2nd Autologous Stem Cell Transplant Research Articles

Safety and efficacy of a new high-dose regimen of panobinostat, gemcitabine, busulfan, and melphalan for 1st or 2nd salvage ASCT for refractory/relapsed or high-risk myeloma: Matched-pair comparisons with concurrent control cohorts.

Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response at ASCT. We enrolled 80 patients, 48 and 32 in the ASCT-1 and ASCT-2 cohorts, respectively; in these two cohorts, high-risk cytogenetics were noted in 33 and 15 patients, respectively; unresponsive disease in 12 and 11 patients, respectively, after a median of 2 and 3 therapy lines, respectively. Transplant-related mortality (TRM) occurred in two ASCT-2 patients. One-year PFS rates were 69% (ASCT-1) and 72% (ASCT-2); 1-year OS rates were 79% (ASCT-1) and 84% (ASCT-2). Minimal residual disease negativity improved after ASCT-1 (8.5%-23%, p < .0001) and ASCT-2 (34%-55%, p = .02), which correlated with improved outcomes. Trial patients and controls (N = 371) had similar TRM and post-ASCT maintenance. Trial patients had better PFS after either a 1st (p = .02) or a 2nd ASCT (p = .04) than matched-paired control patients. In conclusion, panobinostat/GemBuMel is effective for relapsed/refractory or high-risk myeloma patients, with better PFS than concurrent matched controls receiving melphalan or BuMel.

Second Line Treatment and Outcomes of Patients with Multiple Myeloma: A Real World Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Introduction: The treatment of multiple myeloma (MM) has evolved rapidly, with various combinations of immunomodulators (IMiDs), proteasome inhibitors (PIs), corticosteroids and autologous stem cell transplantation (ASCT) utilized in newly diagnosed (ND) patients; in some jurisdictions, monoclonal antibodies (MABs) are also incorporated in first-line treatment. Over the last decade, the standard of care in Canada for NDMM in fit younger patients has consistently been induction (CyBorD/more recently RVD) followed by ASCT and maintenance lenalidomide (len) until progression. In transplant-ineligible patients, bortezomib- or len-based treatments in doublets or triplets have been used frontline. At relapse, options have included re-induction followed by 2nd ASCT or doublet/triplet combinations until progression. Limited comparative data are available to support any one approach. The aim of this retrospective study was to assess the treatment patterns and outcomes of MM patients treated at 1st relapse in a real-world setting. This data may be useful to myeloma stakeholders when evaluating the potential impact of even newer novel immunotherapeutic agents in patients in who have had 1 prior line of treatment. Methods: We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), which is a prospectively maintained disease-specific database with ≥ 9000 patients enrolled from 16 academic sites across Canada. All MM patients who initiated second-line therapy between 01/12/2010 - 30/06/2022 were included and results were analyzed up to 23/05/2023. We aimed to evaluate the following outcomes for each second-line regimen: overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), calculated from the start of second-line therapy. Survival was estimated using Kaplan-Meier methods and compared between groups using the log rank test. Results: A total of 3569 patients were identified: 1638 (45.9%) who had prior ASCT and 1931 (54.1%) non-ASCT patients. 2715 (76%) patients were bortezomib-exposed in first line, 1052 (30%) were lenalidomide-exposed; 22% had high-risk cytogenetics. The most commonly used second-line regimens were Rd in 1325 (37%) of patients, DRd in 346 (10%), CyBorD in 291 (8%), 2nd ASCT in 270 (8%), RVd in 201 (6%) and DVd in 167 (5%). Outcomes including ORR, ≥ VGPR rate, PFS and OS from second-line treatment for regimens with &amp;gt;50 patients are presented in Table 1. Among all patients, the highest ORRs were seen with DRd (90%), 2nd ASCT (89%), Kd/KCd (79%), RVd (78.1%) and KRd (74%); DRd had the highest ≥ VGPR rate (66%). In patients who had received bortezomib-based first line treatment, the second line ORRs were 96%, 98% and 95% for VRd, KRd and DRd, respectively, with a corresponding median PFS of 20 months (VRd), 19 months (KRd) and 28 months (DRd). For patients who had len-based first line treatment, the second line ORRs were 80% for Kd/KCd and 95% for DVd with a median PFS of 16 months (Kd/KCd) and 11 months (DVd), respectively. The median PFS was 41 months after 2 nd ASCT; of these patients, 68% were exposed to bortezomib in first line and 34% were len exposed in first line. The median PFS was 30 months in those who had len maintenance after their 1 st transplant compared to 60 months in those with no initial maintenance. Conclusion: In this real-world observational study we demonstrate that Canadian patients achieved results comparable those noted in prospective clinical trials leading to the approval of these agents in the second-line setting. Triplet combinations with an IMID backbone, including DRd, KRd and Ixa-Rd, had high response rates, with DRd offering the longest PFS. Patients undergoing 2 nd ASCT had ORRs and PFS comparable to DRd, although these results were likely influenced by selection of a population with a favorable response to 1st ASCT . Given the expanding use of IMID, PI and MAB combinations in first-line, our results highlight the need for better modalities at the time of 1 st relapse. Earlier integration of “novel” agents, including CAR-T therapy, bi-specifics, conjugated antibodies and CEL-MoDs-even in the second-line setting–is likely required to improve on these outcomes. The current analysis provides efficacy benchmarks to guide their implementation. Financial Support: CMRG received financial support from Janssen Inc. for the conduct of this study

Second Autologous Stem Cell Transplant as Salvage in Multiple Myeloma – The Oregon Health and Science University Experience

Background: Second autologous transplants (SAT) are routinely performed in the setting of myeloma relapse, though data on outcomes are lacking. We conducted a single-center review of all multiple myeloma patients at OHSU who received SAT (excluding tandems) with responses assessed by International Myeloma Working Group (IMWG) criteria. Results: Sixty-eight patients received SAT between 1999 and 2019. Risk by IMWG was available for 50 patients (10 high-risk). Median age at SAT was 61 (45-74). Median time between 1st and 2nd Autologous stem cell transplantation (ASCT) was 5.5 years (1.1 - 15.2). Median progression-free survival (PFS) after 1st ASCT (available for 53 pts) was 2.5 years (0.3 - 10). The average # of lines of therapy prior to SAT was 2.8 (1-14). SAT prep regimens (available for 67 pts) were: Fifty-one (87%) melphalan 200 mg/m2, 6 (9%) melphalan 140 mg/m2, 1 (2%) BEAM, 1 (2%) melphalan 200 mg/m2 and bortezomib. All used PBSC mobilization. Median overall survival (OS) after SAT was 4.68 years, and median PFS was 1.72 years. By treatment era (1999-2009 vs. 2010-2019), median OS was 1.97 vs. 5.52 years (P = .15). When analyzed by IMWG group (standard/low vs. high risk) median PFS and OS were not significantly different (1.87 vs. 1.61 years and 3.58 vs. 5.91 years, respectively). Treatment-Related Mortality (TRM) occurred in 1 patient (2%). Conclusion: Our experience with SAT for multiple myeloma (MM) shows that it has low TRM and is effective, with median OS >4.5 years, though with a shorter PFS than after 1st ASCT.

