ALBERT

Description: Adoptive immunotherapy based on the injection of allogenic cytotoxic T-lymphocytes (CTL) during or after bone marrow transplant (BMT) has established itself as a potent anti-neoplastic treatment for several malignancies. However this approach is limited by the occurence of graft versus host disease (GVH). Using a previously described murine adoptive immunotherapy model where donor and recipient are mismatched for a single dominant minor histocompatibility antigen (H7a), and where a powerful anti-neoplastic effect is seen without GVH, we sought to determine what rendered cancer cells more vulnerable than normal cells to immune attack. B10.H7a mice were lethally irradiated and reconstituted with B10.H7b (H7a negative) T-depleted bone marrow. On the day of transplant, these mice received a B16.F10 (H7a positive) melanoma challenge. Adoptive transfer of splenocytes obtained from B10.H7b mice previously immunized with B10.H7a splenocytes was performed on day 7 post BMT. Following transfer of those splenocytes containing primed anti-H7a CTL, neither GVH nor vitiligo was noted in recipients despite the fact that H7a is expressed in all tissues and organs. 50% of treated mice, versus 0% of controls rejected the tumor and survived 100 days. Overall survival was increased to 80% when adoptive transfer was carried on day 3 post BMT. The injection of anti-H7b CTL had no effect on melanoma growth. Thus, the anti-tumor activity was T-cell receptor recognition dependent and not a mere bystander effect. In treated mice but not in controls, tumor histology and flow cytometry revealed important CTL infiltration (80% of those CTL being MHC-H7a tetramer positive), increased expression of MHC class I molecules (MHC I) at melanoma cell surface, expression of Rae-1 (an NKG2D ligand), tumor necrosis and decreased angiogenesis. Importantly, normal skin in treated or control animals showed no increased expression of MHC I or Rae-1. B16.F10 melanoma cells express almost no MHC I, and no Rae-1 when cultured in vitro. Co-incubation of B16.F10 cells with INFγ leads to increased MHC I expression but no induction of Rae-1 expression, implying that at least a second factor is present in vivo to account for the expression of this stress ligand. An additional role for INFγ was evidenced when anti-H7a CTL were injected in INFγ receptor knock-out recipients. The angiostatic effect noted after anti-H7a CTL injection was abrogated and no mice were cured. Thus, INFγ-mediated angiostasis on the tumor stroma was crucial for the inhibition of cancer progression. Conclusion: in our model, the differential immune susceptibility of tumor versus normal cells appears to stem from the fact that neoplastic cells are induced to express more MHC I and stress ligands such as Rae-1. Those can respectively increase target antigen density at the cell surface and mediate CTL co-stimulation or cytotoxicity, through NKG2D receptors. Strategies exploiting stress ligand induction as well as the effect of INFγ on MHC expression and angiostasis may contribute to successfully separate anti-tumor from GVH effects.

