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Background Maintenance therapy (MT) deepens response and prolongs progression free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) after frontline regimens. Ixazomib, a 2 nd generation oral proteasome inhibitor (PI), has been approved for MT because of the convenience and tolerability. Aims We conducted this prospective multi-center study to compare the efficacy and safety of Ixazomib (I-MT) or Ixazomib plus Lenalidomide (IL-MT) to Lenalidomide (L-MT) as maintenance regimens in NDMM patients. Methods This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and registered (NCT04217967). NDMM patients were enrolled from 10 centers of North China MM Registry since September 2019. After 4 cycles of front-line induction therapy, patients who reached partial response (PR) would receive autologous stem cell transplantation (ASCT) if eligible, or keep up to 5 cycles of front regimens if ineligible, then start maintenance therapy. Patients did not reach PR would switch to a 2nd-line induction for 2-5 cycles and start MT once PR was achieved. For MT, 4mg of Ixazomib was given on day 1,8,15, and 25mg of Lenalidomide every other day on days 1-21 of a 28-day cycle. Patients in dual drug group were administrated with both Ixazomib and Lenalidomide, dose as listed above. The primary endpoint was PFS from MT. Results A total of 149 patients were enrolled, including 54 in I-MT, 65 in L-MT and 30 in IL-MT. The demographic and clinical characteristics were comparable among three groups at baseline (Table 1), including gender ratio, age, paraprotein isotype, ISS, R-ISS, response status before MT, and ASCT rate. The proportions of patients with high-risk cytogenetic abnormalities (HRCAs), defined as amplification 1q21, deletion 17p, t(4,14) and t(14,16), were comparable. The median follow-up duration since MT was 6.1, 11.1, and 5.9 months in I-MT, L-MT and IL-MT group, respectively. Disease progression developed in 9.3%, 12.3% and 10% (N=5, 8, 3, respectively) patients. The median PFS was not reached (NR) in all groups. Only one death occurred in I-MT group. There were 84%, 72.3% and 83.3% of the patients reached very good partial response (VGPR) or better before MT, while the best response rates rose to 93%, 82.3% and 90% during maintenance. The prevalence of peripheral neuropathy was 18.5% on I-MT, 10.8% on L-MT and 30% on IL-MT. Grade 2 PN occurred in 3, 1, and 0 patients, respectively. The incidence of gastrointestinal events was 11.1%, 1.5% and 20%, respectively. Grade 3-4 hematologic toxicities was 3.7%, 4.6%, and 3.3%. Infection rates were 7.4%, 6.2% and 3.3%. Skin rashes were more common in lenalidomide containing regimens (3.7%, 7.3% and 6.7%). No drug withdrawal was related to adverse events. Conclusions Due to inadequate access to melphalan and low rate of ASCT in China, there is still a gap of PFS in NDMM patients with those in western countries. We herein design this multi-centered prospective study to evaluate if dual drug MT will further strengthen response and make up the gap. Though the primary endpoint--PFS has not been reached in all treatment groups, dual MT improves response most and is quite tolerable. Figure 1. Baseline Characteristics in three groups. Abbreviations: ISS: international staging system; R-ISS: revised-ISS; HRCAs: high risk cytogenetic abnormalities. sCR: stringent complete remission. CR: complete remission. VGPR: very good partial remission. PR: partial remission. * p ＜ 0.05. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The ubiquitin-proteasome pathway (UPP) plays a key role in the intracellular degradation of abnormal and misfolded proteins in eukaryotic cells. Multiple myeloma (MM) is a common hematologic malignancy caused by clonal expansion of malignant plasma cells. Proteasome-targeted drugs such as carfilzomib, which is a selective proteasome inhibitor (PI), could play an important role in the treatment of diseases such as MM.MM cells were treated with different concentrations of carfilzomib and apoptosis as well as the viability of MM cells were measured by flow cytometry analysis and MTT assay. We also measured the effect of carfilzomib on the proliferation of myeloma cells by DNA incorporation of the pyrimidine analog BrdU. The effect of carfilzomib on apoptosis was detected by immunofluorescence TUNEL staining and western blot. We also verified its effect on the STAT1/COX-2/iNOS pathway by western blot.Carfilzomib inhibited the growth of MM cells in a concentration-dependent manner, with the strongest inhibitory activity on RPMI-8226 cells. Carfilzomib also induced apoptosis of MM cells in a concentration-dependent manner, with the strongest effect on RPMI-8226. BrdU assay was then performed with RPMI-8226 cells, and the results showed that carfilzomib inhibited cell proliferation in a concentration-dependent manner. Immunofluorescence TUNEL staining and western blot assays showed that carfilzomib induced apoptosis in a dose-dependent manner, and promoted the expression of apoptosis-related proteins such as cleaved-caspase-3, cleaved-caspase-3, Bax and Bcl2. Western blot also verified that carfilzomib promoted STAT1 inhibition and subsequently inhibited COX-2 and iNOS.Inhibition of the STAT1/COX-2/iNOS signaling pathway by carfilzomib not only inhibited MM cell proliferation, but was also an important mechanism of inducing MM cell apoptosis.

