Implications for the monitoring of patients with multiple myeloma undergoing treatment with the anti-CD38 monoclonal daratumumab

2019 ◽  
Vol 57 (2) ◽  
pp. 178-181 ◽  
Author(s):  
Sally Thirkettle ◽  
Joanne Russell ◽  
Sarah Wilson ◽  
Tasneem Ganijee ◽  
Samar Kulkarni ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Healthcare Workers ◽  
Plasma Cells ◽  
Clinical Laboratory ◽  
Response To Treatment ◽  
Serological Response ◽  
The Novel ◽  
Remission Rates ◽  
Human Igg1 ◽  
Single Laboratory

Background The novel daratumumab immunotherapy is a human IgG1 kappa antibody targeted against CD38, which is almost universally expressed on myeloma plasma cells. Daratumumab has efficacy in clinical trials for the treatment of multiple myeloma; however, it complicates laboratory monitoring of the serological response to treatment, as it is detected by serum electrophoresis and/or immunofixation. Methods Laboratory reports of electrophoresis patterns serially performed in a single laboratory of six patients with relapsed multiple myeloma receiving daratumumab therapy as part a clinical trial were reviewed retrospectively. Results Post administration of daratumumab therapy, an additional band was visible by serum electrophoresis, migrating to the mid-gamma region, which was confirmed as IgG kappa by immunofixation. In five out of the six patients, this band was quantified at <2.0 g/L. For one patient, this band co-migrated with the patient’s disease paraprotein band, so both bands were quantified together. The appearance of an apparent second paraprotein band while receiving treatment for multiple myeloma can cause anxiety for patients, confusion for healthcare workers and may also underestimate complete remission rates. Conclusions The clinical laboratory must be aware of the interference of daratumumab in serum electrophoresis. Effective communication between clinicians and the laboratory is essential for the production of clinically valuable, non-misleading reports for these patients.

scholarly journals Whole-Body Low-Dose Multidetector-Row CT in Multiple Myeloma: Guidance in Performing, Observing, and Interpreting the Imaging Findings

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1320
Author(s):  
Antonio Pierro ◽  
Alessandro Posa ◽  
Costanzo Astore ◽  
Mariacarmela Sciandra ◽  
Alessandro Tanzilli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Plasma Cells ◽  
Traditional Approach ◽  
Response To Treatment ◽  
Whole Body ◽  
Newly Diagnosed ◽  
Low Dose Ct ◽  
Lytic Lesions ◽  
Total Body

Multiple myeloma is a hematological malignancy of plasma cells usually detected due to various bone abnormalities on imaging and rare extraosseous abnormalities. The traditional approach for disease detection was based on plain radiographs, showing typical lytic lesions. Still, this technique has many limitations in terms of diagnosis and assessment of response to treatment. The new approach to assess osteolytic lesions in patients newly diagnosed with multiple myeloma is based on total-body low-dose CT. The purpose of this paper is to suggest a guide for radiologists in performing and evaluating a total-body low-dose CT in patients with multiple myeloma, both newly-diagnosed and in follow-up (pre and post treatment).

scholarly journals Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

2021 ◽  
Author(s):  
Sara Ovejero ◽  
Jerome Moreaux
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Gene Mutations ◽  
Biological Data ◽  
Response To Treatment ◽  
Omics Technologies ◽  
Hematologic Cancer ◽  
Great Heterogeneity ◽  
Causes Of Mortality ◽  
Therapeutic Decision Making

Multiple myeloma (MM), the second most common hematologic cancer, is caused by accumulation of aberrant plasma cells in the bone marrow. Its molecular causes are not fully understood and its great heterogeneity among patients complicates therapeutic decision-making. In the past decades, development of new therapies and drugs have significantly improved survival of MM patients. However, resistance to drugs and relapse remain the most common causes of mortality and are the major challenges to overcome. The advent of high throughput omics technologies capable of analyzing big amount of clinical and biological data has changed the way to diagnose and treat MM. Integration of omics data (gene mutations, gene expression, epigenetic information, and protein and metabolite levels) with clinical histories of thousands of patients allows to build scores to stratify the risk at diagnosis and predict the response to treatment, helping clinicians to make better educated decisions for each particular case. There is no doubt that the future of MM treatment relies on personalized therapies based on predictive models built from omics studies. This review summarizes the current treatments and the use of omics technologies in MM, and their importance in the implementation of personalized medicine.