Description: Many new therapeutic agents have been approved for follicular lymphoma (FL) but none appear to be curative. Despite novel agents, some patients (pts) experience early relapse, become chemorefractory or suffer transformation into more aggressive lymphomas. Options for these pts are limited. High dose chemotherapy with autologous stem transplant (ASCT) prolongs progression free survival (PFS) and overall survival (OS) in FL pts in first relapse and registry data shows favorable outcome with ASCT in cases of histologic transformation. However, ASCT is usually not curative. Myeloablative allogeneic transplant (MT) has produced long term PFS but is hampered by significant non relapse mortality (NRM) while nonmyeloablative transplant (NMT) has a higher relapse rate compared to MT especially in high risk pts. Finally, many transplant studies have excluded these high risk pts such as those with chemorefractory or transformed disease. We hypothesized that a tandem transplant consisting of an ASCT followed by a NMT would confer the same benefit as a MT without the associated high NRM by separating the high dose chemotherapy from graft versus host disease (GVHD) while preserving the graft versus lymphoma effect. The goal of our study was to improve long term PFS in high risk FL pts. We therefore initiated a prospective protocol in April 2003, for pts with high risk relapsed FL as defined by chemorefractory disease, early 1st relapse, 〉1st relapse or transformation into aggressive histology. At least one therapy was attempted to document chemosensitivity prior to ASCT. However, regardless of disease status prior to transplant, pts underwent ASCT followed 3 months later by an outpatient NMT from an HLA-identical sibling. NMT comprised 5 days of fludarabine 30 mg/m2/day and cyclophosphamide 300mg/m2/day followed by an infusion of 〉2x106CD34+ cells/kg. GVHD prophylaxis, chosen to take advantage of the low incidence of acute (a) GVHD and the putative protective effect of chronic (c) GVHD, consisted of tacrolimus starting on day (D) - 8 to achieve levels of 8-12 nmol/L then tapered off by D+100 or D+180 depending on disease risk and of mycophenolate mofetil 1g bid from D+2 to D+50. We previously reported on 27 pts with a follow-up (f/u) of 3 years (yrs). We now report a larger cohort of 40 pts with a median f/u of 8 yrs. Up until July 2015, 40 pts were enrolled with a median age of 50 yrs (34-65). Pts had previously been treated with a median of 3 lines of therapy (2-6). Median time from diagnosis to ASCT was 33 months. Disease status at ASCT was: 14 CR, 16 PR and 10 refractory. Conditioning for ASCT included BEAM/BEAC (n=39), and Cy-TBI (n=1). In addition, 4 pts received radiotherapy after ASCT to sites of previously bulky disease. Median time between ASCT and NMT was 138 days (75-238). Pre NMT disease status was: 25 CR, 12 PR and 3 refractory. Engraftment was prompt in all pts after ASCT and median neutrophil and platelet recovery were respectively 13 days (0-19) and 0 day (0-18) post NMT. Seven pts (18%) developed aGVHD: 2 grade II and 5 grade III. Overall, 29 pts (73%) developed cGVHD: 1 mild, 13 moderate and 15 severe according to NIH revised criteria. Median time to discontinuation of immunosuppression was 22 months. To date, 2 pts have progressed at 11 and 59 months post NMT (one died from relapse and one is now in CR after chemotherapy and DLI) and 5 pts died from either GVHD related complications (n=4) or unknown cause (n=1). All pts alive at last f/u were in CR. With a median f/u of 8 yrs in surviving pts (1-12), OS is 95% at 3 and 5 yrs and 82% at 8 yrs. PFS is 92% at 3yrs, 89% at 5 yrs and 80% at 8 yrs. NRM and relapse rate at 8 yrs are 18% and 6% respectively. Based on our current results in 40 pts, we conclude that ASCT followed by sibling NMT for high risk relapsed FL is associated with excellent disease response and PFS. Furthermore, this tandem strategy appears to be safe and well tolerated. The incidence of cGVHD remains high but could in part explain the impressive PFS in this high risk cohort. This approach should now be further explored in a multi institution setting, include matched