Allo-SCT For Multiple Myeloma Research Articles

Retrospective analysis of allogeneic hematopoietic stem cell transplantation for multiple myeloma after myeloablative conditioning with 8 Gy of total body irradiation

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment option for multiple myeloma (MM), but few patients are eligible due to its high risk of treatment-related toxicity and relapse. Here, we report the feasibility and efficacy of allo-SCT after myeloablative conditioning with 8 Gy of total body irradiation (TBI) for reducing relapse of MM. We retrospectively analyzed data from 30 consecutive patients who received allo-SCT for MM after 8 Gy of TBI at Japanese Red Cross Medical Center between 2012 and 2021. Median age at allo-SCT was 47 (range 31-61) years. Stem-cell sources were peripheral blood from an HLA-matched related donor (MRD, n=5), bone marrow from an HLA-matched unrelated donor (MUD, n=5), bone marrow from an HLA-mismatched unrelated donor (MMUD, n=13), and cord blood (n=7). All patients received conditioning with 8 Gy of TBI combined with Flu/Mel (n=28) or others (n=2). Five-year PFS and 5-year OS were 36.7% and 46.2%, respectively. Sixteen patients died during the observation period (12 of primary disease and 4 of treatment-related toxicity). Patients with VGPR or better before allo-SCT had significantly better PFS (p=0.009) and OS (p=0.01) than others. Patients who received MMUD cells tended to have better PFS than those with other cell sources. Our report showed that allo-SCT for MM after 8 Gy of TBI is feasible, and the better PFS of MMUD suggests graft-versus-myeloma effects.

Posttransplant cyclophosphamide as a platform for immunotherapy after allogeneic stem cell transplantation for multiple myeloma

Abstract Allogeneic stem cell transplantation (alloSCT) is a highly effective, curative therapy for leukemia yet does not provide a survival benefit above autologous SCT in patients with multiple myeloma (MM). To explore this, we developed preclinical models of SCT using C57Bl/6 recipient mice and either C57Bl/6 (ASCT) or C3H.SW (alloSCT) donor grafts. Importantly, these models recapitulated the clinical setting whereby alloSCT provided superior outcomes, compared to ASCT, in recipients bearing MLL-AF9-driven acute myeloid leukemia (AML) but not in those bearing Vk*MYC-MM. Interestingly, we found that MM-specific, T cell-mediated immunity was generated after ASCT, which failed due to MM-induced T cell exhaustion. MM relapse after ASCT could be prevented by TIGIT or PD-1 targeted immune checkpoint inhibition or via depletion of suppressive CSF1-R+ myeloid cells. Conversely, after alloSCT, T cell exhaustion was driven principally by alloantigen and CD8 T cells expressed high levels of PD-1, TIGIT and TIM-3. Furthermore, Vk*MYC myeloma exploited this alloantigen-driven T cell exhaustion via expression of high levels of PD-L1 and CD155 (the cognate ligands for PD-1 and TIGIT), which were expressed minimally on MLL-AF9 AML. To exploit alloSCT in MM, we used post-transplant cyclophosphamide (PT-Cy) to delete high affinity alloreactive T cells that generate the exhausted donor T cell pool. Subsequent administration of CD137 agonists enhanced T cell activation and cytolytic activity within bone marrow, without exacerbating GVHD. Thus, PT-Cy provides a platform for optimizing immunotherapy after alloSCT.

Allogeneic Stem Cell Transplantation for Multiple Myeloma: A 34-Year Experience

Allogeneic Stem Cell Transplantation for Multiple Myeloma: A 34-Year Experience

Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma Improved Overall Survival in Upfront Hematopoietic Stem Cell Transplantation — a Large Retrospective Study By the Chronic Malignancies Working Party of the EBMT