Background Maintenance (MT) after front-line therapy is the current standard for multiple myeloma (MM). However, no adequate data has shown the present situation of maintenance treatment in China yet, and autologous stem cell transplantation (ASCT) rate is still low in eligible newly diagnosed MM (NDMM) patients. Hence, we conducted this retrospective real-world study on efficacy and safety of the mainstream maintenance regimens in non-transplant NDMM patients-thalidomide (T-MT), lenalidomide (L-MT) and bortezomib (B-MT). Methods Clinical data were collected from 9 centers of North China MM Registry, during January 2010 to December 2020. The progression-free (PFS) and overall survival (OS) from maintenance, and drug toxicities were compared in T-MT, L-MT and B-MT groups. Thalidomide 75-150mg/day was administrated in T-MT group. L-MT group received lenalidomide as 25mg every other day or 10mg daily, on day 1-21 of a 28-day cycle. Bortezomib (1.3 mg/m 2 s.c.) was administered every other week or 4 vials every 3 months. Dexamethasone was given along with L or B in some patients. Results A total of 355 patients were enrolled including 159 in T-MT, 143 in L-MT and 53 in B-MT. At baseline, the gender ratio, paraprotein isotype, ISS and R-ISS stage, as well as response status before MT were comparable. Patients on L-MT were significantly older than the other groups. Meanwhile, greater proportions of patients in L-MT and B-MT groups had high-risk cytogenetic abnormalities (HRCA), defined as amplification 1q21 (1q21+), deletion 17p (17p-), t(4,14), t(14,16). The median follow-up duration since maintenance was 40.1, 19.6 and 22.2 months (m) in T-MT, L-MT and B-MT groups, respectively. There were 67.9%, 61.5% and 60.4% patients with T-MT, L-MT and B-MT achieving very good partial response (VGPR) or better before maintenance. Disease progression was recorded in 101 patients (63.5%) with T-MT, 54 (37.5%) with L-MT and 19 (35.8%) with B-MT. While mortality was 46 (28.9%), 22 (15.3%) and 4 (7.5%), respectively. The median PFS was 23m in T-MT, as compared with 26.9m in L-MT and 37.0m in B-MT (p=0.59). Median OS was 91.0M in T-MT, whereas not reached (NR) in the others (p=0.50). Patients reached complete response (CR) or stringent CR (sCR) before MT had prolonged PFS compared to those with VGPR or less in T-MT (28.0m vs 17.0m, p=0.06) and L-MT group (27.4m vs 18.2m, p=0.02), while comparable in B-MT (NR vs 30.8m, p=0.25). Meanwhile, patients in each group had similar OS despite of different responses before MT. Patients with 1q21+ on T-MT had shorter median PFS compared to those without (12.2m vs 21.0m, p=0.08), as well as impaired median OS (53.1m vs 81.0m, p= 0.004), despite various second line therapies. While the PFS of L-MT was 26.9m for patients with 1q21+ and 27.4months for those without (p=0.99). In B-MT group, the PFS was 43.5m and 30.2m (p=0.64), respectively. Median OS was not reached in both L-MT and B-MT. Only a few patients with 17p- in T-MT and B-MT, yet also presented remarkably inferior PFS (7.0m vs 21.0m, p=0.011) and OS (32.0m vs 81.0m, p=0.001) with thalidomide. As for L-MT, PFS (22.2m vs 27.4 m, p=0.19) and OS (NR vs NR, p=0.55) were not of discrepancy between 17p- or without. In B-MT, PFS (30.8m vs NR, p=0.99) was similar, though median OS was not reached, inferior tendency was observed (p= 0.04). As for patients with any adverse CA, T-MT resulted in impaired PFS (12.0m vs 23.0m, p=0.02) and OS (53.0m vs NR, p＜0.01). In contrast, PFS and OS were both comparable in patients with L-MT or B-MT no matter with HRCA or not. The main reason of maintenance withdrawal was disease progression. Among patients with detailed records of adverse effects, adverse event related discontinuation was seen in 