unrelated donors and consider the addition of rituximab post-transplant to reduce the incidence and severity of cGVHD with the hope that relapse will not be increased. Figure 1 Figure 1. Disclosures Busque: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Description: Introduction: High dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (AHCT) are considered standard of care as first line therapy in mantle cell lymphoma (Dreyling et al., 2005; Geisler et al., 2012) and in first line refractory and chemosensitive relapse Non-Hodgkin Lymphoma (NHL) (Philip et al., 1995) . The development of hematopoietic cell transplant comorbidity index (HCT-CI) (Sorror et al., 2009) for recipient selection and transplant risk evaluation have impacted on patient selection. Over the last decade, most transplant program have seen an increase in the median age of AHCT recipients(McCarthy et al., 2013). Limited data are available to optimise elderly patients selection for transplantation while minimising the risk of treatment related toxicity and mortality (TRM). The goal of this study was to identify factors impacting the safety and efficacy of AHCT in the elderly NHL patients in order to better select those who will benefit from this intervention. Method: This is a single center, retrospective study examining outcomes of AHCT in elderly patients (≥60 years old) with NHL. Between January 1st, 2008 and January 1st, 2015, 90 patients met the inclusion criteria and were included in the study. Patients signed an informed consent and the ethics committee of our institution approved the study. Progression-free-survival (PFS) and overall survival (OS) were analyzed according to age at time of transplantation, HCT-CI, lymphoma histology and disease status at time of transplant. Toxicities were analyzed according to age and HCT-CI. Results: Median age at time of NHL diagnostic was 60 years (range 42 to 68) and 63 years at time of transplant (range 60 to 69). One third (33%) of our cohort was ≥65 years old. Histologic sub-type was mainly composed of follicular (36%), mantle cell (20%) and large B-cell lymphoma (38%). 50% of patients had high-risk disease and 31% had low risk disease. HCT-CI was low-risk in 34%, intermediate risk in 40% and high-risk disease in 26%. BEAM/BEAC conditioning regimen was used in 94%. The median graft CD34+/kg cell dose infused was 4.87. The median time to neutrophil engraftment was 10 days (range 8 to 14 days) and platelet recovery was 16 days (range 11 to 43 days). The incidence of febrile neutropenia was 92% with 2% admission to the intensive care unit (ICU) with no difference between patients younger or ≥65 years old. Our cohort received a median of 8 days of antibiotics (range 0 to 41 days). Absolute lymphocyte count 〈 0,3 X 103 cells/uL at 14 days after transplant was associated with higher incidence of septic choc (p=0,024) and ICU admission (p=0,034). Age ≥65 year was not associated with an increase TRM and was surprisingly associated with less total parenteral nutrition (p=0,046) and narcotics uses (P=0,011). The median length of stay was 26 days. The median follow-up was 27 months (range, 1 to 87), median PFS of 46 months (Confidence Interval (CI); 95%, 24,4-67,6) (graph 1) and OS not reached (graph 2). The estimated 5 years OS is 62% and PFS is 40%. Transplant related mortality (TRM) was only 1% at 100 days and 2% at 1year after transplant. The only 2 patients who died from TRM died from cardiac arrest (1 month) and from an unknown cause (3 months). The 1-year progression rate was 30% (graph 3) and mortality rate only 12%. Progressive disease status following first line therapy was associated with a worse PFS compared to the achievement of a complete remission (Hazard Ratio (HR) 2,77; CI 95%, 1,18; 6,49). Progressive disease status at time of transplant was also associated with a lower PFS (HR 9,30: CI 95% 2,55 to 33,92) and OS (HR 13,44: CI 95% 2,68 to 67,48). HCT-CI score did not correlate with OS. International Prognostic Index (IPI), age and treatment type did not influence PFS or OS. Surprisingly, HCT-CI score did not correlate with toxicities, morbidity or mortality. Conclusion: In this single center retrospective study of elderly patients with NHL, AHCT was proven to be safe and effective. Progressive disease at the time of transplant was associated with worse PFS and OS. HCT-CI did not allow the categorization of patients in different prognostics group. Lymphocyte count at day 14 could identify patients at significant risk of complications. Our data suggest that age alone should not exclude patients from transplantation. However, HDT and AHCT should be reserved to chemosensitive patients and avoided in the elderly patient with progressive disease. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative option for multiple myeloma (MM). Unfortunately, relapses remain frequent and randomized controlled trials have yielded equivocal conclusions. Before these trials were published, selected patients were treated with alloHSCT, but factors affecting long-term success have not been clearly defined. We have analyzed our single-center cohort of MM patients receiving a myeloablative alloHSCT in the 1990's in order to evaluate the impact of several factors on outcomes. Methods We performed a retrospective data collection on all patients treated with myeloablative alloHSCT from a sibling donor at our institution. Probabilities of overall (OS) and progression-free survival (PFS), as well as relapse, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) incidences were estimated taking competing risks into account when appropriate. Regression analysis using Cox and Fine & Gray models were used to determine factors influencing outcomes. Severity of chronic GVHD was assessed by the proportion of survivors on systemic immunosuppressive therapy. Results Between 1990 and 2001, 39 patients received a myeloablative alloHSCT. Median age was 46 years (range 24-53) and 68% had Durie-Salmon stage III disease. Twenty patients had received more than 4 cycles of prior chemotherapy and 4 patients had been treated with an autologous HSCT. Complete remission (CR) was achieved before allogeneic transplant in 31% patients. All but one donor were 6/6 HLA matches. AlloHSCT was performed within the first year of diagnosis in 69% of patients. Irradiation-based conditioning was used in 77%; stem cell source was bone marrow in 54% and peripheral blood (PB) in 46% of patients. With a median follow-up of 13 years, cumulative incidences of progression and NRM were 43% (95%CI: 26-59; Fig. 1) and 38% (22-54), respectively. Cumulative incidences of grade II-IV acute and extensive chronic GVHD were 29% (16-44) and 40% (24-55). Probabilities of 10-year OS and PFS were 33% (95%CI: 19-48; Fig. 2) and 29% (95%CI: 16-44) In multivariate analysis, the most significant protective factor against relapse was the use of PB as cell source (HR 0.34, CI: 0.14-0.82). The only protective factor for PFS was CR status before transplantation (HR 0.28, CI: 0.09-0.89). Nevertheless, the effect of these variables on overall survival was inconclusive (respectively: HR 0.51, CI 0.22-1.17, and HR 0.39, CI: 0.13-1.19). The time-dependent effect of chronic GVHD on PFS was also statistically non-significant (HR 0.47, CI: 0.14-1.59). The probability of being on systemic immunosuppressive treatment for GVHD in alive patients was 31% (CI: 13-58) at 10 years. Conclusions Myeloablative alloHSCT performed for MM in the 1990's in selected patients allowed a high probability of disease control but with major toxicity as shown by the high NRM risk. A third of patients are alive 10 years after transplantation. Achievement of CR before alloHSCT and the use of PB stem cells were protective against transplant failure. However, small sample size does not allow us to draw conclusions on the effect of other pre-transplant characteristics and GVHD on OS. The risk of relapse in our cohort being comparable to published results in frontline reduced-intensity alloHSCT, superiority of myeloablative HSCT for advanced disease can be hypothesized. Prohibitive NRM risk should encourage efforts to reduce early and late toxicity through better patient and donor selection, conditioning regimen and GVHD prophylaxis. Disclosures: No relevant conflicts of interest to declare.

