MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods

[EN] In patients with multiple myeloma, obtaining posttreatment minimal residual disease (MRD) negativity is associated with longer progression-free survival and overall survival. Here, we compared the diagnostic performance of a single 10-color tube with that of a EuroFlow 8-color 2-tube panel for MRD testing. Bone marrow samples from 41 multiple myeloma patients were tested in parallel using the 2 approaches. Compared with the sum of the cells from the EuroFlow two 8-color tubes, the Memorial Sloan Kettering Cancer Center (MSKCC) single 10-color tube had a slight reduction in total cell number with a mean ratio of 0.85 (range, 0.57-1.46; P < .05), likely attributable to permeabilization of the cells. Percent of plasma cells showed a high degree of concordance (r2 = 0.97) as did normal plasma cells (r2 = 0.96), consistent with no selective plasma cell loss. Importantly, concordant measurement of residual disease burden was seen with abnormal plasma cells (r2 = 0.97). The overall concordance between the 2 tests was 98%. In 1 case, there was a discrepancy near the limit of detection of both tests in favor of the slightly greater theoretical sensitivity of the EuroFlow 8-color 2-tube panel (analytical sensitivity limit of MSKCC single 10-color tube: 6 cells in 1 million with at least 3 million cell acquisitions; EuroFlow 8-color 2-tube panel: 2 cells in 1 million with the recommended 10 million cell acquisitions)

Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma

Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5′ untranslated region (UTR) and 3′ UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.</p

Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma

Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5′ untranslated region (UTR) and 3′ UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.</p

Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect® MM Registry

Maintenance therapy after autologous stem cell transplantation (ASCT) is recommended for use in multiple myeloma (MM); however, more data are needed on its impact on health-related quality of life (HRQoL). Presented here is an analysis of HRQoL in a Connect MM registry cohort of patients who received ASCT ± maintenance therapy. The Connect MM Registry is one of the earliest and largest, active, observational, prospective US registry of patients with symptomatic newly diagnosed MM. Patients completed the Functional Assessment of Cancer Therapy-MM (FACT-MM) version 4, EuroQol-5D (EQ-5D) questionnaire, and Brief Pain Inventory (BPI) at study entry and quarterly thereafter until death or study discontinuation. Patients in three groups were analyzed: any maintenance therapy (n = 244), lenalidomide-only maintenance therapy (n = 169), and no maintenance therapy (n = 137); any maintenance and lenalidomide-only maintenance groups were not mutually exclusive. There were no significant differences in change from pre-ASCT baseline between any maintenance (P = 0.60) and lenalidomide-only maintenance (P = 0.72) versus no maintenance for the FACT-MM total score. There were also no significant differences in change from pre-ASCT baseline between any maintenance and lenalidomide-only maintenance versus no maintenance for EQ-5D overall index, BPI, FACT-MM Trial Outcomes Index, and myeloma subscale scores. In all three groups, FACT-MM, EQ-5D Index, and BPI scores improved after ASCT; FACT-MM and BPI scores deteriorated at disease progression. These data suggest that post-ASCT any maintenance or lenalidomide-only maintenance does not negatively impact patients' HRQoL. Additional research is needed to verify these findings

Autologous stem cell transplantation improves quality of life in economically challenged, Brazilian multiple myeloma patients