scholarly journals Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

2021 ◽  
Author(s):  
Sara Ovejero ◽  
Jerome Moreaux
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Gene Mutations ◽  
Biological Data ◽  
Response To Treatment ◽  
Omics Technologies ◽  
Hematologic Cancer ◽  
Great Heterogeneity ◽  
Causes Of Mortality ◽  
Therapeutic Decision Making

Multiple myeloma (MM), the second most common hematologic cancer, is caused by accumulation of aberrant plasma cells in the bone marrow. Its molecular causes are not fully understood and its great heterogeneity among patients complicates therapeutic decision-making. In the past decades, development of new therapies and drugs have significantly improved survival of MM patients. However, resistance to drugs and relapse remain the most common causes of mortality and are the major challenges to overcome. The advent of high throughput omics technologies capable of analyzing big amount of clinical and biological data has changed the way to diagnose and treat MM. Integration of omics data (gene mutations, gene expression, epigenetic information, and protein and metabolite levels) with clinical histories of thousands of patients allows to build scores to stratify the risk at diagnosis and predict the response to treatment, helping clinicians to make better educated decisions for each particular case. There is no doubt that the future of MM treatment relies on personalized therapies based on predictive models built from omics studies. This review summarizes the current treatments and the use of omics technologies in MM, and their importance in the implementation of personalized medicine.

Wilms´Tumor 1 Protein Is Highly Expressed on Malignant Plasma Cells and Provides a Novel Target for Immunotherapeutic Approaches

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 98-98 ◽  
Author(s):  
Guenther Koehne ◽  
Satyajit Kosuri ◽  
Ekaterina Doubrovina ◽  
Tao Dao ◽  
Andrew Scott ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Therapeutic Potential ◽  
Wilms Tumor ◽  
Human Igg1 ◽  
Wilms Tumor 1

Abstract Introduction: The Wilms' tumor 1 (WT1) protein is a tumor associated antigen that is potentially targetable by immunotherapeutic approaches. We have demonstrated the overexpression of WT1 in myeloma cells by IHC and in HLA-A*0201+ pts by staining with a high-affinity fully human IgG1 mAb (ESK1) specific to the RMFPNAPYL/HLA-A*0201 complex on malignant plasma cells. We report initial results from pts with plasma cell leukemia (PCL) or relapsed/refractory multiple myeloma (rMM) who have been treated with CD34-selected allo transplants followed by the administration of donor-derived WT1-specific T-cell infusions to induce an immunotherapeutic effect. Methods: In situ expression of WT1 was assessed by IHC analyses using a sequential double staining technique of MoAbs specific for CD138 and WT1.For staining with the RMFPNAPYL/HLA-A*0201 complex, BM samples were blocked with human FcR Blocking Reagent and then directly stained with MoAbs specific for CD38, CD56, CD45 and ESK1 or its isotype control human IgG1 and were analyzed by flow cytometry. WT1-specific T cells were generated from the original stem cell donors by sensitization of CD3+ enriched T-cell fractions with autologous APCs loaded with the pool of overlapping pentadecapeptides of WT1 (Invitrogen, Boston, MA). Cells were propagated in vitro with weekly restimulation and supplementation with IL-2 beginning at day 10-16. After 35-49 days, T-cells were harvested, counted and tested for antigen specific cytotoxicity, HLA-restriction, lack of alloreactivity and sterility. Pts received CD34-selected PBSC allografts after myeloablative cytoreduction with busulfan, melphalan and fludarabine. Pts were treated with 3 infusions of donor-derived WT1-specific T-cell infusions (5x10e6 cells/kg) starting 6 weeks post allo HSCT and at 4 weekly thereafter. Results: Marrow from all pts with immunohistochemical documented plasma cell involvement stained positive for WT1 IHC while WT1 staining remained negative in pts in CR. Only pts expressing HLA-A*0201 that stained positively for WT1 by IHC also demonstrated expression of WT1 by the RMFPNAPYL/HLA-A*0201 complex, whereas pts lacking HLA-A*0201 but with active disease stained positive for WT1 IHC but not ESK1 staining. Of 7 pts, 3 PCL and 4 rMM, treated with WT1-specific T cells, 4 pts had persistent disease post CD34-selected allotransplant. Of these 4 pts 2 pts developed a striking rise of WT1-specific T-cell frequencies and developed a complete remission post WT1 CTL infusions lasting for >2years. Conclusion: WT1 is overexpressed on malignant plasma cells and serves as a target for potential immunotherapeutic approaches in pts with multiple myeloma. Pts with persistent PCL following CD34-selected allografts treated with adoptive transfer of donor-derived WT1-specific cytotoxic T cells can achieve long lasting remission underscoring the therapeutic potential of T-cells specific for immunogenic WT1 peptides expressed on malignant plasma cells. Disclosures O'Reilly: Atara Biotherapeutics: Research Funding.

Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3735-3741 ◽  
Author(s):  
Rafael Fonseca ◽  
Emily A. Blood ◽  
Martin M. Oken ◽  
Robert A. Kyle ◽  
Gordon W. Dewald ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cyclin D1 ◽  
Plasma Cells ◽  
Statistical Significance ◽  
Eastern Cooperative Oncology Group ◽  
Cell Labeling ◽  
Phase Iii ◽  
Response To Treatment ◽  
Monoclonal Proteins

The t(11;14)(q13;q32) results in up-regulation of cyclin D1 and is the most common translocation detected in multiple myeloma, where it is also associated with a lymphoplasmacytic morphology. We performed an interphase fluorescent in situ hybridization (FISH) study to determine the clinical and biologic significance of the abnormality when testing a large cohort of myeloma patients. Bone marrow slides from multiple myeloma patients entered into the Eastern Cooperative Oncology Group phase III clinical trial E9486 and associated laboratory correlative study E9487 were analyzed using interphase FISH combined with immune-fluorescent (cytoplasmic immunoglobulin–FISH) detection of clonal plasma cells. We used FISH probes that hybridize to the 14q32 and 11q13 chromosomal loci. The t(11;14)(q13;q32) was correlated with known biologic and prognostic factors. Of 336 evaluable patients, 53 (16%) had abnormal FISH patterns compatible with the t(11;14)(q13;q32). These patients appeared to be more likely to have a serum monoclonal protein of less than 10 g/L (1 g/dL) (28% vs 15%, P = .029) and a lower plasma cell labeling index (P = .09). More strikingly, patients were less likely to be hyperdiploid by DNA content analysis (n = 251, 14% vs 62%, P &lt; .001). Patients with the t(11;14)(q13;q32) appeared to have better survival and response to treatment, although this did not reach statistical significance. Multiple myeloma with the t(11;14)(q13;q32) is a unique subset of patients, not only characterized by cyclin D1 up-regulation and a lymphoplasmacytic morphology, but is also more frequently associated with small serum monoclonal proteins and is much less likely to be hyperdiploid. These patients do not have a worsened prognosis as previously thought.

scholarly journals Imprinting of Mesenchymal Stromal Cell Transcriptome Persists even after Treatment in Patients with Multiple Myeloma

2020 ◽  
Vol 21 (11) ◽  
pp. 3854
Author(s):  
Léa Lemaitre ◽  
Laura Do Souto Ferreira ◽  
Marie-Véronique Joubert ◽  
Hervé Avet-Loiseau ◽  
Ludovic Martinet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Complete Response ◽  
Response To Treatment ◽  
Local Context ◽  
Newly Diagnosed ◽  
Healthy Donors ◽  
Cell Neoplasm ◽  
Cell Transcriptome

Introduction. Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of malignant plasma cells (MM cells) in the bone-marrow (BM) compartment. BM mesenchymal stromal cells (MSC) from newly diagnosed MM patients were shown to be involved in MM pathogenesis and chemoresistance. The patients displayed a distinct transcriptome and were functionally different from healthy donors’ (HD) MSC. Our aim was to determine whether MM–MSC also contributed to relapse. Methods. We obtained and characterized patients’ MSC samples at diagnosis, two years after intensive treatment, without relapse and at relapse. Results. Transcriptomic analysis revealed differences in gene expression between HD and MM-MSC, whatever the stage of the disease. An easier differentiation towards adipogenesis at the expense of osteoblatogeneis was observed, even in patients displaying a complete response to treatment. Although their transcriptome was similar, we found that MSC from relapsed patients had an increased immunosuppressive ability, compared to those from patients in remission. Conclusion. We demonstrated that imprinting of MSC transcriptome demonstrated at diagnosis of MM, persisted even after the apparent disappearance of MM cells induced by treatment, suggesting the maintenance of a local context favorable to relapse.