BackgroundAllogeneic hematopoietic stem cell transplantation (AlloSCT) for treatment of multiple myeloma (MM) is controversial mainly due to high non-relapse mortality (NRM) with myeloablative conditioning. However, AlloSCT is probably the only treatment that result in cure of a small fraction of patients. Treosulfan is a prodrug of a bifunctional alkylating agent which has both myelotoxic and immunosuppressive properties. Conditioning regimes with treosulfan have been tried in various hematologic neoplasia such as AML and MDS indicating low NRM and increased progression free survival (PFS). Previous studies on use of treosulfan condition in AlloSCT for MM indicated feasibility, stable engraftment and low NRM. In the present study we have analysed the results of low and high dose treosulfan respectively on OS, RFS, relapse incidence and NRM as well as results of Treosulfan conditioning compared to non-Treosulfan reduced intensity conditioning (RIC) and non-Treosulfan myeloablative conditioning (MAC).Patients and MethodsWe conducted a retrospective analysis of 4544 patients with MM undergoing AlloSCT 2008-2016 reported to the EBMT data registry. Out of 537 patients receiving Treosulfan based conditioning the impact of dose could be analysed in 441. Three hundred and twenty-seven patients received a total dose of >36g/m2 and 114 <=36g/m2.These patients were compared to 2830 patients receiving RIC, and 1177 receiving MAC. 1103 patients were transplanted upfront and 3441 patients in later lines following relapse/progression. Patient characteristics shown in table 1.ResultsThe 5-year OS in upfront Treosulfan conditioned patients was 62%, which was significantly superior to both non-Treo RIC and MAC patients respectively, apparently due to a tendency for lower NRM (10%) albeit a higher relapse rate (Table 2). Patients in later lines of conditioning had either low NRM (3rd line) or no significant difference (2nd line) (Table 2). Heterogeneity in the material makes it difficult to interpret results in the patients transplanted late in the course of the disease.A higher total treosulfan dose, >36g/m2, showed a tendency for improved OS and RFS compared to the lower dose treosulfan as well as RIC and MAC (table 2) respectively.In multivariate analysis of upfront transplanted patients, with a model adjusted for ISS score at diagnosis, age, Karnofsky score, response at AlloSCT, interval between diagnosis and transplant, donor type and donor - patient sex match, treosulfan and RIC retained significance for OS, HR 0.57 (P=0.006) and RFS, HR 0.65 (P=<0.005). For 2nd line Treosulfan RFS was significantly worse, HR 1.46 (P=<0.005) while there was no significant difference for OS between conditioning regimes in 2nd or for OS and RFS in 3rd line (table 2). The factors associated with most inferior OS in upfront line of conditioning was Karnofsky <90 and ISS score III at diagnosis. ISS score III at diagnosis was also associated with inferior OS also in 2nd and 3rd line (Table 2) A less then partial response at AlloSCT was consistently a factor associated with inferior RFS regardless of line of treatment with HR 1.67 (P=<0.005) in upfront, HR 1,63 (P=<0.005) in 2nd line and HR 1,66 (P=<0.005) for 3rd line or later (Table 2)In multivariate analysis of treosulfan based conditioning regimes, upfront line of conditioning was superior for OS, PFS and relapse as expected (Table 3). Notably was an increased hazard ratio for donor-patient sex match other than female to male in OS, PFS as well as relapse, HR 1.64 (P=0.02), HR 1.66 (P=0.004) and HR 1.83 (P=0.003) respectively (Table 3).ConclusionsConditioning upfront with Treosulfan containing regimens for AlloSCT in multiple myeloma, is associated with a superior overall survival and a low NRM, however with a slightly higher relapse rate compared to other regimens. A higher dose > 36g/m2 tends to further improve OS, RFS and relapse rate without increasing NRM. The better results of Treo conditioning in female to male transplants as compared to other sex combinations and in contrast to MAC transplants may be due to the overall lower NRM with treosulfan, thus utilizing the GVM more effectively as indicated by the trend for lower relapse rate. In conclusion, Treosulfan containing regimens appear to be of value in upfront AlloSCT. Prospective studies on Treosulfan conditioning are warranted to further define the best dosing in MM AlloSCT. [Display omitted] DisclosuresNiederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Garderet:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Kroeger:Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding.

A Phase I Trial of 90Y-BC8-DOTA (Anti-CD45) Monoclonal Antibody in Combination with Fludarabine and TBI As Conditioning for Allogeneic Peripheral Blood Stem Cell Transplant to Treat High Risk Multiple Myeloma

Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells.Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA‐matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin >3.5 mcg/mL, LDH >1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT.Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were >95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD.Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal:Seattle Genetics: Consultancy, Research Funding. Becker:GlycoMimetics, Inc.: Research Funding. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees.