OBJECTIVES: 1) To characterize the impact of multiple myeloma on the quality of life of patients treated in two public institutions in São Paulo State, Brazil, using a generic Short Form 36 Health Survey and a questionnaire specific for oncologic patients (QLQ-C30) upon diagnosis, after the clinical treatment, and at day +100 after autologous stem cell transplantation; 2) to evaluate whether autologous stem cell transplantation can improve the quality of life of our economically challenged population aside from providing a clinical benefit and disease control. METHODS: We evaluated 49 patients with multiple myeloma (a total of 70 interviews) using the two questionnaires. The scores upon diagnosis, post-treatment/pre-autologous stem cell transplantation, and at D+100 were compared using ANOVA (a comparison of the three groups), post hoc tests (two-by-two comparisons of the three groups), and paired t-tests (the same case at two different times). RESULTS: Of the included patients, 87.8% had a family budget under US $600 (economic class C, D, or E) per month. The generic Short Form 36 Health Survey questionnaire demonstrated that physical function, role-physical, and bodily pain indices were statistically different across all three groups, favoring the D+100 autologous stem cell transplantation group (ANOVA). The questionnaire specific for oncologic patients, the QLQ-C30 questionnaire, confirmed what had been demonstrated by the Short Form 36 Health Survey with respect to physical function and bodily pain, with improvements in role functioning, fatigue, and lack of appetite and constipation, favoring the D+100 autologous stem cell transplant group (ANOVA). The post hoc tests and paired t-tests confirmed a better outcome after autologous stem cell transplantation CONCLUSION: The questionnaire specific for cancer patients seems to be more informative than the generic Short Form 36 Health Survey questionnaire and reflects the real benefit of autologous stem cell transplantation in the quality of life of multiple myeloma patients in two public Brazilian institutions that provide assistance for economically challenged patients.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP)Santa Casa de Misericórdia de São Paulo Faculdade de Ciências MédicasUniversidade Federal de São Paulo (UNIFESP) Departamento de MedicinaCedars-Sinai Outpatient Cancer CenterUNIFESP, Depto. de MedicinaSciEL

Characterization of rare germline variants in familial multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells, characterized by the presence of monoclonal immunoglobulin, known as M protein1. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS) which is also a precursor of immunoglobulin light chain (AL) amyloidosis. Previous studies have reported a 2- to 4-fold increased risk of MGUS or MM in first-degree relatives of MM or MGUS patients, suggesting the existence of inherited susceptibility. For many years, high-risk germline predisposing genes have been lacking for MM. However, recent sequencing efforts have proposed a few novel candidates, most notably loss-offunction (LoF) variants in the tumor suppressor gene DIS3 and in the histone demethylase gene KDM1A, and others as recently reviewed in detail in Pertesi et al. In addition to the suspected rare, high-penetrance variants, genome-wide association studies have identified over 20 common, low-penetrance variants associated with the risk of MM; these were estimated to account for about 15% of the familial MM risk

Frequent and specific immunity to the embryonal stem cell–associated antigen SOX2 in patients with monoclonal gammopathy

Specific targets of cellular immunity in human premalignancy are largely unknown. Monoclonal gammopathy of undetermined significance (MGUS) represents a precursor lesion to myeloma (MM). We show that antigenic targets of spontaneous immunity in MGUS differ from MM. MGUS patients frequently mount a humoral and cellular immune response against SOX2, a gene critical for self-renewal in embryonal stem cells. Intranuclear expression of SOX2 marks the clonogenic CD138− compartment in MGUS. SOX2 expression is also detected in a proportion of CD138+ cells in MM patients. However, these patients lack anti-SOX2 immunity. Cellular immunity to SOX2 inhibits the clonogenic growth of MGUS cells in vitro. Detection of anti-SOX2 T cells predicts favorable clinical outcome in patients with asymptomatic plasmaproliferative disorders. Harnessing immunity to antigens expressed by tumor progenitor cells may be critical for prevention and therapy of human cancer

The Ongoing Confusion Over Ongoing Royalties 1

In eBay Inc. v. MercExchange LLC, the Supreme Court correctly concluded that courts had both the power and the responsibility to decide whether a successful patent owner needed injunctive relief, and whether the imposition of that relief would unduly harm either the defendant or the public. 3 The application of the traditional four-factor equity test has led, for the first time, to a significant number of cases in which courts find patent infringement but refuse to enjoin continued infringement. That in turn has raised the question &quot;what happens then?&quot; The basic answer seems clear as a matter of policy: while the patentee can&apos;t enjoin infringement, the infringer should have to pay for the right to continue infringing. But that basic answer conceals three subsidiary issues: do courts have the authority to award an ongoing royalty, who decides what that royalty should be, and how should that royalty be calculated. To date, courts have largely ignored the first and second questions. While they have addressed the third, they haven&apos;t done so in a particularly satisfactory manner. In this article I endeavor to answer these questions