The 2016 International Myeloma Working Group consensus recommendations emphasize high-sensitivity methods for minimal residual disease (MRD) detection, treatment response assessment, and ...prognostication. Next-generation sequencing (NGS) of IGH gene rearrangements is highly specific and sensitive, but its description in routine clinical practice and performance comparison with high-sensitivity flow cytometry (hsFC) remain limited. In this large, single-institution study including 438 samples from 251 patients, the use of NGS targeting the IGH and IGK genes for clonal characterization and monitoring, with comparison to hsFC, is described. The index clone characterization success rate was 93.6% (235/251), which depended on plasma cell (PC) cellularity, reaching 98% when PC ≥10% and below 80% when PC <5%. A total of 85% of cases were successfully characterized using leader and FR1 primer sets, and most clones showed high somatic hypermutation rates (median, 8.1%). Among monitoring samples from 124 patients, 78.6% (147/187) had detectable disease by NGS. Concordance with hsFC was 92.9% (170/183). Discordant cases encompassed 8 of 124 hsFC MRD+/NGS MRD- patients (6.5%) and 4 of 124 hsFC MRD-/NGS MRD+ patients (3.2%), all with low-level disease near detection limits for both assays. Among concordant hsFC MRD-/NGS MRD- cases, only 5 of 24 patients (20.8%) showed subsequent overt relapse at 3-year follow-up. HsFC and NGS showed similar operational sensitivity, and the choice of test may depend on practical, rather than test performance, considerations.
The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low ...coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (
),
and
Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as
and
. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor ...conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack.
We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster.
No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort (
= 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure.
Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.
Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd ...and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48-64%) for VRd and 67% (60-75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27-42%) for VRd and 52% (45-60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75-87%) and 90% (85-95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60-78%) for VRd and 75% (65-85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81-94%) and 93% (87-99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8-61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24-51%) and 69% (58-82%) for VRd and 58% (47-71%) and 88% (80-97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.
We describe an explicit and simple subset of the discrete hypercube which cannot be exactly covered by fewer than exponentially many hyperplanes. The proof exploits a connection to communication ...complexity, and relies heavily on Razborov's lower bound for disjointness.
Anonymous Zether, proposed by Bünz, Agrawal, Zamani, and Boneh (FC'20), is a private payment design whose wallets demand little bandwidth and need not remain online; this unique property makes it a ...compelling choice for resource-constrained devices. In this work, we describe an efficient construction of Anonymous Zether. Our protocol features proofs which grow only logarithmically in the size of the "anonymity sets" used, improving upon the linear growth attained by prior efforts. It also features competitive transaction sizes in practice (on the order of 3 kilobytes).Our central tool is a new family of extensions to Groth and Kohlweiss's one-out-of-many proofs (Eurocrypt 2015), which efficiently prove statements about many messages among a list of commitments. These extensions prove knowledge of a secret subset of a public list, and assert that the commitments in the subset satisfy certain properties (expressed as linear equations). Remarkably, our communication remains logarithmic; our computation increases only by a logarithmic multiplicative factor. This technique is likely to be of independent interest.We present an open-source, Ethereum-based implementation of our Anonymous Zether construction.
According to a conjecture attributed to Hartshorne and Lichtenbaum and proven by Ellingsrud and Peskine 18, the smooth rational surfaces in P4 belong to only finitely many families. We formulate and ...study a collection of analogous problems in which P4 is replaced by a smooth fourfold X with vanishing first integral Chern class. We embed such X into a smooth ambient variety and count families of smooth surfaces which arise in X from the ambient variety. We obtain various finiteness results in such settings. The central technique is the introduction of a new numerical invariant for smooth surfaces in smooth fourfolds with vanishing first Chern class.
All patients with a diagnosis of multiple myeloma (MM) have a preceding, asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or ...smoldering multiple myeloma (SMM). While most patients with monoclonal gammopathy of undetermined significance have a very small rate of progression, SMM is a widely heterogeneous condition where a fraction of patients will progress to symptomatic MM rather quickly, while others will experience an indolent clinical course. The differentiation between progressive and stable precursor condition thus represents one of the most important unmet clinical needs in the MM community. The ability to identify patients at high-risk of progression before major clonal expansion and onset of end-organ damage would enable strategies for early prevention and perhaps more effective intervention. All proposed criteria to predict the progression of myeloma precursor conditions are built around indirect markers of disease burden and, therefore, are generally able to accurately identify only a small fraction of patients in whom progression to MM is already occurring. Leveraging whole genome and exome sequencing, it has been shown that patients with stable myeloma precursor conditions are characterized by either absence or lower prevalence of distinct genomic events that are detectable in progressive precursor condition years before the progression. In this review, we discuss evolving genomic concepts and tools; and their ability to differentiate myeloma precursor conditions into two distinct entities: one benign (monoclonal gammopathy of benign significance) and another malignant (asymptomatic multiple myeloma).
Purpose of Review
Multiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease ...(MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM.
Recent Findings
MRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consolidation and maintenance settings, including recent data from influential studies and retrospective analyses. We navigate existing data, leverage the increased resolution of longitudinal MRD assessments, and comment on trials in progress to explain our current utilization of MRD in the clinic.
Summary
MRD transcends traditional response assessments by providing a window into disease-treatment interaction over time. As a strong patient-level surrogate, MRD has limited current use in individualizing treatment, but is poised to comprehensively shape treatment strategies at many key points in a patient’s MM course.
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