Yuji Shimura

T(11;14) (q13;q32) occurs in approximately 15%–25% of multiple myeloma (MM) cases and has traditionally been regarded as a standard cytogenetic risk factor. However, recent evidence suggests that MM with t(11;14) exhibits heterogeneous biological characteristics and clinical outcomes distinct from those associated with other cytogenetic risk categories. In a post hoc analysis of the prospective JSH‐MM‐15 study, we investigated the prognosis of newly diagnosed MM patients to identify prognostic features unique to t(11;14)‐positive cases and to evaluate treatment factors influencing outcomes. Among 482 patients evaluated for t(11;14), 131 (27%) were positive. Overall survival (OS) in t(11;14)‐positive patients was intermediate between standard‐ and high‐risk groups, whereas progression‐free survival (PFS) was comparable to that of high‐risk cases. Deep response rates, including ≥ complete response (CR)/stringent CR and ≥ very good partial response, were lower in t(11;14)‐positive MM than in other risk groups, and these responses were not associated with survival in t(11;14)‐positive cases, in contrast to t(11;14)‐negative MM. Compared with t(11;14)‐negative MM, t(11;14)‐positive patients more frequently expressed CD20 and less frequently expressed CD56 on myeloma cells. Exploratory analyses showed that, despite higher ≥ CR rates, OS was worse in patients with CD20‐negative/CD56‐negative tumors among t(11;14)‐positive MM. Among CD20‐positive patients, PI‐containing regimens were associated with better OS, although no significant PFS benefit was observed. These findings support the biological and clinical heterogeneity of t(11;14)‐positive MM and highlight the need for prospective validation of subgroup‐specific treatment outcomes.

Summary: To identify strategies to prevent the induction of monocytic myeloid‐derived suppressor cells (M‐MDSCs) in multiple myeloma (MM), we analysed molecular changes in myeloma and myeloid cells within peripheral blood mononuclear cells (PBMCs) that promote M‐MDSC induction during co‐culture. We then examined the effects of cereblon E3 ligase modulators (CELMoDs), iberdomide (IBER) and mezigdomide (MEZI), compared with pomalidomide (POM), on M‐MDSC induction from PBMCs during co‐culture with human myeloma‐derived cell lines (HMCLs). Co‐culturing PBMCs with HMCLs increased inflammatory, interleukin (IL)‐6‐Janus kinase‐signal transducer and activator of transcription (JAK‐STAT)3 and tumour necrosis factor (TNF)‐α‐associated gene expression in HMCLs, while decreasing interferon‐related genes in myeloid cells. CELMoDs inhibited M‐MDSC induction, with 7.5 nM IBER and 1 nM MEZI as effective as 1 μM POM. In this context, CELMoDs and POM reduced inflammatory genes, including those involved in TNF‐α signalling via nuclear factor‐kappa B (NF‐κB), in HMCLs and lowered pro‐inflammatory genes, including C‐C motif chemokine ligand 5 (CCL5). Conversely, in myeloid cells, CELMoDs and POM enhanced immune‐activating pathways linked to interferon responses. Furthermore, CELMoDs and POM reduced candidate soluble mediators associated with M‐MDSC induction, such as migration‐inhibitory factor (MIF) and IL‐10, in myeloid cells and decreased IL‐10 secretion from IL‐10‐producing HMCLs. In summary, CELMoDs effectively inhibit M‐MDSC induction by altering gene expression in co‐cultured HMCLs and myeloid cells, while also suppressing mediators like IL‐10 and MIF.

In ALK‐negative anaplastic large cell lymphoma (ALCL), gene rearrangements of DUSP22 and TP63 are considered mutually exclusive. The former predicts a favorable prognosis, while the latter is generally unfavorable. We report the first case of ALK‐negative ALCL in a leukemic phase with small cell pattern transformation, harboring double‐hit rearrangements of the DUSP22 gene by inv(6)(p25q21) and TP63 gene by TBL1XR1‐TP63 inversion. Despite the resistance to chemotherapies, the patient remained in remission with allogeneic stem cell transplantation over 20 months. Recognizing this pathologically and genetically rare condition is needed for prompt diagnosis and therapeutic decision‐making in ALK‐negative ALCL.

Background: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. Objective: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. Methods: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. Results: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. Conclusion: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.