Second Autologous Stem Cell Transplantation in Poor Stem Cell Mobilizers Multiple Myeloma Patients

Second Autologous Stem Cell Transplantation in Poor Stem Cell Mobilizers Multiple Myeloma Patients

Prognostic Impact of Tandem Autologous Stem Cell Transplantation (ASCT) in Different Response Subgroups after 1st ASCT

Prognostic Impact of Tandem Autologous Stem Cell Transplantation (ASCT) in Different Response Subgroups after 1st ASCT

Impact of Daratumumab on Stem Cell Collection, Graft Composition and Engraftment Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as &amp;lt; 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC &amp;gt;1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count &amp;gt;20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, &gt;3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or &gt;3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

20 Years of Transplant Program in Multiple Myeloma - a Single Centre Experience

Aims: The aim is to present the results of 20 years of autologous stem cell transplant (ASCT) program in multiple myeloma (MM) at our site.Patients and methods: Since 1997 till 2017, a cohort of 348 patients underwent ASCT at the Department of Hemato-Oncology of the University Hospital Olomouc. Altogether 274 were 1st ASCT, 62 were 2nd transplants, the rest were tandem or third ASCT. The patients had standard baseline characteristics, including age, gender, immunoglobulin and light chain type, Durie-Salmon (DS) and International Staging System (ISS).The induction regimens for 1st ASCT included VAD (vincristin, adriamycine, dexamethasone) in 34%, THAL in 15%, BTZ based regimens in 34%, the rest (17%) were combined polychemotherapeutic regimens. The re-induction regimens before 2nd ASCT included CAD (cyclophosphamide, adriamycine, dexamethasone) in 27%, BTZ in 31% and THAL based regimens in 18%, other patients (24%) had LEN based regimens, polychemotherapy or no re-induction. 163 patients (47%) had maintenance, mostly interferon based (25%), conventional chemotherapy based (9%) or THAL based (7%), and 53% of patients had no maintenance.We assessed response rates, ie the rate of complete remission (CR), very good partial remission (VGPR), partial remission (PR), minimal response (MR), stable disease (SD), progressive disease (PG) and overall response rate (ORR) based on International Myeloma Working Group (IMWG) criteria. The survival measures of individual treatment lines were assessed by means of progression free survival (PFS). We assessed the efficacy of ASCT with respect to treatment line, pre-transplant and post transplant response achieved (day+100), and with respect to DS and ISS as well as to treatment modality used for induction and maintenance.For statistical estimation we used Kaplan-Meier curves, Log rank test (Mantel-Cox), Post-hoc tests according to Dunn, Pearson ChiSquare test, Fisher´s Exact Test, Kruskal-Wallis test, and McNemar-Bowker Test.Results: The response rates after 1st ASCT were following: CR 32,1%, VGPR 26,5%. PR 34,8%, MR and SD 3% and PG 3,4%. Median PFS after 1st ASCT was 35 months and it corresponded to the depth of treatment response: CR 48 months, VGPR 36 months, PR 33 months, MR and SD 13 months, PG 9 months, p<0,0001. Pre-transplant responses showed a trend towards better outcomes with deeper responses but beyond statistical significance (p = 0,077). Advanced DS stage correlated with worse PFS (stage I 58 months, stage II 42 months, stage III 31 months). Patients under age 59 years tended to have slightly better PFS (37 vs 34 months, p = 0,078).Both pre and posttransplant responses were significantly better after novel drugs than conventional chemotherapy, still, there was no statistically significant difference in PFS. None of the maintenance (chemotherapy, interferon, THAL-based) lead to a better PFS. There were very few patients treated with BTZ, LEN or ixazomib maintenance precluding valid statistical analysis. There were no differences in either responses or PFS with regard to treatment line but there were only 19 patients not having ASCT as their first regimen.The response rates after 2nd ASCT were as follows: CR 26,7%, VGPR 13,3%, PR 38,3%, MR+SD 8,3% and PG 13,3%. Median PFS after 2nd ASCT was 20 months, decreasing with inferior responses (CR 34,8 months, VGPR 22,5 months, PR 33,1 months, MR and SD 18,8 months, PG 6,6 months p<0,0001). There were no differences in PFS with respect to either ISS, DS stage or re-induction regimen. Patients transplanted in their first relapse tended to have better PFS than in later relapses.Conclusion: The use of ASCT is still the gold standard in MM. Regardless of treatment line, it achieves significant outcomes. Novel drugs induce deeper pre-transplant responses, still, the major advantage against conventional chemotherapy is in the speed of response and absence of severe adverse events, enabling more patients to reach ASCT. Maintenance therapy accounts for better survival, however, this is true only for novel drugs (such as bortezomib, lenalidomide) whereas older modalities including interferone, post-transplant chemotherapy, steroids or thalidomide do not possess such activity. The second ASCT is comparable to to current treatment modalities in relapsed MM with fair post-transplant outcomes as well as PFS, with high rate of complete responses.Supported by the grant IGA-LF-2018-004 andMH CR - RVO (FNOl, 00098892). DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Consolidation Following Upfront ASCT for Multiple Myeloma Deepens Disease Response and MRD-Negative Rate without Compromising Response to Subsequent Bortezomib Salvage: Results of a Phase II Study

