Xinyi Xiong

We report the first case of using teclistamab, a BCMA × CD3 bispecific antibody, in a 63‐year‐old male with κ ‐light chain deposition disease (LCDD) involving the kidneys and probably the heart. The patient initially responded to daratumumab‐pomalidomide‐dexamethasone but experienced hematologic relapse. Salvage therapy with teclistamab induced a rapid and sustained hematologic complete response without cytokine release syndrome or neurotoxicity. Renal and cardiac functions remained stable. This case provides critical early evidence that BCMA‐directed immunotherapy may serve as an effective salvage strategy for this rare plasma cell disorder, addressing a significant unmet therapeutic need.

Multiple myeloma (MM) remains incurable despite major therapeutic advances, underscoring the unmet need for earlier and genetically informed intervention. The rationale for such intervention lies in the stepwise evolution of MM from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), during which genetic alterations accumulate and drive the emergence, expansion, and evolution of malignant clones. In 2025, three landmark cohort studies using whole-exome or whole-genome sequencing (WES/WGS) proposed distinct but relevant genomic frameworks for reclassifying disease risk in MGUS and SMM. Despite differences in design and analyses, these frameworks converge on several principles: (i) the malignant genomic architecture of myeloma is established well before clinical progression; (ii) a substantial fraction of clinically defined precursor disease already harbors the hallmarks of overt myeloma; and (iii) WES/WGS-derived features meaningfully improve clinical risk models. In this perspective, we critically reviewed these three contemporaneous frameworks and synthesize their convergent implications, not previously consolidated for clinical use, into a practical approach toward genomics-guided management of myeloma precursor conditions.

Primary light-chain amyloidosis (pAL) is caused by plasma cell (PC) clones that secrete misfolded free light chains that deposit. Anti-CD38 antibody daratumumab is the first-line therapy, while ∼10–30% of patients exhibit suboptimal responses (PTGES2/3–PTGER2/4 axis driven by PTGS2 expressing myeloid-derived suppressor cell–like CD38⁻ CD14⁺ monocytes that expanded with treatment; and (ii) an immunosuppressive non-classical MHC I axis, in which PCs exerted inhibitory interactions ( HLA-E–KLRK1 , HLA-G–LILRB1 , HLA-F–LILRB1 ). Consistent with these cell-cell interactions, myeloid cells and NK cells showed functional impairment, while T cells were more exhausted; all three cell types exhibited increased interferon-γ responses in suboptimal versus good responders. This atlas reveals amyloidogenic PCs’ resistance to daratumumab and an inflammatory–immunosuppressive niche driven by prostaglandin and non-classical MHC I, underpinning suboptimal responses.

Few studies have reported that venetoclax, a selective BCL2 inhibitor, has shown promising efficacy in relapsed/refractory AL amyloidosis (RRAL), especially among patients harboring t(11;14). We retrospectively reviewed 29 RRAL patients treated with venetoclax between July 2022 and January 2025. Treatment was given for suboptimal prior response (45%), hematologic progression (38%), or rising involved free light chain not meeting progression criteria (17%). Venetoclax induced rapid and deep responses: 79% achieved very good partial response (VGPR) or complete response (CR), and 52% achieved stringent FLC response. High t(11;14) (> 10%) patients achieved ≥ VGPR in 91% versus 33% in low t(11;14) (p = 0.008). Cardiac responses occurred in 59% of evaluable patients. At a median follow-up of 19.7 months, one-year overall survival and event-free survival were 96.6% and 82.6%, respectively; two deaths were due to cardiac progression. Venetoclax was well tolerated, with mostly grade 1–2 adverse events, except one grade 3 leukopenia/neutropenia with grade 3 infection. These results support venetoclax as an effective and safe therapy for RRAL, particularly in t(11;14) patients, and highlight the need for prospective studies to refine patient selection and optimize treatment strategies.

Plasma cell disorders (PCDs) are marked by the clonal proliferation of abnormal plasma cells and bone marrow plasma cells (BMPCs), causing various clinical complications. These PCDs include subtypes with distinct clinical features. Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are more common and relatively well-studied. In contrast, primary light-chain amyloidosis (AL) and POEMS syndrome (POEMS) are rare and remain less understood. To investigate the role of clonal hematopoietic (CH) mutations and potential interconnections in these diseases, we sequenced CH mutations in lymphoid and myeloid lineages, as well as myeloma driver gene mutations, in BMPCs from affected patients. Recurrent lymphoid CH mutations (in FAT1, KMT2D, MGA, and SYNE1) and myeloma driver gene mutations (in ZFHX3 and DIS3) were found in the dominant clonal and subclonal plasma cell populations. These moderately aging-associated lymphoid CH mutations had a higher burden in MM than in AL or POEMS. Binary matrix factorization of these mutations revealed the subgroups associated with progression-free survival (PFS) (observed in MM, AL, and POEMS), age at diagnosis (in AL and POEMS), serum differential free light chain (dFLC) levels, plasma cell burden (in AL), and serum vascular endothelial growth factor (VEGF) levels (in POEMS). Moreover, the poor PFS associated with MGA or SYNE1 mutations was confirmed across MM, AL, and POEMS. CH mutations partially explained the shared pathogenesis of MM, AL, POEMS, and MGUS, and helped identify patient subgroups with specific clinical features.

The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.