In search of the optimal platform for Post-Allogeneic SCT immunotherapy in relapsed multiple myeloma: a systematic review.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients. Eleven studies were included. Median PFS ranged from 5.2 to 36.8 months and OS was 13.0 to 63.0 months. The relapse related mortality at 1 year varied between 0 and 50% and TRM between 8 and 40%. Lowest GvHD incidences were reported for conditioning regimens with T-cell depletion using ATG or graft CD34+ selection. Similar strategies could lay the foundation for a post-transplant immune platform, this should be further evaluated in prospective clinical trials.

Allogeneic Stem Cell Transplantation for Multiple Myeloma: a Single Center Experience

IntroductionThe use of allogeneic stem cell transplantation (Allo-SCT) in patients with multiple myeloma (MM) remains controversial, but it offers prolonged disease free survival in some patients. It is unclear which patients should undergo Allo-SCT, what conditioning regimen should be used, and what the timing of the transplant should be in the course of the disease. Therefore, we sought to contribute our center's experience to the growing body of literature.MethodsWe performed a retrospective observational cohort study of all patients who underwent Allo-SCT for multiple myeloma at our center between January 1, 1992 and May 31, 2016. Categorical variables were compared using Pearson's chi-square test and the Kaplan-Meier method was used for the overall survival curves.ResultsThirty-four patients underwent Allo-SCT for multiple myeloma and were included in this analysis. The median age was 40 years and 21 (62%) were male. Nineteen patients (56%) underwent Allo-SCT as upfront therapy, 1 (3%) underwent tandem autologous stem cell transplant (auto-SCT) followed by Allo-SCT, and 14 (41%) had salvage Allo-SCT at the time of relapse. Twenty-four (70.5%) patients had a matched related donor, 1 (3%) had a mis-matched related donor, 8 (23.5%) had matched unrelated donor and matching in 1 (3%) was not available. Myeloablative conditioning was given in 18 patients (52.9%) and non-myeloablative conditioning in 13 (38.2%) with 3 (8.8%) missing. The conditioning regimens included: 5 (15%) Flu-Mel, 7(20.6%) Flu-Bu, 13 (38%) Bu-Cy ± TBI, 6 (17.6%) MelVPTBI, and 3 (8.8%) were missing. Median overall survival (OS) for all patients was 72.5 months from diagnosis (figure 1) and 26.5 months from the time of Allo-SCT. For the 19 patients who had upfront Allo-SCT, median OS from diagnosis was 7.4 years compared to 5.3 years for those having salvage Allo-SCT (figure 2). However, in the upfront group 6 (32%) were alive 10 years post Allo-SCT and the survival curve reaches plateau, whereas in the salvage group, no patient was alive after 8 years post Allo-SCT. There was no difference in median survival between myeloablative and non myeloablative conditioning (2.9 versus 1.33 years, p=0.925). There have been 20 deaths in our cohort (59%); 5 (14.7%) from transplant related mortality within 1 year, 9 (26.5%) from disease progression, and 6 (17.6%) transplanted remotely whose cause of death is unknown.ConclusionsOur data suggest that Allo-SCT offers prolonged disease free survival in some patients. In our small cohort, a greater proportion of patients undergoing upfront Allo-SCT achieved long term survival, raising the possibility that this group of patients may benefit more from Allo-SCT. Further prospective studies are needed to clarify the role of Allo-SCT in MM. [Display omitted] [Display omitted] DisclosuresKew:Celgene: Honoraria. McCurdy:Celgene: Honoraria.

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce long-term remission in multiple myeloma (MM), but the role of allo-SCT in MM is controversial due to the high rate of treatment-related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high-risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo-SCT. We therefore analyzed the outcome of one hundred and forty-seven patients with MM who received an allo-SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow-up of 88.8 months. For the first-line setting, median progression-free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10-yr OS of 51%. We found no difference in outcome for patients with high-risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high-risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto-SCT. Therefore, if applied at all in these patients, improvement of allo-SCT is needed, focusing on reduction of TRM and more effective immunotherapy.