Background: Consolidation after high dose therapy and autologous stem cell transplant (ASCT) for multiple myeloma (MM) can improve response depth and prolong progression free survival (PFS), but it is important to ensure good quality of life (QoL) and responsiveness to further salvage therapy. We conducted a single-arm Phase II weekly bortezomib consolidation trial (BCT) to assess outcomes in MM patients receiving upfront ASCT.Methods: Bortezomib-na•ve patients with at least stable disease at 3-4 months post-high dose melphalan 200mg/m2 with ASCT received up to 8 cycles of bortezomib (1.3mg/m2 days 1,8,15,22 in a 4-week cycle), 17 intravenously (IV) and 23 subcutaneously (SC). The primary endpoint was disease response (IMWG) at 6 and 12 months post-ASCT. Other endpoints were MRD by multiparametric flow cytometry (patient 15 onwards) at 6 and 12 months post-ASCT, toxicity, PFS, overall survival, osteoblast function and Qol (EORT-QLQ-C30). Serum basic alkaline phosphatase (bALP) and ostocalcin (OC) were measured by ELISA.Results: The study recruited 40 patients between December 2009 and March 2014 at a median of 3.4 months post-ASCT. The median age was 61 years (range 43-69); 55% male; isotypes were: 22 (59%) IgG, 9 (24%) IgA, 1 (3%) IgD, 5 (14%) light chain only, 1 non-secretory and 2 unknown. Induction regimens pre-ASCT were thalidomide (33, 87%), idarubicin and dexamethasone (5, 13%). and unknown in 2.One patient was withdrawn prior to commencement (unfit for treatment) and 3 patients stopped trial treatment after 1 cycle (2 toxicity, 1 disease progression). Of 36 patients who completed >1 cycle of bortezomib, 10 stopped treatment early (5 toxicity, 4 patient choice, 1 disease progression); median number of cycles received was 8. Eleven (28%) patients experienced a total of 15 grade 3 adverse events (AE); 6 (neuropathy, 3 in IV group, 18% cf 3 in SC group, 13%), 4 (infection), 1 (fatigue), 2 (haematological), 2 other. One patient had a grade 4 infection (cycle 1, treatment discontinued) and 1 grade 4 back pain. EORTC-QLQ-C30 scores for global health status and physical, emotional and social functioning did not change significantly throughout treatment.After a median follow up of 44.4 months, 18 (45%) are alive without progression, 20 (50%) are alive with progression and 2 (5%) died after progression. BCT improved response depth in assessable patients who completed >1 cycle (n=34). Disease response at trial entry: 4 (12%) sCR/CR, 19 (56%) VGPR, 10 (29%) PR, 1(3%) SD, cf. response at 12 months post-ASCT: 7 (21%) sCR/CR, 22 (65%) VGPR, 4 (12%) PR, 1(3%) PD. Biochemical response depth improved in 12 patients. 19 patients had MRD testing at 3 (where available) or 6 months post-ASCT and again at 12 months, 10 were MRD+ at the earlier time point, of whom 4 converted to MRD- at 12 months. Of the 9 MRD- patients, all remained negative at 12 months. 15 patients (44%) had improvement in biochemical and/or MRD response at 12 months.Median PFS was 38.5 months (95%CI 29.1-47.9)(Figure). Patients who were MRD- at 12 months had median PFS of 49.2 months (95%CI 35.3-63.2) compared with 22.0 months (95%CI 21.5-22.6) in MRD+ patients (p=0.03).Of the 22 patients who relapsed, 12 received bortezomib-based salvage regimens, 5 received carfilzomib-based regimens and 5 have not started second-line therapy. Disease responses in patients receiving bortezomib salvage was 8 (67%) VGPR, 4 (33%) PR. Four patients went on to have a 2nd ASCT. In the 17 patients receiving salvage, median 2nd PFS from start of second line was 14.8 months (95%CI 8.2-18.0).At 3 months post-ASCT, levels of the osteoblast markers bALP and OC were significantly higher in CR/VGPR patients, compared to patients with PR or less (p=0.04 and 0.03, respectively). Neither marker changed significantly following BCT.Conclusions: For patients with MM, consolidation with weekly bortezomib post-ASCT is well tolerated and deepens disease response and MRD negativity without compromising the response to subsequent bortezomib-based salvage therapy. Patients who are MRD- at 12 months enjoy a median PFS of 4 years. This low intensity post-ASCT strategy deserves further study in the context of current and evolving protocols for newly diagnosed patients. [Display omitted] DisclosuresYong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Newly Diagnosed Myeloma (MM) Patients (Pts) with High-Risk (HR) Cytogenetics By FISH: Is There a Role for Tandem Autologous Stem Cell Transplantation (ASCT)?

Background: Recent analyses have suggested that newly diagnosed multiple myeloma (MM) patients with the high-risk (HR) chromosomal abnormalities del 17p and t(4;14) detected by FISH may benefit from bortezomib (BTZ)-based induction therapy and tandem autologous stem cell transplantation (ASCT) (Sonneveld P et al, J Clin Oncol 2013;31: 3279). At Princess Margaret Cancer Centre, we have offered upfront tandem ASCT for HR pts with del 17p, t(4;14) and/or t(14;16) and now retrospectively review the results of this approach.Methods: After obtaining Institutional Research Ethics Board approval, we used Princess Margaret Myeloma Database to identify HR MM pts who underwent tandem ASCT between June 2005 and January 2015. We performed a retrospective chart review to investigate the survival outcome of this group of patients.Results: Between 06/05 and 01/15, 52 HR pts underwent tandem ASCT at Princess Margaret Cancer Centre. 21 had del 17p, 20 had t(4;14), 5 had t(14;16), 3 had both t(4;14) + del 17p and 3 had both t(14;16) + del 17p. Median age was 56.5 yrs (range 31-71); 34 were male. ISS stage was I in 12, II in 15, III in 12 and N/A in 13 pts. The majority (42 pts) received BTZ-based induction therapy which consisted of CyBorD in 38; 11 pts required a 2nd regimen before ASCT. The median time from diagnosis to 1st ASCT was 6.7 mos (range 4.8 -45.7) and the median time between transplants was 3.7 mos (range 0.9- 6.6); 30 pts received lenalidomide (len) between ASCTs to prevent early relapse. All but 2 pts (96%) received maintenance therapy after the 2nd ASCT which included thalidomide in 7 (13%), len +/- steroids in 39 (75%) and BTZ +/- len in 4 (8%) of all pts. Thirty-six (69%) received both BTZ-based induction and len maintenance after the 2nd ASCT. No transplant-related deaths occurred. Median follow-up is 26.3 mos (range 9.1 to 104.3).The median overall survival in all 52 pts from diagnosis was 31.1 mos (range 11.9 to 110.8) with a median PFS of 24.0 mos (9.1 to 83.6); median survival after progression was only 8.2 mos (0.1-62.8) mos in the 16 pts who relapsed after the 2nd ASCT. Table 1HR Group#Calculated from diagnosisCalculated from 2nd ASCTMedian PFS, mos (range)Median OS, mos (range)Median PFS, mos (range)Median OS, mos (range)t(4;14)2322.4 (11.4-58.1)29.9 (17.7-84.4)7.0 (0.2-23.5)17.3 (5.4-73.6)Del 17p2724.4 (9.1-83.6)35.0 (11.9-110.8)11.2 (1.3-69.4)25.3 (3.8-99.6)t(14;16)827.4 (10.3-55.4)30.6 (11.9-55.4)16.9 (2.2-48.1)19.7 (3.8-48.1)Both BTZ-induction + len maint3622.2 (10.3-55.4)30.5 (11.9-67.5)8.1 (1.4-48.1)18.7 (3.8-57)No BTZ-induction + len maint1627.2 (9.1-83.6)49.5 (22.0-110.8)12.1 (0.2-69.4)24.5 (6.9-99.6)Conclusions: 1) MM pts with HR cytogenetics, particularly those with t(4;14), have a short PFS and OS after tandem ASCT; 2) even following BTZ-based induction therapy and len maintenance, outcomes with tandem ASCT are suboptimal in HR pts; 3) further investigations are necessary to identify novel strategies for the management of HR MM in the era of modern therapeutic agents. DisclosuresChen:Celgene: Consultancy, Honoraria, Research Funding. Kukreti:Janssen Ortho: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Tiedemann:Janssen Ortho: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Trudel:Oncoethix: Research Funding; Novartis: Honoraria; Trillium Therapeutics Inc.: Research Funding; BMS: Honoraria; Amgen: Honoraria, Speakers Bureau; Celgene: Equity Ownership, Honoraria, Speakers Bureau. Reece:Lundbeck: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Research Funding; Merck: Research Funding; Millennium Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Research Funding.