Description: Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus 〉80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

Description: Introduction: Multiple myeloma (MM) remains incurable with standard therapies. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for these patients. We hypothesized that bortezomib (BTZ) consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could improve quality of response while decreasing relapse and cGVHD. We also sought to determine prospectively the predictive value of bone marrow minimal residual disease (MRD) evaluation using a highly sensitive flow cytometry assay. Methods: Newly diagnosed myeloma (NDMM) patients ≤65 years with high-risk (HR) features (based on cytogenetics, ISS 3 or plasma cell leukemia) or ≤50 year regardless of risk status with an 8/8 HLA matched donor are eligible to participate in this prospective trial. After a BTZ-based induction and ASCT, outpatient NMA alloSCT is performed with either fludarabine and cyclophosphamide (sibling donor) or fludarabine and TBI 2 Gy (unrelated donor) followed by peripheral blood stem cells. GVHD prophylaxis consists of tacrolimus and MMF. BTZ is initiated on day +120 post-alloSCT at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow MRD evaluation is performed on 10x106 nucleated cells with highly sensitive (≥10-5) next-generation flow cytometry using the 8-color EuroFlow protocol (CD45, CD38, CD138, CD56, CD19, CD27, CD81, CD117, CyIgκ and CyIgλ) before alloSCT, before BTZ and every 3 months for 2 years. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated prospectively. Results: As of June 29th 2018, 37 patients have been enrolled with a median age of 53 (range: 35-64) years. ISS 3 is found in 43% and HR cytogenetics in 54% (5% del17p, 14% t(4;14), 22% gain 1q21 and 14% 〉1 HR cytogenetics). Induction consisted of CyBorD (81%) or VTD (19%) for a median of 4 (range: 4-7) cycles. Median times from induction to ASCT and from ASCT to alloSCT were 5.8 and 4.4 months, respectively. Sibling and unrelated donor transplants were performed in 43% and 57%, respectively. KPS and HCT-CI were 90 (range 80-100) and 1 (range 0-3), respectively. Median follow-up is 21 (range 0-39) months after alloSCT. Of enrolled patients, 34 have started BTZ and received 92.5% of planned doses, with no dose reduction needed for toxicity. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ included diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1 BK) and nocardial brain abscesses (n=1). Cumulative incidences of grade II-IV and III-IV aGVHD were 26% and 11%. Incidences of all grade, moderate/severe and severe cGVHD at 24 months were 61%, 47% and 10%, respectively, with mostly mouth, skin and liver involvement. Compared to 27 historical controls who did not receive BTZ after tandem transplant, the incidence of moderate/severe cGVHD was much lower in BTZ recipients (47 vs 78%; p=0.002). After reviewing each target organ involvement, mouth and eye cGVHD were significantly less severe with BTZ. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a 24-month non-relapse mortality of only 8%. BTZ consolidation improved depth of response, increasing ≥CR rate from 64% to 85% and iCR rate from 25% to 59%, regardless of cytogenetic abnormalities (Table 1). Probability of progression-free survival (PFS) at 24 months was 65% (CI 95%: 42-81) while overall survival (OS) was 90% (CI 95%: 70-97; Fig. 1A). The cumulative incidence of progression at 24 months was 28%. Importantly, the presence of ≤50 myeloma cells in the bone marrow 10 months post-alloSCT (after 6 months of BTZ) was associated with a significantly lower probability of progression (15% versus 80%; p=0.03; Fig. 1B). Conclusion: Tandem ASCT-NMA alloSCT followed by BTZ consolidation results in a remarkably high rate of ≥CR, including iCR. For the first time in allogeneic transplant recipients, MRD evaluation using the EuroFlow protocol demonstrates that identification of ≤50 myeloma cells in the bone marrow 10 months after alloSCT/6 months after BTZ seems predictive of a better outcome. If confirmed, this landmark could be used to design future therapeutic interventions in order to decrease the risk of relapse after tandem transplant. Finally, BTZ following alloSCT is safe and may contribute to decrease both incidence and severity of cGVHD. Disclosures Leblanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Cohen:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent. Sauvageau:ExCellThera: Employment, Equity Ownership. Roy:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

