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Background: To date, the only potential curative treatment for multiple myeloma (MM) remains allogeneic (allo) hematopoietic cell transplant (HCT), although, most patients will eventually relapse. In relapsed patients, donor lymphocyte infusions (DLIs) have been reported to control disease, but the optimal strategy prior to and doses of DLIs remain unclear. With this study (NCT03413800), we aimed to investigate the efficacy and toxicity of lenalidomide and dexamethasome (Len/Dex) followed by escalating pre-determined doses of DLIs in MM patients who relapsed after allo HCT., Methods: Patients aged 18-65 years with relapsed MM following upfront tandem autologous (auto)/allo HCT were eligible. Treatment consisted of six cycles of Len/Dex followed by three standardized doses of DLIs: 5 × 10 6 CD3+/kg, 1 × 10 7 /kg and 5 × 10 7 /kg every 6 weeks. Bone marrow minimal measurable disease (MRD) using flow cytometry (10 -5 ) was performed at enrolment, then every 3 months for 2 years or until disease progression, in a subset of patients. The primary endpoint was efficacy as measured by progression-free survival (PFS) at 2 years following Len/Dex/DLIs. Secondary objectives were safety including GVHD, response including MRD status and overall survival (OS)., Results: A total of 22 patients participated in this study, including 62% with high-risk cytogenetics. With a median follow-up of 5.3 years (range: 4.1-6.1), PFS and OS were 26.5% (95% CI: 10.4-45.9%) and 69.2% (95% CI: 43.3-85.1%), respectively. Overall, the best responses achieved post-Len/Dex + DLIs were complete remission in 9.1%, very good partial response in 50%, and progressive disease in 40.9%. Among the nine patients tested for MRD, only two achieved a negative status after receiving DLIs. Six patients died, all due to disease progression. No acute GVHD was observed after DLIs. We report a very low incidence of moderate/severe chronic GVHD of 18.2% with no need for systemic immunosuppressants one year after diagnosis. No unexpected adverse events were observed. Interestingly, a positive correlation between response to Len/Dex re-induction and response to DLIs was found ( p = 0.0032)., Conclusions: Our findings suggest that Len/Dex/DLIs in second line treatment after upfront tandem auto/allo HCT in relapsed MM patients remains feasible and safe. With a potential correlation between induction chemotherapy and DLI responses, more potent induction regimens together with higher doses of DLIs should be considered in the future.

Allogeneic hematopoietic cell transplantation (HCT) has curative potential in myeloma but remains hampered by high rates of relapse and chronic graft-versus-host disease (GVHD). We hypothesized that bortezomib (BTZ) as maintenance therapy after allo HCT could not only decrease the incidence of relapse but also the incidence and severity of chronic GVHD. The primary endpoint of this study was to determine whether BTZ maintenance decreases the incidence and severity of chronic GVHD using National Institutes of Health (NIH) criteria. The secondary endpoints were to determine the immunosuppression burden, organ involvement and survival (overall survival, progression-free survival) in patients either receiving or not receiving BTZ. In this retrospective study, we compared the outcome of 46 myeloma patients who received BTZ after upfront tandem auto-allo HCT between 2008 and 2020 to 61 patients without maintenance. We explored the impact of BTZ maintenance on incidence and severity of chronic GVHD using the 2014 NIH criteria. At 2 years, incidences of overall (61.2% versus 83.6%; P = .001), and moderate/severe chronic GVHD (44.5% versus 77.0%; P = .001) were significantly lower in BTZ recipients who had less mouth (43% versus 67%; P = .018) and eyes (9% versus 41%; P = .001) involvement at initial diagnosis. We report a lower use of systemic steroids (45.1% versus 76.4%; P < .001), mycophenolate mofetil (15.5% versus 28.2%; P = .031) and tacrolimus (34.5% versus 70.6%; P < .001) in BTZ recipients. Probability of being alive and off systemic immunosuppressants at 3 years was 77% in BTZ recipients and 56% in controls (P = .046). To date, there is no difference in survival between both groups. In summary, BTZ maintenance improved incidence and severity of chronic GVHD and should be considered as a valid option in myeloma patients receiving upfront tandem auto-allo HCT., Competing Interests: Conflict of interest statement There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Despite novel drugs and autologous HCT, MM remains incurable, with short survival in patients with poor biological characteristics. Allo HCT may be curative in some patients but is hampered by high rates of toxicity and relapse. We hypothesized that bortezomib (BTZ), with its anti-myeloma and immunologic properties, could improve PFS and cGVHD after allo HCT in newly diagnosed MM patients. In this prospective phase II study, we included 39 young (≤50 years) and high-risk patients who received a tandem auto-allo HCT followed by BTZ. Patients had prospective minimal residual disease (MRD) evaluations using Next-Generation Flow cytometry prior to allo HCT, prior BTZ and every 3 months for 2 years. With a median follow-up of 48 months, we report PFS and OS at 5 years of 41% and 80%, with a non-relapse mortality of 12%. Incidences of grade II-IV aGVHD at 12 months and moderate/severe cGVHD at 2 years were 26% and 57%. In a multivariate analysis model including cytogenetics, ISS and MRD status, MRD positivity prior to allo HCT (HR 3.75, p = 0.037), prior BTZ (HR 11.3, p = 0.018) and 3 months post-BTZ initiation (HR 9.7, p = 0.001) was highly predictive of progression. Peritransplant MRD assessment thus strongly predicts disease progression., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression., Methods: In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only., Results: With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P ≤ .001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P ≤ .001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P = .550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P = .002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P = .062); median PFS was also similar., Conclusion: Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)