The Efficacy and Long-Term Outcomes of ASCT in POEMS Syndrome: A Multicenter Retrospective Study in Japan

Backgrounds: POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, l-type M protein, VEGF elevation and systemic manifestations. The standard treatment of the disease has not been established through clinical trials, but autologous stem cell transplantation (ASCT) has been shown to be effective in patients with the syndrome. However, the efficacy and long-term outcomes of POEMS patients underwent ASCT have not been systematically studied.Purpose and Methods: To clarify the efficacy and long-term outcomes of the patients underwent ASCT, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) TRUMP database. The definition and evaluation of response and progression/relapse was according to the criteria of Mayo Clinic (Blood.2012; 120:56-62).Results: Between January 2000 and December 2011, 94 patients were registered to the TRUMP database, male 57 and female 37, with the median age of 52 years (range 28-72). All patients underwent PBSCT except for one who received both PBSCT and BMT. Two patients underwent 2nd ASCT. The median time to ASCT from the time of diagnosis of POEMS was 205 days (range: 16-3870 days). Peripheral blood stem cells were collected using either cyclophosphamide with G-CSF, G-CSF alone, or etoposide with G-CSF as mobilizing agents with a median of 1 apheresis procedure. Thirteen of the 68 patients (19.1%) needed additional harvest procedures, and two patients received G-CSF with plerixafor. Median total collected CD34+ cell dose was 4.0x106/kg (0.6-37.2x106/kg).The conditioning regimen was melphalan in 93/94 (99%): 68 patients (70.8%) received melphalan ≥ 200 mg/m2. Median infused CD34+ cell dose was 3x106/kg (0.02-20x106/kg). Periengraftment syndrome was recognized in 11 of the evaluable 68 patients (16.2%). After ASCT, patients’ performance status (PS) was dramatically improved (ECOG PS 3-4; 33.7% to 8.2%). The best initial responses were as follows: hematologic response; CRH/VGPRH/PRH 38/51 (74.5%), NRH 13/51 (25.4%), clinical response; CR/PR 56/61 (91.2%), SD 4/61 (6.6%), PD 1/61 (1.6%), VEGF response; CRv/PRv 34/35 (97.1%), NRv 1/35 (2.9%). 17 patients relapsed/progressed after ASCT. Four patients had radiographic relapse, 7 patients had symptomatic progression, and 10/12 (83.3%) patients had elevated VEGF. There was no hematologic relapse/progression. With the median follow up of 26 months (range 1-102 months), 10 patients died and the overall survival at 4 years was 89.9%. Sixteen patients received post-transplant treatment (planned tandem ASCT:1, steroids: 7, Bor: 1, Thal: 11, Ren: 9, VAD: 1, RT: 1). The causes of death were; disease progression (4), infection (3; PCP 1, bacterial 2), and others (3).Conclusion: We show the long-term outcomes of patients with POEMS syndrome treated with ASCT. These data suggest the promising role of ASCT in patients with POEMS syndrome both in producing prolonged survival and improving quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High-Dose Gemcitabine Combined With Busulfan and Melphalan (Gem/Bu/Mel) With Autologous Stem-Cell Transplant (ASCT) In Refractory and Relapsed Myeloma

IntroductionMore active high-dose (HD) regimens are needed for refractory myeloma, where single-agent melphalan offers poor outcomes. Registry data suggest that busulfan/melphalan might be superior to melphalan in 1st-line treatment of chemosensitive patients. While gemcitabine has potent activity in vitro against resistant myeloma cell lines, this drug has shown little activity in patients with resistant myeloma when tested in short 30-min infusions. Gemcitabine cytotoxicity correlates with the intracellular accumulation of its active triphosphate metabolite, which is optimized when infused at a fixed dose rate (FDR) of 10 mg/m2/min. We previously developed a HD regimen of Gem/Bu/Mel, infusing gemcitabine at FDR and exploiting its inhibition of DNA damage repair, with a manageable toxicity profile. In its phase 1 trial (Nieto, BBMT 2012) Gem/Bu/Mel showed some encouraging signs of activity in patients with refractory myeloma. Thus, we wished to study Gem/Bu/Mel in refractory myeloma patients who either had an estimated CR likelihood <15% with high-dose melphalan or had disease that previously failed HD Mel, whose median PFS after a 2nd ASCT is typically ≤1 year (Qazilbash, Cancer 2006; Michaelis, BBMT 2013). MethodsPatients ages 18-70, with myeloma treated in 1st-line therapy with lenalidomide, bortezomib or thalidomide, plus ≥1 of the following 3 criteria: no response to 1st-line therapy, relapse after 1st-line therapy, or relapse after prior ASCT, along with adequate end-organ function, were eligible for this phase 2 study. Gemcitabine was given on days -8 and -3 as a loading dose of 75 mg/m2 followed by FDR infusion of 1,800 mg/m2. Busulfan was given on days -8 to -5 targeting AUC 4,000/day x 4. Melphalan was given at 60 mg/m2/day x 2 (days -3 and -2). The primary study endpoint was CR rate (determined by day 100 before starting maintenance treatment); secondary endpoints were CR+VGPR, RR, PFS and OS. This trial was sized with >85% power to detect a CR rate ≥20%, which was considered clinically significant. ResultsBetween 11/10 and 6/13, 60 patients were enrolled, all of whom had failed at least 1 line of therapy (Table).Age57 (39-65)ISS stage at diagnosis124 (40%)218 (30%)318 (30%)Median # prior lines of treatment (range)3 (2-10)Primary refractory (IMWG criteria: never achieved a minimal response or better with any therapy)9 (15%)Relapsed and refractory (IMWG criteria: nonresponsive while on salvage therapy or progressive within 60 days of last therapy)24 (40%)High-risk cytogeneticsOverall20 (33%)17p-9 (15%)t(4;14) or t(14;16)4 (7%)1q+6 (10%)Cytogenetic 13q-6 (10%)Extramedullary disease5 (8%)Renal failure at diagnosis15 (25%)Hypercalcemia at diagnosis10 (17%)Prior ASCT25 (42%)Status at HDC (CR / PR / no response)9 / 30 / 21PD at HDC14 (23%)Neutrophils and platelets engrafted on d+10 (8-13) and d+11 (9-16), respectively. There were 3 treatment-related deaths (4.9% TRM: 1 pneumonia, 1 cardiac arrest with unrevealing autopsy, 1 E coli sepsis). Toxicities: mucositis (50% G2, 18% G3), rash (20% G2, 6% G3), asymptomatic transaminase elevation (17% G2, 8% G3) and bilirubin elevation (3% G2, 10% G3) (no cases of VOD), with no renal, cardiac, neurological or pulmonary toxicity. Among 49 patients with measurable disease at transplant and evaluable for response, the CR rate was 24.5% (95% CI, 16-32.5%), 42% CR/VGPR rate (36-50%), and 77.5% RR (71-83%). Posttransplant maintenance was given to 38 patients, using lenalidomide (N=23), bortezomib (N=11), thalidomide (N=3) and bendamustine (N=1). At median f/u of 16 months (range, 2-31), the PFS and OS rates are 55% (median 15 months) and 77% (median not reached), respectively (Figure). In the subset of 25 patients receiving Gem/Bu/Mel as a 2nd salvage ASCT, there were 1 CR, 2 VGPR and 7 PR for a CR+VGPR of 19%, RR 62.5%, with 52% PFS (median 15 months) and 68% OS (median NR). In the subset of 20 patients with high-risk cytogenetics (N=20), there were 28% CR, 56% CR+VGPR and 83% RR, with 55% PFS (median 14 months) and 80% OS (median NR). [Display omitted] ConclusionsGem/Bu/Mel is a safe and highly active HD regimen in refractory myeloma and warrants its further study in earlier stages of this disease. Disclosures:Nieto:Otsuka Pharmaceuticals: Research Funding. Off Label Use: Gemcitabine not approved for myeloma. Qazilbash:Otsuka Pharmaceuticals: Research Funding.