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) relapse and the curability of MM remains limited. Genetically defined high-risk MM represents a subgroup with an aggressive disease course despite novel agents. Allogeneic hematopoietic cell transplantation (allo-SCT) is a potentially curative option in MM that has several advantages including a tumor-free graft, and the potential for sustained immune-mediated disease control. However, historically high treatment-related mortality (TRM) and conflicting reports from prospective studies in the United States and European Union have limited the utilization of this modality. Meanwhile, newer preparative regimens, planned maintenance strategies and improvements in supportive care have led to a decline in TRM and better survival in recent years. The allo-SCT platform also provides additional options of immunotherapy at relapse including donor lymphocyte infusions, immunomodulatory drug maintenance and withdrawal of immune suppression. In this article, we provide an in-depth review of literature for allo-SCT and other immunotherapy options, as well as the authors' approach to using allo-SCT in MM.

Allogeneic SCT in Multiple Myeloma: Limited Predictive Value of Chimerism Analysis for Heralding Relapse/Progression Due to Extramedullary Disease

Background Allogeneic stem cell transplantion (allo SCT) for multiple myeloma (MM) takes advantage of a tumor cell-free graft along with potential immunosurveillance of residual malignant plasma cells. However, multiple factors such as treatment-related mortality (TRM) and morbidity and post-allo disease progression question the more widespread use of allo SCT. The induction of an early complete donor chimerism (DC) is thought to be associated with a low incidence of relapse and improved survival. Interestingly, data on chimerism analysis are relatively scarce for allo SCT in MM. Therefore, we retrospectively evaluated longitudinal DC results by short tandem repeat (STR)-based techniques from a single lab. Data were correlated with a set of baseline and outcome variables. In addition, disease- and treatment related factors like extramedullary disease (EMD), acute and chronic graft-versus-host disease (GvHD) and post-transplant consolidation were analyzed for impact on outcome.Patients and methods We identified 118 MM patients (pts) receiving non-myeloablative allo SCT at two German centers between 01/2006 and 12/2014. 90% of pts underwent allo SCT at relapse. Median follow-up was 42 months (mos), median overall survival (OS) 25 mos (range, 1-106) and TRM was 15%. Two-thirds of pts had received treosulfan/fludarabine as conditioning regimen. Median interval between MM diagnosis and allo SCT was 40.5 mos (range, 7-175) and median number of prior treatment lines was 3 (range, 1-10). 24 pts received allografts from matched related donors, 61 from matched-unrelated donors, and 33 pts from mismatched donors. Chimerism analysis was performed by STR-PCR on whole blood and T cell subsets using a validated multiplex STR-assay with a documented sensitivity of 1%. Response assessment was performed according the international myeloma working group guidelines.Results 1398chimerism samples (mean: 12/patient, 119 marrow, 1279 blood)) were analyzed. Median interval from allo SCT to first assessment was 15 (range, 3-62) days. Median duration of chimerism sampling was 24 mos. No graft rejections occurred. Full DC (> 99%) was achieved in 117/118 pts. Pts who lost full DC had a significantly shorter progression free survival (PFS) than those with sustained DC (HR 0.2; p<.0001). OS, however, was not different. In patients who developed disease progression, loss of DC versus sustained DC was not predictive for outcome. In spite of relapse, a full DC was found in peripheral blood in 82% and in 45% in bone marrow samples of pts, respectively. With respect to clinical predictors of outcome, the occurrence of acute GvHD had no impact on PFS nor OS. In contrast, induction of chronic GvHD was associated with prolonged PFS (HR 0.50; p=.0088) and OS (HR 0.39; p<.001). Despite the induction of full DC in the blood, 13/118 (11%) of pts not in complete response received preemptive donor lymphocyte infusions (DLI). DLI without any concomitant signs of graft rejection or disease progression was associated with favourable OS (HR 0.43; p=.0067). When analysing relapse patterns after allo SCT, a 35% rate of EMD was observed. Interestingly, OS was not different when compared to intramedullary relapses. However, when allo SCT was performed as part of a consolidation therapy for prior EMD or plasma cell leukemia, OS was significantly shorter than compared to patients without EMD history (median OS 6 vs. 41 mos, p=.0035) Nevertheless, 25% of these EMD patients showed long-lasting remissions beyond 4 years. High risk cytogenetics (del17p, t(4;14) and +1q21), CMV reactivation or use of ATG had no impact on outcome.Conclusions To the best of our knowledge, this is the largest study of serial DC analysis in a cohort of clinically well characterized MM pts. The robust engraftment in almost all patients as well as the lack of graft rejections indicate the severe immunosuppression in MM due to pre-treatment and underlying disease. On the other hand, the most important predictors for PFS and OS was the occurrence of cGvHD. Preemptive DLI may further improve tumour control. The frequent spread of myeloma to extramedullary sites can be interpreted as an escape to more immuno-privileged regions as compared to the bone marrow. This pattern clearly limits the potential of prolonged serial DC analysis as the only tool for relapse detection. Our observations underscore the need to prospectively evaluate complementary strategies in this setting. DisclosuresEinsele:Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Knop:Celgene Corporation: Consultancy.

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future.

A prospective study of lenalidomide monotherapy for relapse after Allo-SCT for multiple myeloma

Allo-SCT can result in long-term remission in patients with multiple myeloma (MM), although its overall role in disease management remains controversial. We evaluated lenalidomide monotherapy response and tolerability among 18 patients with MM who progressed or relapsed after Allo-SCT, who were enrolled a median of 12 months (range 3-104) following transplant. Treatment duration of lenalidomide was 8 months (range 1-57). Ten patients required dose reductions from 25 to 5-20 mg at a median of three cycles (range 1-12): eight for neutropenia, one for thrombocytopenia and one for myalgias and weakness. Serious adverse events (N=5) included H1N1 influenza (2), bacterial pneumonia (2) and fever, myalgia and hypoxia. Two patients died at 3 and 5 months of gastrointestinal or hepatic GVHD occurring within 1 month of dosing. Responses included complete response (CR) (5), very good partial response (2), partial response (PR) (3), minimal response (1) and stable disease (2) for an overall response rate (≥ PR) of 56%. Ten patients discontinued therapy for progressive disease (PD) at a median of 8.5 (1-43) months. Six patients died from PD. Five patients remained on therapy at 39 months (range 14-57), with four in CR. Lenalidomide for relapse of MM after Allo-SCT can result in extended disease control (>12 months) in 50% of patients.

IMPACT OF PRETRANSPLANT DONOR AND RECIPIENT CYTOMEGALOVIRUS SEROSTATUS ON OUTCOME FOR MULTIPLE MYELOMA PATIENTS UNDERGOING REDUCED INTENSITY CONDITIONING ALLOGENEIC STEM CELL TRANSPLANTATION.

Scope of the study was to investigate the impact of pre-transplant CMV serostatus of the donor and/or recipient on the outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). To our knowledge no data are available in the literature about this issue.We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer center at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]−/recipient [R] −) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D−/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%).Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs. intermediate: 29% vs. high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively.Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this group of patients, warranting further prospective studies.

Impact of Pretransplant Donor and Recipient Cytomegalovirus Serostatus On Outcome for Multiple Myeloma Patients Undergoing Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

AbstractAbstract 4496 Purpose:To investigate the impact of pre-transplant CMV serostatus of donor or recipient on outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). Patients and methods:We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer centre at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R]-) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%). Results:Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs intermediate: 29% vs high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively. Conclusion:Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients, warranting further prospective studies.Table 1Patient and transplantation characteristicsPatient and transplantation characteristicsn = 99 (%)Patients Age (median) [range]53 years [27–67]Male gender59 (60)Myeloma-subtypeIgG52 (53)IgA23 (23)Light Chain12 (12)Bence jones8 (8)Other4 (4)Cytogenetics at diagnosisNormal14 (14)Del(13) or Del (17) or t(4;14)24 (24)NA61 (62)Median number of prior chemotherapies before Allo-SCT [range]2 [1–5]1 line27 (27)2 lines46 (47)3 lines15 (15)>3 lines11 (11)Median number of prior Auto-SCT [range]2 [1–4]157 (58)231 (31)> 28 (8)Status of Myeloma at Allo-SCTCR12 (12)VGPR10 (10)PR/SD66 (67)PD11 (11)Median interval between Auto- and Allo-SCT months [range]19 [1–89]Donor typeMRD73 (74)URD26 (26)Donor/recipient sex mismatch48 (48)ABO compatibilityYes63 (64)No36 (36)Donor/recipient CMV serostatusD−/R− (low risk)17 (17)D+/R− (intermediate risk)14 (14)D+/R+ (high risk)31 (31)D−/R+ (high risk)37 (37)Donor Median age years (range)46 (20–71)Conditioning regimenFlu + Bu + ATG68 (69)Flu + TBI25 (25)Other RIC6 (6)GvHD prophylaxisCSA56 (57)CSA+MMF41 (41)MMF2 (2)Stem cell sourcePeripheral Blood88 (89)Bone Marrow9 (9)Cord blood2 (2)Stem cell dose median [range]CD34+ × 106/kg5.41 [0.16–12.8]CD3+ × 106/kg299 [5–745] Legend:CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; Flu, fludarabine; Bu, busulfan; ATG, antithymocyte globulin; CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; MRD, matched related donor; URD, unrelated donor; GVHD, graft versus host disease; CSA, cyclosporine A; MMF, mycophenolate mofetyl.Table 2CMV reactivationCumulative incidence of CMV reactivationpAll patients (n=99)39%CMV serostatusLow risk (n=17)0%0.001Intermediate risk (n=14)29%High risk (n=68)50%Donor type*MRD (n=72)38%0.427URD (n=24)46%Graft source*PBSC (n=88)38%0.215Bone marrow (n=8)63%Transplantation period<2006 (n=42)33%0.368>=2006 (n=57)43%Conditioning regimen with ATGYes (n=68)43%0.164No (n=31)29%CMV detection methodpp65 (n=65)38%0.819PCR (n=34)39%Acute GVHD$HR=2.1 [1.1–3.9]0.032Chronic GVHD$HR=0.8 [0.1–8.6]0.837$The occurrence of GVHD was analysed as a time dependent variable Disclosures:No relevant conflicts of interest to declare.

Allo-SCT for multiple myeloma in the era of novel agents: a retrospective study on behalf of Swiss Blood SCT

Despite the introduction of novel drugs, cure of multiple myeloma remains rare. Allo-SCT can induce long-term remission, but randomized studies in advanced disease are lacking and the influence of novel drugs remains unclear. In our retrospective analysis of all patients with myeloma allografted in Switzerland, 95 patients were transplanted between 1988 and 2011. Most patients were heavily pre-treated, and 53% received novel drugs before transplant. In all, 51% were allografted after relapse or progression. Transplant trends changed over time with an increase in reduced intensity conditioning and unrelated donors. At the time of analysis 47 patients remained alive, with a median follow-up of survivors of 53 months. Acute GVHD II-IV and chronic GVHD (cGVHD) occurred in 49% and 53%, respectively; TRM at 5 years was 18%. Five-year OS and PFS were 51% and 29%, respectively. Patients who received transplant upfront vs after relapse had a significantly better outcome, as well as those who had a related donor and achieved CR post transplant. We found no impact of pre-treatment with novel drugs or cGVHD. Although long-term remission following allo-SCT can be achieved, GVHD and TRM remain major limitations. Our series suggests that benefit is highest when allo-SCT is used early in the disease.

Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma

Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti-myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46-64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs-host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients.

Allo-SCT for multiple myeloma: a review of outcomes at a single transplant center

Allogeneic stem cell transplant for multiple myeloma (MM) is one treatment associated with long-term disease-free survival. The high incidence of treatment-related mortality and relapses, however, are important reasons for controversy about the role of allografting in the management of MM. We reviewed our results of allografting for MM spanning a period of 34 years in order to better define long-term outcomes and identify areas of progress as well as areas requiring improvement. A total of 278 patients received allogeneic marrow or PBSCs after high-dose myeloablative (N=144) or reduced intensity, non-myeloablative (N=134) regimens. In multivariable analysis, adjusting for differences in patient groups, reduced intensity/non-myeloablative transplants were associated with significantly less acute GVHD, lower transplant mortality, better PFS and overall survival. There were no significant differences in relapse, progression or chronic GVHD, when adjusted. In multivariable analysis of patients receiving only non-myeloablative transplants, decreased overall survival and PFS were associated with relapse after a prior autograft and a β2 microglobulin >4.0. Transplant mortality was reduced and only influenced by a prior tandem autograft.

Reduced Intensity Conditioning Regimens Do Not Offer a Survival Advantage to Myeloma Patients Receiving Allogeneic Stem Cell Hematopoietic Transplantation: A Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC) Registry Study,

Abstract 4113 Purpose:Despite the raise of major new drugs in the management of multiple myeloma (MM), it is still an incurable disease and allogeneic stem cell transplantation (alloSCT) is currently the sole potential curative therapy mediated by a graft-versus-myeloma (GVM) effect. For over ten years, reduced intensity conditioning regimens (RIC) in alloSCT has been developed to maintain the GVM effect and to decrease the high transplanted related mortality (TRM) associated with myeloablative conditioning (MAC) in myeloma patients. Yet, as numerous studies have assessed RIC alloSCT versus autologous SCT, only few data provides a comparison between RIC and MAC for MM in large series. Our study aims to compare RIC and MAC alloSCT for MM on a large retrospective French cohort. Methods:We report a retrospective multicenter study based on the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry, evaluating the outcome of patients undergoing alloSCT for MM. Between 1995 and 2009, 811 patients allografted for MM were registered. Data concerning disease characteristics and the allograft procedure were screened using the French Promise® database; computerized discrepancy errors and data verification of every single file ensure data quality, important missing data were directly retrieved in each centre.We assign the type of conditioning regimen for each patient according to the registry’s data reported by the local physician and check this information according to the following rules. We consider as myeloablative (MAC) all regimens containing > 8 mg/kg oral busulfan, > 600 cGY TBI, ≥ 200 mg/kg cyclophosphamide or combinations as BEAM like regimens. All other chemotherapy combinations with or without TBI are defined as RIC regimens generally including fludarabine. Patients were excluded when major data or conditioning information were not available; 566 patients (70% of the entire cohort) were finally eligible for analysis, 478 RIC and 88 MAC.Chi-squared test and T-test were used for comparisons. Survival analyses (Overall survival, OS; progression-free survival, PFS) are made using the Kaplan-Meier curve and log rank test. Multivariate analysis is made using the Cox proportional hazards model. Results:The RIC and MAC populations were statistically different regarding age (respectively 53 versus 46 years, p<.0001), number of prior transplant (> 1 prior transplant in 94% RIC versus 77% MAC, p<.0001), time to transplantation (<12 months after diagnosis in 22% RIC versus 38% MAC, p=.001) and stem cell source (peripheral blood 84% RIC versus 52% MAC, p<.0001, and bone marrow 10% RIC versus 45% MAC, p<.0001).The 2-year OS is 69.5% after RIC and 79.9% after MAC (p<.0001); 5-year OS is 49.7% after RIC and 60.2% after MAC (p<.0001, fig.1). The 2 year PFS is 49.3% and 70.1% and 5-year PFS is 29.6% and 40.8% after RIC and MAC respectively (p<.0001, fig.2).Factors associated with better OS and PFS in multivariate analysis are the following in the whole cohort: < 12 months between diagnosis and alloSCT (p=.0078 and p=.0037, respectively); disease status at transplantation (at least partial response, p=.0409 and p=.0026); no or limited acute graft-versus-host disease (GvHD) (p<.0001 and p=.0094) and presence of chronic GvHD (p<.0001 and p<.0001). On multivariate analysis, the intensity of conditioning regimen (RIC vs MAC) do not appear statistically significant for OS (p = 0.64) and PFS (p = 0.17). For patients transplanted between 2006 and 2009, neither high risk-cytogenetic nor bortezomib use before transplantation seems to affect the outcome in multivariate analysis. [Display omitted] Conclusions: In the French practice, MAC regimens have had more limited indications due to their higher toxicity. This study suggests that the outcome after MAC-alloSCT is comparable to that after RIC-alloSCT with a trend to a better OS in the late follow-up (after 5 years) after MAC. The aspect of flattening in the survival curves suggests that the anti-tumoral action of the conditioning regimen remains essential on the anti-myeloma effect after alloSCT and that should be considered in the transplantation procedure. Disclosures:No relevant conflicts of interest to declare.

High-dose chemotherapy with autologous stem cell rescue for relapse after allo-SCT in multiple myeloma

High-dose chemotherapy with autologous stem cell rescue for relapse after allo-SCT in multiple myeloma