Description: Introduction: Allogeneicstem cell transplantation (alloSCT) is the only curative modality for newly diagnosed multiple myeloma (NDMM) patients (pts). However, we have previously shown in a large cohort of 92 pts that relapse remains common (49%) and the incidence/severity of chronic GVHD is significant (79%) after tandem auto-allo SCT in NDMM pts (Ahmad et al. BMT 2016;51:529). We hypothesized that a tandem auto-nonmyeloablative (NMA) alloSCT followed by bortezomib (btz) consolidation might be safe, while decreasing both the severity/incidence of chronic GVHD and the risk of relapse in young and/or high-risk NDMM pts. In addition, we hypothesized that btz might further increase depth of responses after alloSCT. Methods: NDMM pts with either ISS stage III, plasma cell leukemia, abnormal cytogenetics defined as t(4;14) with ISS II or III, t(14;16), t(14;20), 17p-, 1p-, or 1q+ in ≥ 10% of purified plasma cells or age ≤ 50 years with a 6/6 sibling or 8/8 unrelated donor were prospectively enrolled in this phase II trial. After a btz-based induction with ≥ partial response and autologous (A) SCT, outpatient NMA alloSCT was performed with either a conditioning of fludarabine 30 mg/m2 x 5 days and cyclophosphamide 300 mg/m2 x 5 days (sibling donor) or fludarabine 30 mg/m2 x 3 days and TBI 2Gy (unrelated donor), followed by G-CSF mobilized stem cells infusion. Acute GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. Btz 1.3 mg/m2 SC every 2 weeks was started on day +120 after alloSCT for 1 year. Bone marrow aspirates before alloSCT, before starting btz and every 3 months thereafter were prospectively collected for 2 years in order to assess the impact of btz on minimal residual disease (MRD) by a highly sensitive (≥10-5) multiparametric flow cytometry using the 8-color Euroflow protocol evaluating ≥ 10 x 106 cells/specimen. MRD negativity was defined as the detection of 〈 30 clonal aberrant plasma cells. Response evaluation is based on IMWG criteria including immunophenotypic complete response (iCR) defined as a stringent CR (sCR) plus a negative MRD. Immunophenotypic remission (iR) is defined as MRD negativity regardless of other disease status. Results: As of 06/30/2016, 20 MM pts have been enrolled and 18 allotransplanted (8 siblings; 10 unrelated); median age is 54.5 (range 35-63) years. Of these pts we report: age ≤ 50 (n=6), ISS stage III (n=10) or poor risk cytogenetics (n=7; 5 with 1q+, 2 with t(4;14)). Pts received initial induction with VTD (n=7) or CyBorD (n=11), followed by ASCT (melphalan 200 mg/m2; median CD34+/kg infused: 7.2 x 106). Median times from diagnosis to ASCT and from ASCT to alloSCT were 7.0 (range: 5.3-11) and 4.8 (range: 3.0-7.0) months, respectively. All pts allotransplanted (median CD34+/kg infused: 7.4 x 106) engrafted. With a median follow-up of 282 (range: 22-562) days after alloSCT, 15 pts have received 221 of 239 (92%) planned doses of btz. Observed grade ≥3 non-hematologic adverse events include btz-induced diarrhea (n=1), herpes mucositis despite adequate prophylaxis (n=1), viral hemorrhagic cystitis (n=3) and asymptomatic EBV reactivation (n=4) requiring rituximab. In contrast, CMV reactivation was infrequent. None of the pts developed or exacerbated pre-existing peripheral neuropathies. Fifteen pts were followed ≥ 7 months after alloSCT; acute GVHD occurred in 3 pts (1 grade II; 2 grade III) and chronic in 10 (67%; 3 mild; 7 moderate). Two pts died from grade III acute GVHD. Nine pts (60%) required hospitalization for a median of 13 days (8-184). Response rates after induction, ASCT, alloSCT and btz are shown in Table 1. Most notably, depth of response improved after btz, with 6 pts (40%; 2 with 1q21, 1 with t(4;14), 2 normal and 1 unknown) in iCR and 4 pts (27%; 1 with 1q21, 2 normal and 1 unknown) in sCR. An additional 20% of pts not in iCR or sCR were in iR with negative MRD. No patient developed extramedullary disease. Conclusions: Our major finding is a high sCR + iCR of 67% in young and/or high-risk NDMM pts following tandem auto-alloSCT and btz consolidation. Although our follow-up is still short, our results are encouraging for an eventual low relapse rate. Additionally, administration of btz 1.3 mg/m2 SC every 2 weeks starting on day +120 after alloSCT is safe and well tolerated. Finally, close monitoring of EBV should be performed prospectively in alloSCT recipients who receive a proteasome inhibitor in order to better assess the risk of viral reactivation. Disclosures Sebag: Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria.