With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear. Through gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance. MM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice. Our research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.

Interleukin-32 promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells Interleukin-32α promotes the proliferation of multiple myeloma cells by inducing production of IL-6 in bone marrow stromal cells

Despite concerns about an increased risk of adverse outcomes following coronavirus disease (COVID‐19) in multiple myeloma patients treated with anti‐CD38 Abs, the impact of COVID‐19 on this group of patients is unclear. We tried to evaluate the clinical outcomes of these patients. We collected data from 1036 patients with multiple myeloma and enrolled 509 cases with COVID‐19. We divided enrolled patients into daratumumab or nondaratumumab cohorts based on whether they had received daratumumab‐based treatment within 6 months of COVID‐19 infection. We applied a propensity score matching method to reduce the bias of baseline characteristics, and then compared the incidence of adverse outcomes between these two cohorts. A total of 117 patients were enrolled in the daratumumab cohort, and 392 patients in the nondaratumumab cohort. After propensity score matching, 204 patients were matched. The proportions of patients who developed COVID‐19 pneumonia (59.8% vs. 34.3%, p < 0.001), were hospitalized (33.3% vs. 11.8%, p < 0.001) and developed severe disease (23.5% vs. 6.9%, p = 0.001) were higher in the matched daratumumab cohort. By multivariate analysis, daratumumab exposure was an independent risk factor for severe disease. An ECOG performance status >2 and history of chronic kidney disease were independent risk factors for COVID‐19‐related mortality among patients who received daratumumab‐based therapy. This study suggested that multiple myeloma patients exposed to daratumumab were at a higher risk of adverse outcomes from COVID‐19.

Background: Tumor flare reaction (TFR) is a clinical syndrome, which is mainly associated with painful and swollen lymph nodes or splenomegaly, slight fever, bone pain, and skin rash during treatment with immune-related drugs, causing difficulty in distinguishing TFR from disease progression. Brentuximab vedotin (BV) and programmed death 1 (PD-1) inhibitor are two ideal drugs used for the treatment of classic Hodgkin lymphoma, but few studies have reported their adverse effects in association with TFR. The efficacy and safety of monotherapy or combination therapy with these drugs needs to be further evaluated. It is essential to determine whether treated patients can develop TFR, thus enabling more accurate diagnosis and treatment. Case presentation: A 26-year-old female patient, diagnosed with classic Hodgkin lymphoma, had received 2 + 3 cycles of ABVD chemotherapy (a combination of adriamycin, bleomycin, vinblastine, and dacarbazine) and 4 cycles of PD-1 inhibitor (tislelizumab) therapy but exhibited poor efficacy. Subsequently, she was given combination therapy of BV (100 mg) + tislelizumab (200 mg). However, a slight fever, painful and swollen axillary lymph nodes, multiple skin rashes with pruritus, joint pain, and fatigue with poor appetite appeared during the treatment. Ultrasound (US) scans revealed that multiple lymph nodes were significantly enlarged. After treatment with low-dose dexamethasone and cetirizine, the symptoms were alleviated. A biopsy of the left axillary lymph node revealed that lymphoid tissue exhibited proliferative changes, without tumor cell infiltration. These findings were consistent with the clinical and pathological manifestations of TFR. Conclusion: Combination therapy with BV and PD-1 inhibitor was effective in the treatment of relapsed or refractory classic Hodgkin lymphoma. The results suggest that the combination therapy may cause TFR, and biopsy and also continuous imaging observation are important to determine the disease stage. This approach allows clinicians to decide whether to continue the current treatment plan, and alerts them to the occurrence of excessive activation of the immune system.

Introduction: Although the combination of venetoclax (VEN) and hypomethylating agents (HMAs) results in impressive efficacy in acute myeloid leukemia (AML), there is still a subset of patients who are refractory. We investigated the outcomes of AML patients with monocytic differentiation who were treated with frontline VEN/HMA.Methods: A total of 155 patients with newly diagnosed AML treated with frontline VEN/HMA were enrolled in the study. Monocyte‐like AML was identified by flow cytometry with typical expression of monocytic markers, and M5 was identified according to French, American, and British category. We compared the outcomes of patients with different characteristics.Results: The rate of complete remission (CR) and CR with incomplete recovery of blood counts (CRi), progression‐free survival (PFS), and overall survival (OS) in monocyte‐like AML were inferior to those in nonmonocyte‐like AML (CR/CRi rates, 26.7% vs. 80.0%, p < 0.001; median PFS, 2.1 vs. 8.8 months, p < 0.001; median OS, 9.2 vs. 19 months, p = 0.013). CR/CRi rate in M5 was lower than that in non‐M5 (60.7% vs. 75.5%, p = 0.049). Multivariate analyses showed that monocyte‐like AML was associated with lower odds of CR/CRi and higher risk of progression.Conclusion: Our study suggested that newly diagnosed AML with a monocytic immunophenotype had a poor prognosis with VEN/HMA treatment.

Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for extramedullary relapse in NDMM patients were analyzed. Among the 471 NDMM patients, a total of 267 patients had disease relapse during follow-up, including 64 (24.0%) patients with extramedullary relapse. Extramedullary relapse was more common in patients with younger age, IgD subtype, elevated LDH, extensive osteolytic lesions, extramedullary involvement, and spleen enlargement at the time of MM diagnosis. Survival analysis showed that extramedullary relapse patients had significantly worse median OS than patients with relapse but without extramedullary involvement (30.8 months vs. 53.6 months, p = 0.012). Multivariate analysis confirmed that elevated LDH (OR = 2.09, p = 0.023), >2 osteolytic lesions (OR = 3.70, p < 0.001), extramedullary involvement (OR = 3.48, p < 0.001) and spleen enlargement (OR = 2.27, p = 0.011) at the time of MM diagnosis were independent risk factors for extramedullary relapse in NDMM patients. Each of the above four factors was assigned a value of 1 to form the extramedullary relapse prediction score, and the 3-year extramedullary relapse rates of patients in the 0–2 and 3–4 score groups were 9.0 % and 76.7 %, respectively. This study suggested that extramedullary relapse was associated with poor clinical characteristics and poor prognosis in NDMM patients. The extramedullary relapse prediction score model composed of LDH, osteolytic lesions, extramedullary involvement and spleen enlargement has a better ability to predict extramedullary relapse than the existing ISS and R-ISS stages.