5.3%(n=5), 6.1%(n=3) and 0 patients in T-MT, L-MT and B-MT, respectively. Conclusions In this multi-centered real-world maintenance study, thalidomide, lenalidomide or bortezomib after front-line therapy in non-transplant NDMM patients has similar PFS and OS. However, patients on L-MT and B-MT have greater proportion of HRCAs, which drags down survival in T-MT especially with 1q21+ and 17p-, while L-MT and B-MT mostly reverses the negative effects. Clinicians in the real practice prefer to select lenalidomide or bortezomib as maintenance in patients with HRCAs, while thalidomide is still an option for patients with standard risk. Figure 1. A) Baseline characteristics in three groups. * p＜ 0.05. B) PFS of the three groups. C) OS of the three groups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Purpose: To explore the efficacy and toxicity of adoptive immunotherapy with donor lymphocyte infusion(DLI) after allogeneic nonmyeloablative stem cell transplantation (allo-NST). Methods: We retrospectively sum up the clinical data of 28 patients who had been performed with allo-NST among 41 patients and had been treated with DLI for 72 times between October 1999 and October 2004. Among these patients, there are 20 chronic myeloid leukemia (CML), 16 acute leukemia (AL), 2 multiple myeloma (MM) and 3 solid tumor. We used two different preparative regimens with or without Fludarabin. Cyclosporin A and MMF were used in the prevention of graft versus host disease (GVHD). The median dose of DLI was positive CD3 cells 2.7×107/kg (1.0×107/kg–2.0×108/kg). According to the patients’ situation and chimerism, we divided these patients into two groups, one group included 15 patients whose chimerism decreased for the reason of disease relapsed or advanced, the other included 13 patients whose chimerism decreased because of disease remission or stable. We analysis the change of chimerism and patients’ situation after DLI and the side effects of DLI. Results: Among 28 patients, there are 16 CML, 6 acute myeloid leukemia (AML), 3 acute lymphocytic leukemia (ALL), 1 MM and 2 solid tumor. 13 of them were with increased donor chimerism and 11 of them were with full chimerism. In 11 of the 16 CML patients, whose chimerism decreased because of relapsed or advanced, only one patient who achieved partial remission (PR) and other 10 died for the sake of no effect after DLI. With DLI, 5 patients whose chimerism decreased during the course of disease remission got increasing donor chimerism, 3 got complete remission (CR), 2 got PR, 4 survived and 1 PR patient died of GVHD. Among 6 AML patients with DLI, 1 died due to disease relapsed or advanced and decreased chimerism, other 5 who were with disease remission or stable situation and decreased chimerism obtained CR and survival according to the increased donor chimerism after DLI. Among 3 B-ALL patients post DLI, one alive and the other two died. One MM patient died of no effect. Two late phrase lung cancer patients got PR. One has survived for 14 months and another died of lung virus infection. Their rates of donor chimerism were higher than 80 percent and 96 percent. Among all these 28 patients, their average following up time was 30 months (10–66 months). 12 of them survived (42.6 percent) and total efficient rate was 57.14 percent. 3 developed grade II aGVHD that was DLI-associated. 1 died and 5 was complicated with grade II to IV cGVHD (3 extensive and 2 local). Given active treatment, they were alive. 2 patients had ever been with transient complete blood cell decreasing and had recovered after active surppoting treatment. Conclusion: DLI is a potential therapy that can make chimerism increase and prevent disease relapse post allo-NST. Its toxicity and side effects can be accepted.