ALBERT

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.