Continuous Infusion Cyclophosphamide and Low Dose Total Body Irradiation (CICy/ldTBI) As a Conditioning Regimen for Tandem Autologous Transplant in Multiple Myeloma

AbstractAbstract 4524 Background:Cytotoxic therapy and autologous stem cell transplant (ASCT) remain the mainstay of multiple myeloma (MM) treatment due to both depth of remission as well as relative safety. Improvements in event free survival (EFS) and overall survival (OS) have been reported in patients undergoing tandem transplant. High-dose melphalan (200mg/m2) is one of the most widely used conditioning regimens. Its use, however, is associated with high levels of toxicity with transplant related mortality (TRM) approaching 5% in some studies. When total body irradiation (TBI) is added to melphalan, the risk of infectious complications and TRM increase. Methods:Between June 2001 and July 2011, 21 MM patients underwent tandem ASCT at our institution as part of a prospective phase II clinical study. The patients received cyclophosphamide (CY), busulphan, and etoposide as a conditioning prior to their first ASCT. Patients were assessed after the first ASCT and offered either 2nd tandem ASCT if they achieved ≤ partial remission (PR) or maintenance therapy if they achieve ≥ very good partial remission (VGPR). For patients undergoing tandem ASCT, a novel conditioning regimen was used which included: cyclophosphamide 1500mg/m2/day continuous IV infusion on day -7 through day -4 followed by twice daily TBI at 150 cGy on day -2 and -1. Melphalan 140 mg/m2was substituted for TBI if prior radiation did not allow for further irradiation.The median patient age was 59 years (51–70) and the group consisted of 10 males and 11 females. 17 patients received CICy/ldTBI while 4 patients received CY/melphalan due to prior history of radiation. At the time of the 2ndASCT, 18 patients were in PR, 2 were in VGPR, and 1 had progressive disease (PD). Information regarding the duration of neutropenia, presence of neutropenic fever, infectious complications, and transfusion requirements were collected. Treatment response assessment was based on the uniform response criteria published by The International Myeloma Working Group. Results:Median duration of neutropenia with CICy/ldTBI was 10 days (range, 8–20). 16 patients (76.2%) developed at least one neutropenic fever episode of >38° C. After fever, mild diarrhea was the most common adverse effect (42.9%). 1 patient each (4.8%) developed a limited subdural bleed, pulmonary embolus, neutropenic colitis, bacterial pneumonia, possible fungal pneumonia, hemorrhagic cystitis, and septic shock. 19 patients (90.5%) required transfusion support (red blood cells, platelets, or both) in the post-transplant period. Grade I-II mucositis was seen in 4 patients. All patients were alive at D100. After tandem transplant, 4 patients had entered complete remission (CR) (19.0%). There were 7 VGPR (33.3%) and 6 patients were in PR (28.6%). The median progression free survival (PFS) and overall survival (OS) was 20 and 38 months, respectively. Conclusions:Our results suggest favorable outcomes without TRM in a selected group of high risk myeloma patients who receive CICy/ldTBI as a conditioning regimen prior to their second tandem ASCT. Disclosures:No relevant conflicts of interest to declare.

Response Post-First Autologous Stem Cell Transplantation for Multiple Myeloma May Identify Patients Who Will Benefit From Tandem Transplants: A Single Center Prospective Phase II Study- an Update

AbstractAbstract 2023 Background:The role of tandem and salvage autologous stem cell transplant (ASCT) in multiple myeloma (MM) has been a subject of interest for many myeloma investigators. Further, the role of tandem ASCT in patients achieving very good partial remission (VGPR) or complete remission (CR) has not been studied prospectively. Methods:We conducted a prospective phase II clinical trial in which enrolled MM patients are assessed after the first ASCT. Patients achieving ≤ partial remission (PR) were offered 2nd tandem ASCT followed by maintenance therapy. Patients that were found to be ≥VGPR were offered maintenance therapy followed by salvage ASCT at the time of relapse.Busulfan 0.75 mg/kg PO q 6 hr days -8 through -5, Cyclophosphamide (Cy) 60 mg/kg IV days -3 and -2, and Etoposide 10 mg/kg IV days -4 to -2 were used as the conditioning regimen for the first ASCT. Patients receiving a second ASCT received 96-hour (days -6 to -3) continuous IV Cy 6 gr/m2 and low dose total body irradiation (loTBI) 600 cGy (days -2 and -1). Etoposide was omitted if patients were ≥65 years. Melphalan 140 mg/m2 was used in lieu of TBI if prior irradiation did not allow for TBI. Results:Between the years 2001–2009, 76 patients were enrolled into the study. 54 patients achieved ≥VGPR. 31 patients had ≤ PR and were offered ASCT. Of these patients, 21 patients ultimately received tandem ASCT and 1 patient had tandem autologous-allogeneic transplants. Reasons for not receiving the planned tandem ASCT were lack of socioeconomic resources, physical co-morbidities, and patient refusal. There were no treatment related mortalities in the ASCT patients.Progression-free (PFS) and overall (OS) were compared between the single ASCT (n=54) and tandem ASCT (n=21) groups. The median PFS for the single ASCT group was 27 months (range, 3–107) and 21 months (range, 7–101) in the tandem group (P=0.814). OS was 76 months (range, 5–144) vs. 38 months (range, 12–128), respectively (P=0.121). At the time of submission, a total of 26 (48%) patients in the single ASCT group and 6 (30%) patients in the tandem group are still alive.Among the tandem patients, 2 later underwent salvage ASCT and 3 went on to receive non-myeloablative allogeneic transplants. In the single ASCT group, 6 had salvage ASCT and 7 had allogeneic SCT. All salvage transplants were done at a median of 30 months (range, 8–90) from the last ASCT.Patients who declined tandem transplant had a median PFS of 20 months (range 4–38). Patients who did not quality for tandem ASCT had a median PFS of 28 months (range 3–107) (p–0.08). Median OS between the two groups was 53 months (range 5–95) and 57.5 months (12–144), respectively (p–0.67). Conclusions:Patients who achieve ≥VGPR after 1st ASCT have similar PFS and a trend toward better OS than patients who had tandem ASCT. Thus, the use of such response criteria may identify a group of lower risk patients that will do well without upfront tandem ASCT. Disclosures:No relevant conflicts of interest to declare.

Abstract 4618: Response post first autologous stem cell transplantation (ASCT) for multiple myeloma identify patients who may benefit from tandem transplants: A single center prospective phase II study

Abstract The role of tandem transplants as well as a later salvage second transplant has been in the center of interest for many myeloma investigators. Also, the need for tandem ASCT in patients (pts) achieving very good partial remission (VGPR) or complete remission has not been studied prospectively. We conducted a prospective phase II clinical trial in which enrolled myeloma pts are assessed after the first ASCT and offered either 2nd tandem ASCT if they achieve ≤ PR or maintenance if they achieve ≤ VGPR. These latter pts received 2nd salvage transplant after relapse. The conditioning regimens used were different for the two ASCT: Busulfan 0.75 mg/kg PO q 6 hr days –8 through –5, Cyclophosphamide (CP) 60 mg/kg IV days –3 and –2, and Etoposide 10 mg/kg IV days –4 to –2 for the first ASCT, and 96 hr (days –6 to –3) continuous IV CP 6 gr/m2 and total body irradiation (TBI) 600 cGy (days –2 and –1) for the second ASCT. Etoposide was omitted if pts were ≤ 65 year old, and TBI was substituted by melphalan 140 mg/m2 if prior radiation did not allow TBI. Between the years 2001-2009, 76 pts were enrolled. Of the 31 pts planned to have tandem ASCT, 20 received tandem ASCT, 2 additional pts had tandem auto-allo transplants and one patient had progressive disease. The primary reasons for not receiving the planned tandem ASCT were lack of socioeconomic resources and physical co-morbidities. Maintenance treatment was offered to both groups of pts. There were no treatment related mortalities in the ASCT pts. We compared the progression-free (PFS) and overall (OS) survival following the first ASCT between pts who received tandem ASCT (n=20) and pts who received single ASCT (n=54). The median PFS for tandem pts was 27 mo (range, 10-93) versus 28 mo for single ASCT (range, 4-99) (P=0.889); the OS was 38 mo (range, 11-120) versus 72 mo (range, 5-136), respectively (P=0.293). At the present time, a total of 7 (35%) and 30 (55%) pts are still alive in the tandem and single ASCT groups, respectively. Among the tandem pts, 2 underwent salvage ASCT and one non-myeloablative allogeneic transplant (allo-SCT); while in the single ASCT group 6 had salvage ASCT and 6 had allo-SCT. All salvage transplants were done at a median of 37 mo (range, 8-91) from 1st ASCT. In conclusion, pts who achieve ≤ VGPR after 1st ASCT have similar PFS and may be better OS than pts who had tandem ASCT. Thus, the use of such response criteria may identify a group of lower risk pts that will do well without the upfront tandem ASCT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4618. doi:1538-7445.AM2012-4618

Matched-Pair Analysis Comparing Outcomes of Second Autologous Stem Cell Transplantation and Chemotherapy As a Salvage Therapy in Patients with Multiple Myeloma Who Relapsed After Front-Line Autologous Stem Cell Transplantation

Abstract 1990 Introduction:Autologous stem cell transplantation (ASCT) is a standard of care for younger multiple myeloma patients (pts). However, nearly all pts undergoing ASCT will relapse and require salvage therapy. Several investigators have reported 2nd ASCT might be a feasible and effective treatment modality in some pts. However, these studies contained small number of pts with 2nd ASCT and did not compare with outcomes of salvage therapy using novel agents. Thus, the aims of this study are to investigate outcomes of 2nd ASCT in pts relapsed after front-line ASCT and identify the impact of 2nd ASCT compared to modern systemic therapy in the novel agent era. To minimize the heterogeneity between the 2 groups, matched-pair design was chosen. Methods:The data of 48 pts between 1998 and 2010 with 2nd ASCT after relapse of front-line ASCT identified from web-based registry (www.myeloma.or.kr) were analyzed. Pts with tandem ASCT or salvage allo-SCT were excluded. The goal of this study was to perform a matched-pair analysis, each patient with 2nd ASCT was matched to three pts from a cohort of 517 pts treated with systemic chemotherapy after relapse of prior ASCT. The pts were matched for 9 potential prognostic factors: age at relapse (<60 vs ≥60), serum creatinine (sCr) at diagnosis (<2mg/dL vs ≥2mg/dL), ISS (I vs II vs III), serum LDH level (normal vs elevated), cytogenetics (del(13q)/hypodiploidy vs others), Induction therapy at first ASCT (VAD vs novel agents), Conditioning regimen at first ASCT (≤MEL140 vs >MEL140), response to front-line ASCT (≥VGPR vs <VGPR), and time to progression (TTP) since first ASCT (<18months vs ≥18months). At least 8 of these factors should be matched between the four matched pts. Finally, 48 pts with 2nd ASCT were matched to 144 pts with systemic chemotherapy. Results:The median age at relapse was 55.5 (range, 33.4–68.5) years and 106 pts (55%) were male. The ISS was I(54, 28%)/II(84, 44%)/III(54, 28%). Serum LDH level was elevated in 133 (69%) and sCr ≥2mg/dL was in 35 (18%). The data of conventional cytogenetic analysis was available in 156 pts (79%). Thirty-three (21%) were abnormal. Of these, 26 pts (79%) had complex chromosomal abnormalities, 15 (45%) del(13q), and 6 (18%) hypodiploidy. One hundred sixty (83%) received VAD as induction therapy for first ASCT. Conditioning regimen for first ASCT was MEL 140–200 mg/m2 in 187 (97%). Fifty-six (29%) received maintenance therapy after first ASCT. Response to front-line ASCT was 67 CR (35%), 39 VGPR (20%), 68 PR (35%), 13 MR/SD (7%), 5 PD (3%). The median TTP after first ASCT was 12.0 (range, 1.1–83.8) months, and pts with ≥18 months of TTP after first ASCT were 57 (30%). After matching process, we identified it was successful because the distribution of 9 matching variables and unmatched other variables (ECOG performance status, hypercalcemia, bone lesions) was balanced between 2 groups.2nd ASCT conditioning consisted of MEL alone in 45 (94%), the remaining 3 had MEL with busulfan or bortezomib. Only one transplant-related death occurred following 2nd ASCT. Novel agents used as salvage therapy in their course of disease were bortezomib in 151 (79%), thalidomide in 138 (72%), and lenalidomide in 6 (3%). Thalidomide was less frequently used in the 2nd ASCT group than the systemic chemotherapy group (58% vs 80%, p=0.016).With a median follow-up of 55.3 (range, 3.4–140.0) months, the 2nd ASCT group revealed significantly better progression-free survival (median, 18.0 [95% CI, 15.2–20.8] months vs 9.1 [6.7-11.5] months, p=0.017, respectively) and overall survival (OS; median, 55.5 [46.2-64.8] months vs 25.4 [16.7-34.1] months, p=0.035, respectively) than the systemic chemotherapy group. In multivariate analysis for OS, <18 months of TTP after first ASCT (HR, 2.77; 95% CI, 1.49–5.14), ISS III (HR, 2.04; 95% CI, 1.09–3.82), and salvage systemic chemotherapy (HR, 1.88; 95% CI, 1.09–3.22) were independent prognostic factors for worse OS. Conclusion:The outcomes of salvage 2nd ASCT appear superior to those of systemic chemotherapy, even fewer pts in the 2nd ASCT group received thalidomide. Additionally, 2nd ASCT was an independent prognostic factor for better OS. Considering current low mortality of 2nd ASCT, our results might provide a substantial evidence for performing 2nd ASCT in relapsed myeloma pts and suggest the value of performing a prospective randomized trial comparing 2nd ASCT and systemic chemotherapy in pts relapsed after front-line ASCT. Disclosures:No relevant conflicts of interest to declare.

Upfront Tandem Autologous Stem Cell Transplant Is Superior to Autologous or Allogeneic Stem Cell Transplant After Failure of a 1st Autologous Transplant,

Abstract 4094Disease progression remains the main cause of treatment failure after autologous stem cell transplant (SCT) in patients with multiple myeloma (MM). It is unclear what is the best salvage therapy after failure of a 1st autologous SCT in MM.We performed a retrospective study comparing 2nd autologous (auto-auto) versus 2nd allogeneic (auto-allo) SCT in patients progressing or relapsing after their 1st autologous SCT and compare their outcomes with patients receiving sequential planned double autologous (tandem) SCT as part of their upfront therapy for MM.The data was collected from CIBMT reports and medical records at Texas Transplant Institute from 2001 to 2010. Patient's characteristics and outcomes are described in table 1. Response to 1st and 2nd SCT was determined at 100 days post transplant and classified as good (stringent complete remission [sCR], complete remission [CR], very good partial remission [VGPR]) or poor (partial remission [PR], stable disease [SD] or progressive disease [PD]). All patients in the auto-allo group received a reduced intensity regimen. 20% of the patients in the auto-auto group received maintenance therapy after their 1st transplant with either thalidomide or lenalidomide and 10% of the patients in the auto-allo group received maintenance therapy after their 1st transplant either with thalidomide. None of the patients in the tandem group received maintenance therapy. The overall survival was calculated from the date of the 2nd transplant to the known date of death in all groups. Patients in the auto-allo group (15.9 months) had a worse median survival than in the auto-auto group (39 months) with both of them having a worse survival compared to patients undergoing tandem transplants (64.3) (p value = 0.003) (FIGURE).Table:PATIENT CHARACTERISTICS AND OUTCOMESTandem (n=29)Auto-Auto (n=32)Auto-Allo (n=10)Median age, years (range)62 (41–78)62.5 (45–81)54 (43–63)Median days from diagnosis to 1st transplant224.5 (93–1344)226 (117–1074)254.5 (101–416)Median days from 1st to 2nd transplant149 (99–189)847 (210–4158)350 (88–1281)Median total CD34+ cell infused 1st transplant3.29 (2–12)5.87 (2–28)6.03 (2–14)2nd transplant3.22 (2–9)4.47 (2–19)5.25 (3–11)Median WBC engraftment11 (9–13)11 (9–47)N/AMedian Platelet engraftment16 (10–19)15 (10–23)N/ACytogenetics High Risk17%3%10%ISS at 1st transplant I31%41%40%II34%12%0III14%6%10%ISS at 2nd transplant I48%53%40%II17%9%0III10%13%10%Response to 1st transplant Good10%63%70%Poor80%25%20%Response to 2nd transplant Good52%47%30%Poor41%41%70%Median Followup (months)57.1 (3.4–76.7)24.6 (10.5–87.8)48.0 (31.9–64.0)Maintenance Therapy after 1st transplant028%10% [Display omitted] Forward stepwise Cox regression analysis was used to measure factors affecting overall survival. Factors used for analysis included age, cytogenetics (high risk = mutated p53, t(14;16), t(4;14), del 13), International Staging System (ISS) before 1st and 2nd SCT, use of maintenance therapy after 1st SCT, days from diagnosis to 1st SCT and days from 1st to 2nd SCT, CD34+ cells infused at 1st and 2nd SCT. Age and ISS of III at 2nd transplant were identified as factors affecting survival in the auto-auto group (hazard ration of 1.081 and 5.700, respectively).In conclusion, overall survival after salvage from 2nd autologous stem cell transplant is longer than after a 2nd allogeneic transplant. Upfront, planned tandem autologous stem cell transplant is superior to both salvage strategies. Larger, randomized trials are needed to confirm these results. Disclosures:Shaughnessy:Otsuka: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau.

“Early-FDG-PET” but Not Macrophage Infiltration In Diagnostic Specimen Seems to Predict Clinical Course of Hodgkin Lymphoma

AbstractAbstract 4826 Background:Hodgkin Lymphoma (HL) is a highly curable malignancy that mostly affects young adults; currently, considering all patients more than 75% of them will be cured and the ones diagnosed with early stage disease have a chance of cure over 90%. However, despite these very satisfactory results, about 20% of patients still die from progressive disease and non-specific related Hodgkin's mortality, mostly due to late toxic effects, continues to rise with time. Consequently, the optimal treatment should be designed based on prognostic models, but currently all of them predict the outcome of treatment with imperfect accuracy. Since from recent studies “early FDG–PET” and lately tissue macrophages infiltration seem to be powerful predictors, we hypothesized that macrophage infiltration could be the shadow of the inflammatory microenvironment that FDG-PET identifies in HL and that persist at early assessment in patients who will fail to respond to treatment. Consequently we decided to verify this hypothesis analyzing a group of patients with HL diagnosed and treated at our institution. Patients and methods:on the basis of availability of paraffin embedded diagnostic specimen and “early PET” assessment, we selected a cohort of 24 patients (M/F: 12/12) with Hodgkin Lymphoma, diagnosed and treated at our institution between February 2007 and February 2010. Before starting treatment all patients completed staging with whole body CT scan, FDG-PET and bone marrow biopsy. Ten patients had stage II disease, 10 patient stage III and 4 patients stage IV; median age was 33 years. Programmed treatment consisted of 4–6 cycles of ABVD and, if indicated, involved-field radiation therapy. Patients repeated CT scan and FDG-PET after two cycles and after completion of therapy. Macrophage infiltration in paraffine-embedded diagnostic specimen was retrospectively determined by immunohostochemistry. Results:After two cycles of ABVD, FDG-PET was negative in 18/24 patients (75%), while FDG-PET was positive in the six remaining patients (25%). Overall 20 out of 24 patients (83%) achieved a CR, however two of them had an early relapse (within 6 months), so they underwent 2nd line therapy plus autologous stem cell transplantation (ASCT), both obtaining a second CR. Among the four remaining patients, one achieved only a PR and entered salvage protocol with 2nd line treatment plus ASCT, two achieved a CR after second line treatment and the last one was refractory to 3 lines of treatment and finally was enrolled in an investigational protocol. With a median follow up of 18.5 months, 21 out of 24 patients are alive in CR, a patient is alive in PR and two patients died, due respectively to pulmonary thromboembolism and ARDS (after mediastinal irradiation). Five out six patient (83%) with persistent positive “early FDG-PET” failed their first line treatment. About macrophage percentage in the diagnostic specimen, evaluated and classified according to the criteria reported in the recent paper by Dr Steidl and coworkers, one patient (4%) was classified with score 1, twelve (50%) with score 2 and eleven (46%) with score 3. Among the six patients with persistent positive “early-FDG-PET”, one of them had score 1 (and never obtained CR), three had score 2 and two score 3. Conclusions:with the limitation of a small cohort of patients and the lack of gene-expression assays, our data do not seem to support our hypothesis neither to confirm the recently reported prognostic impact of macrophage infiltration in diagnostic specimen. Disclosures:No relevant conflicts of interest to declare.

