance treatment with the immunomodulatory drug (IMiD) lenalidomide led to an improved progression-free survival (1). The vast majority of MM patients will eventually suffer a relapse or progression of their disease. Novel therapies such as pomalidomide(POM), a next-generation IMiD approved for patients with relapsed / refractory myeloma (RRM), and carfilzomib have expanded treatment options and increased progression-free survival. Despite the role of new therapies, salvage ASCT remains an effective and useful tool for many patients. Reinduction therapy followed by salvage ASCT should be considered in patients who have responded well to their initial transplant and have had a progression-free interval of at least 12-18 months (2). It is an open question, however, whether patients will derive a similar benefit from consolidation/maintenance (CM) treatment after salvage ASCT as they do in the first-line setting. In this report, we describe the clinical course of 4 consecutive patients who received CM treatment with POM after salvage therapy with high-dose melphalan (HDM) followed by ASCT. Since POM has received FDA-approval for the treatment of patients with RRM, we have placed 4 patients on CM treatment with POM following

BEAM Conditioning Regimen Has Higher Toxicity Compared With High-Dose Melphalan for Salvage Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Salvage autologous stem cell transplantation (ASCT) is increasingly used for eligible patients with multiple myeloma (MM) for progress after conventional chemotherapy. We recently used BEAM (BCNU, etoposide, cytarabine, and melphalan) conditioning for patients with myeloma receiving salvage ASCT whose disease progressed after a first ASCT with high-dose melphalan (HDM). We report safety and efficacy of BEAM salvage ASCT in MM in comparison with HDM-based salvage ASCT. Between 2008 and 2013, 43 consecutive patients received salvage ASCT for MM (19 with HDM; 24 with BEAM). The BEAM group had a higher incidence of infections, intensive level of care, and fever (19 vs. 13 patients; P = .02), whereas the melphalan group had a higher incidence of mucositis (7 vs. 2 patients; P = .03). Other toxicities were not different. There was no significant difference in disease status and response rate before and after salvage ASCT between the 2 groups. The median time of follow-up after salvage ASCT was 5 and 9 months and the median progression-free survival (PFS) times were 7.7 and 12.1 months (P = .82) for BEAM and melphalan, respectively. BEAM seemed to be associated with higher toxicity with comparable efficacy to HDM ASCT. Longer follow-up is needed to determine whether there is any significant difference in PFS between the 2 groups.

Second Autologous Stem Cell Transplant: An Effective Therapy for Relapsed Multiple Myeloma

Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m2 (n = 43), 180 mg/m2 (n = 1), 140 mg/m2 (n = 22), and 100 mg/m2 (n = 9). The median age at second ASCT was 59 years (range, 36 to 75), and 58% (n = 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval between first and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression-free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P = .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P = .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P = .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies.

Third Autologous Salvage Transplant at Late Myeloma Relapse Is Associated with Favourable Overall Survival and Contributes to Improvement of Exhausted Bone Marrow Function

Background High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been the mainstay of first-line treatment in multiple myeloma for nearly two decades. As the majority of patients (pts.) will experience relapse, we continuously are in need of effective salvage strategies such as the era of the “novel agents” is offering. The “next generation” compounds such as pomalidomide or carfilzomib significantly improve prognosis. However, virtually all drug combinations need to be delivered continuously through (subsequent) disease progression, thereby contributing to exhaustion of bone marrow function. This in turn leads to compromised full-dose treatment, which would be necessary to conquer refractory disease. Given these challenges and considering a long interval since the initial exposure to melphalan (Mel) a further autotransplant seems reasonable. Whether a third autotransplant still is effective in patients who have initially received tandem ASCT and may overcome therapy-induced exhausted bone marrow function is unclear. Therefore, we assessed the outcomes of pts. receiving a third melphalan-based salvage ASCT (ASCT3).Methods We queried the databases of six German myeloma centres for cases that were offered a third autotransplant after uniform melphalan-based tandem ASCT as part of their first-line therapies.Results 55 pts. with a median age of 58 years at diagnosis (range, 36 – 72) and of 63 (range, 38 – 77) at ASCT3 were identified. ASCT3 was performed at a median of 63 (range, 14 – 355) months (mos.) from myeloma primary diagnosis and a median interval from initial tandem autotransplant of 51 (range, 5 – 131) mos. Median progression-free survival (PFS) from primary tandem transplant had been 23 mos. (range, 4 – 94). 45 pts. (82%) had either received bortezomib and/or lenalidomide, and 37 pts. both. Eleven pts. had been double refractory and 23 pts. at least had been refractory to one of the novel agents prior to their 3rd transplant. In 45 cases cytogenetic analysis had been available, of which 9.1% could be classified as ”high-risk” (17p13 del, t(4;14), t(14;16), amp1q21, del1p). At ASCT3, median administered Mel-dose had been 100mg/m2 (range, 30-200). 50 pts. received autografts, which had been harvested at first-line treatment while 5 pts. had successfully undergone additional stem cell mobilisation. Median number of re-infused CD34+ cells was 3.0 (range, 0.4 – 15.7) x 10exp6/kg body weight with all patients achieving stable engraftment. A remarkable improvement of platelet count (PLT) and haemoglobin (Hb) within 3 mos. of ASCT3 could be achieved. PLT improvement occurred in 53% and Hb improvement (when compared to pre-ASCT3 values) in 64% of pts. Beyond that, overall response rate (partial response (PR) or better) was 59% with 8 pts. (15%) achieving CR, 6 pts. (11%) VGPR and an additional 18 pts. (33%) PR, respectively. 23 pts. (42%) suffered from grade 3 non-hematologic toxicities and in one case a grade 4 toxicity was documented. Non-relapse mortality (NRM) within 3 mos. after ASCT3 was 5%. Median PFS after ASCT3 was 6 mos. for the whole group and 2 mos. for the group with “high risk” cytogenetics (p=0,06), respectively, whereas median OS (30 mos.) was identical. In case of double-refractory myeloma, PFS did not differ significantly (3 mos. vs. 7 mos., p=0.35) whereas there was a significant difference in median OS (12 mos. vs. 35 mos., p=0.002) in comparison with non-refractory pts., respectively.Conclusions Our analysis indicates that salvage ASCT at late relapse is feasible and associated with a 6 mos.’ additional PFS interval but also contributes to improved hematopoietic function. Pts. may thus tolerate further conventional lines of treatment what is suggested by an OS of 30 mos. In addition, ASCT offers a substantial treatment-free interval when compared to either “next generation” novel drug. In this series, unfavourable cytogenetics were associated with a trend for worse PFS but not OS outcomes, meanwhile being double refractory was linked with clearly inferior OS. Interestingly, median duration of storage of their autografts of 52 mos. (range, 1 – 154) did not impair engraftment after salvage transplant. DisclosuresNo relevant conflicts of interest to declare.

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study (OMB110928)

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study (OMB110928)

Comparative effectiveness analysis of different salvage therapy intensities used for diffuse large B-cell lymphoma in Northern or Southern Alberta: an instrumental variable analysis

To date, no clinical trial has addressed salvage therapy intensity for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We sought to determine whether the more intensive salvage chemotherapy approach used in Southern Alberta (SAB) compared to the conventional dose salvage approach used in Northern Alberta (NAB) affects the rates of autologous stem cell transplant (ASCT) and survival in patients with relapsed DLBCL. Using instrumental variable analysis, we examined 147 consecutive patients with relapsed/refractory DLBCL from 2004 to 2010 who received salvage therapy in SAB (n = 70) or NAB (n = 77). Patients treated in SAB had higher rates of: salvage chemotherapy response (85.0% vs. 54.0%, p = 0.001), ASCT (61.4% vs. 41.6%, p = 0.016) and 4-year overall survival (41% vs. 20%, p = 0.002) than those in NAB, respectively. This study supports the hypothesis that selective use of intensive salvage chemotherapy leads to higher rates of ASCT and survival in this population.

The role of FDG-PET imaging as a prognostic marker of outcome in primary mediastinal B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that arises in the mediastinum from B-cells of thymic origin. Optimal management of patients with PMBL remains controversial. The present study evaluates outcomes of 27 PMBL patients treated with R-CHOP with or without radiation therapy (RT). It investigates the role of both interim and posttreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) as prognostic markers of outcome. Additionally, it assesses postprogression therapies in the six patients who had progressive disease. At a median follow-up of 41.5 months (range: 6.1–147.2 months), OS was 95.5% (95% CI = 71.9–99.4) and progression-free survival (PFS) was 70.4% (95% CI = 49.4–83.9) for the entire cohort. The negative predictive values of interim and posttreatment FDG-PET scans were both 100%. Patients who failed initial therapy and were treated with salvage regimens and autologous stem cell transplantation (ASCT) all achieved and maintained CR. PMBL patients can achieve excellent outcomes with minimal toxicities when treated with R-CHOP with or without RT. Negative interim and negative posttreatment FDG-PET results identified PMBL patients who achieve long-term remission. However, the significance of both positive interim and positive posttreatment FDG-PET results needs to be better defined. Those who failed initial therapy were successfully treated with salvage regimens and ASCT.

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial

Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. Cancer Research UK.