scholarly journals Multiple Myeloma Relapse Is Associated with Increased NFκB Pathway Activity and Upregulation of the Pro-Survival BCL-2 Protein BFL-1

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4668
Author(s):  
Ingrid Spaan ◽  
Anja van de Stolpe ◽  
Reinier A. Raymakers ◽  
Victor Peperzak
Keyword(s):  
Multiple Myeloma ◽  
Target Genes ◽  
Plasma Cells ◽  
Signal Transduction Pathway ◽  
Therapy Resistance ◽  
The Novel ◽  
Pathway Activity ◽  
Nfκb Pathway ◽  
Patient Prognosis ◽  
Induced Apoptosis

Multiple myeloma (MM) is a hematological malignancy that is still considered incurable due to the development of therapy resistance and subsequent relapse of disease. MM plasma cells (PC) use NFκB signaling to stimulate cell growth and disease progression, and for protection against therapy-induced apoptosis. Amongst its diverse array of target genes, NFκB regulates the expression of pro-survival BCL-2 proteins BCL-XL, BFL-1, and BCL-2. A possible role for BFL-1 in MM is controversial, since BFL-1, encoded by BCL2A1, is downregulated when mature B cells differentiate into antibody-secreting PC. NFκB signaling can be activated by many factors in the bone marrow microenvironment and/or induced by genetic lesions in MM PC. We used the novel signal transduction pathway activity (STA) computational model to quantify the functional NFκB pathway output in primary MM PC from diverse patient subsets at multiple stages of disease. We found that NFκB pathway activity is not altered during disease development, is irrespective of patient prognosis, and does not predict therapy outcome. However, disease relapse after treatment resulted in increased NFκB pathway activity in surviving MM PC, which correlated with increased BCL2A1 expression in a subset of patients. This suggests that BFL-1 upregulation, in addition to BCL-XL and BCL-2, may render MM PC resistant to therapy-induced apoptosis, and that BFL-1 targeting could provide a new approach to reduce therapy resistance in a subset of relapsed/refractory MM patients.

scholarly journals Multiple Myeloma: Heterogeneous in Every Way

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1285
Author(s):  
Anaïs Schavgoulidze ◽  
Titouan Cazaubiel ◽  
Aurore Perrot ◽  
Hervé Avet-Loiseau ◽  
Jill Corre
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Single Cell Analysis ◽  
Hematological Malignancy ◽  
Residual Disease ◽  
Response To Treatment ◽  
Routine Practice ◽  
Cell Analysis ◽  
Focal Lesions ◽  
Patient Prognosis

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells (PCs) in the bone marrow (BM). Despite considerable advances in terms of treatment, patients’ prognosis is still very heterogeneous. Cytogenetics and minimal residual disease both have a major impact on prognosis. However, they do not explain all the heterogeneity seen in the outcomes. Their limitations are the result of the emergence of minor subclones missed at diagnosis, detected by sensible methods such as single-cell analysis, but also the non-exploration in the routine practice of the spatial heterogeneity between different clones according to the focal lesions. Moreover, biochemical parameters and cytogenetics do not reflect the whole complexity of MM. Gene expression is influenced by a tight collaboration between cytogenetic events and epigenetic regulation. The microenvironment also has an important impact on the development and the progression of the disease. Some of these determinants have been described as independent prognostic factors and could be used to more accurately predict patient prognosis and response to treatment.