Second Autologous Stem Cell Transplant (ASCT) as Salvage Therapy in Patients with Relapsed Multiple Myeloma.

Abstract 1217Poster Board I-239 BackgroundSingle autologous stem cell transplant (ASCT) is considered the standard of care after induction therapy for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. MethodRetrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. ResultsBetween February 1997 and July 2009, 79 MM pts received a second ASCT for relapsed MM at our institution. Median age was 60 yrs (range 39-72) at second transplant. 48 pts (61%) were male. Immunoglobulin subtype included IgG (42), IgA (21), light chain (11), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140-200 mg/m2 in 67, busulphan and cyclophosphamide in 1, and combinations of MEL with etoposide (E) or TBI in the rest. 2nd ASCT conditioning consisted of MEL alone in 76, the remaining 3 had MEL with either TBI or E. The median time to relapse after the first transplant was 2.72 years (0.81-8.26), with a median interval between transplants of 3.61 years (1.63-9.59). Response to first transplant in 78 evaluable patients was 13 CR/nCR (17%), 56 PR/VGPR (72%), 9 MR/SD (12%). Nineteen pts received maintenance therapy between transplants. Two transplant-related deaths occurred following 2nd ASCT. In 73 evaluable patients, response to second transplant was 11 CR/nCR (15%), 57 PR (78%), 6 MR/SD (8%). After 2nd ASCT, with median follow up 5.92 years (71 months), median progression-free survival (PFS) was 18.5 months and median overall survival (OS) was 4.4 years. Long term progression-free status based on the progression-free interval after 1st ASCT is summarized Table 1. PFS based on progression free interval after 1st ASCT is outlined in Figure 1. Conclusions2nd ASCT is a feasible and safe salvage therapy in relapsed MM patients. It is effective in providing a median progression free survival of 18.5 months and median overall survival of 4.4 years (52.8 months) after 2nd ASCT. This is comparable if not better than modern salvage chemotherapies. The longer the disease free interval after 1st ASCT the more effective 2nd ASCT is at extending both progression free survival and overall survival. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT.Table 1Outcomes Based on Time to Progression Post 1st ASCTGroup# of patientsMedian PFS post 2nd ASCT (months)P valueMedian OS post 2nd ASCT (months)P valueEntire Cohort7918.552.8< 24 months1512.742.224-36 months3017.052.7>36 months3432.60.0196Not reached0.1104 [Display omitted] DisclosuresChen:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria.

Post Tandem Autologous Stem Cell Transplant Maintenance Therapy with Bortezomib Improves Remission Duration and Quality of Response in Multiple Myeloma Patients.

Abstract 4939 BackgroundSingle or tandem Autologous Stem Cell Transplantation (ASCT) has been considered standard approach in adult (<65y) Multiple Myeloma (MM) patients (pts), however post ASCT disease progression occurs in the majority of cases suggesting that post ASCT maintenance treatment might be useful. The role of Bortezomib in the post-ASCT context is still not well defined. In December 2007 this single center study was activated in the aims to assess the impact of Bortezomib maintenance a) on time to progression (TTP), b) the possible toxicity related to a prolonged administration of the agent. Patients and MethodsBetween October 2002 and July 2008, at Hematology Unit of S. Giovanni Hospital, 24 pts (median age 59.5y, min 38-max 67y) with newly diagnosed intermediate/advanced MM underwent single (8), or tandem (16) ASCT, respectively. Of these, 13 pts autotransplanted (8 single and 5 tandem) between 2002 and 2007, who did not receive any treatment post-ASCT, were considered as historic control group, while the remaining 11 autotransplanted from December 2007 to September 2008, received Bortezomib as maintenance treatment. Maintenance schedule consisted of Bortezomib as single agent given at dosage 1.5 mg (total dose) every 15 days until progression. Response was evaluated according to the International Myeloma Working Group uniform response criteria, while minimal residual disease (MRD) was assessed every 3 months on bone marrow (BM) samples by 6-colour BDFACS CANTO II. Abnormal plasma cells (APC) were identified using an Ab panel against the following markers: CD38, CD138, CD19, CD20, CD45, CD56, CD117, CD28, CD200. The condition was optimized in order to obtain a sensitivity level ' 1×10-3 (<0.01). Moreover, the presence of peripheral neuropathy (PN) was monitored before maintenance start, then every 3 mo by neurophysiologic tests including motor and sensory conducting studies. ResultsIn the Bortezomib group, post -2nd ASCT, 5 pts achieved complete (CR) or a very good partial response (VGPR), 4 partial response (PR), and 2 maintained stable disease (SD), respectively; the overall response rate was 82%, with 45% CR+VGPR. Maintenance was started in a median time of 3.8 mo (min 1.7 - max 13.7 mo). As of July 2009, after a median maintenance length of 16.2 mo (min 4.1 - max 19 mo), all 11 pts are alive. As disease status, of the 4 pts in PR after 2nd ASCT, 1 achieved stringent CR (sCR), 1 CR and 2 progressed, respectively. The 5 pts who were previously in CR/VGPR maintained the same type of response, with no detectable MRD (< 0.01), except 1 pt who shifted to PR. Finally, of the 2 pts in SD, 1 persisted in SD after 10 months from the beginning of the Bortezomib maintenance, while the other one progressed. Thus, to date, of the 11 pts entered in the study, 55% are sCR+CR+VGPR, with an overall response rate of 63%. It is noteworthy that the 3 pts who relapsed (at 3, 4, 16 mo from maintenance start) had chromosome 13 deletion at diagnosis. Considering that not all pts underwent 2nd ASCT, TTP was evaluated from 1st ASCT. In the Bortezomib group (median follow-up 26 mo; range: 15 – 33 mo), median TTP has not yet been reached, whereas in the control group (median follow-up 34 mo; range: 14 – 62 mo), median TTP was 13 mo (log-rank P<0.01) (Fig 1). Finally, none of the pts in the Bortezomib group experienced grade 3 or 4 haematologic toxicity and/or PN requiring dose reduction or discontinuation of the drug. ConclusionThe preliminary results of this single center study, even though limited to a small cohort of pts, suggest that Bortezomib as single agent in post-ASCT maintenance may improve the quality of previously achieved response and prolong TTP. However, these preliminary results need to be confirmed by a longer follow-up and a randomized multicenter study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.