Performance of Free Light Chain Assays in Clinical Practice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 757-757 ◽  
Author(s):  
Jerry A. Katzmann ◽  
Angela Dispenzieri ◽  
Roshini S. Abraham ◽  
Robert A. Kyle
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Light Chain ◽  
Test Performance ◽  
Plasma Cells ◽  
Clinical Laboratory ◽  
Lymphoproliferative Disease ◽  
Free Light Chain ◽  
Al Amyloidosis ◽  
Light Chain Deposition Disease

The quantitative assay for free light chains (FLC) is a recently introduced commercial product (FREELITETM, The Binding Site, Ltd.) that has been reported to be sensitive and specific for detecting and monitoring free light chain diseases such as primary systemic amyloidosis (AL), light chain deposition disease (LCDD), non-secretory multiple myeloma (NSMM), and LCMM (light chain multiple myeloma). We have prospectively evaluated the test performance in clinical practice. Results : In 2003, our Clinical Laboratory received samples for FLC assays from 1020 Mayo Clinic patients. The majority of these patients (88%) had plasma cell disorders (PCD). All 120 patients who did not have PCD had normal K/L FLC ratios. Among these, 52 had non-AL amyloidosis: localized amyloid (23), hereditary (16), senile (6), secondary (3), and amyloid of unknown type (4). The 68 other patients who did not have a PCD were being tested because of peripheral neuropathy, rule out AL, anemia, proteinuria, lymphoproliferative disease, and a number of other indications with small numbers of patients (n=13). Among the monoclonal gammopathy patients were 330 with MM, 269 AL, 115 MGUS, 72 SMM, 22 plasmacytomas, 20 NSMM, 9 macroglobulinemia, 7 LCDD, and a variety of other diagnoses with smaller numbers of patients. The sensitivity of the K/L FLC ratio was 100% in LCDD (7/7) and 70% in NSMM (14/20). The 6 NSMM patients with normal K/L FLC ratios had all been treated with SCT and 5 of the 6 had achieved hematologic remission by bone marrow plasma cells. Among the 110 AL patients who had not been previously treated and who had a FLC assay performed within 120 days of diagnosis, the sensitivity of the K/L FLC ratio was 92% compared to 71% for serum IFE and 84% for urine IFE. Using all 3 assays, there was 99.1% (109/110) sensitivity for detecting monoclonal light chain in AL. Conclusion : The performance of the FLC assay in this prospective analysis matches the results from published retrospective validation studies.

scholarly journals Multiple myeloma BM-MSCs increase the tumorigenicity of MM cells via transfer of VLA4-enriched microvesicles

2019 ◽  
Vol 41 (1) ◽  
pp. 100-110
Author(s):  
Mahmoud Dabbah ◽  
Osnat Jarchowsky-Dolberg ◽  
Oshrat Attar-Schneider ◽  
Shelly Tartakover Matalon ◽  
Metsada Pasmanik-Chor ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Translation Initiation ◽  
Clinical Characteristics ◽  
Drug Response ◽  
Plasma Cells ◽  
Response To Treatment ◽  
Disease Therapy

Abstract Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where their interactions impede disease therapy. We have shown that microvesicles (MVs) derived from BM mesenchymal stem cells (MSCs) of MM patients promote the malignant traits via modulation of translation initiation (TI), whereas MVs from normal donors (ND) do not. Here, we observed that this phenomenon is contingent on a MVs’ protein constituent, and determined correlations between the MVs from the tumor microenvironment, for example, MM BM-MSCs and patients’ clinical characteristics. BM-MSCs’ MVs (ND/MM) proteomes were assayed (mass spectrometry) and compared. Elevated integrin CD49d (X80) and CD29 (X2) was determined in MM-MSCs’ MVs and correlated with patients’ staging and treatment response (free light chain, BM plasma cells count, stage, response to treatment). BM-MSCs’ MVs uptake into MM cell lines was assayed (flow cytometry) with/without integrin inhibitors (RGD, natalizumab, and anti-CD29 monoclonal antibody) and recipient cells were analyzed for cell count, migration, MAPKs, TI, and drug response (doxorubicin, Velcade). Their inhibition, particularly together, attenuated the uptake of MM-MSCs MVs (but not ND-MSCs MVs) into MM cells and reduced MM cells’ signaling, phenotype, and increased drug response. This study exposed a critical novel role for CD49d/CD29 on MM-MSCs MVs and presented a discriminate method to inhibit cancer promoting action of MM-MSCs MVs while retaining the anticancer function of ND-MSCs-MVs. Moreover, these findings demonstrate yet again the intricacy of the microenvironment involvement in the malignant process and highlight new therapeutic avenues to be explored.

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