Abstract LB-299: Cynomolgus monkey plasma cell gene signature to quantify thein vivoactivity of a half-life extended anti-BCMA BiTE® for the treatment of multiple myeloma

Abstract B-cell activating factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) are produced by the BM microenvironment of patients with multiple myeloma (MM) and are growth factors of multiple myeloma cells (MMC). BAFF has three receptors: BAFF-R, TACI and BCMA, and APRIL has 2 receptors: TACI and BCMA. Using real time RT-PCR and FACS analysis, we found that TACI and BCMA are expressed by MMC, unlike BAFF-R. Gene expression profiling (GEP) of purified MMC from newly-diagnosed patients has indicated that primary MMC with high TACI expression (TACI[suphigh] MMC) have a mature plasma cell gene signature linked to a dependence on the bone marrow environment. In contrast, primary MMC with a low TACI expression (TACI[suplow] MMC) have a gene signature of proliferating plasmablasts. TACI expression was either undetectable (11 HMCLs) or present (7 HMCLs) on a panel of 18 HMCLs, whereas BCMA expression was detected in all HMCLs with sensitive real-time RT-PCR and FACS analysis. GEP of the 18 HMCLs were determined with Affymetrix U133 DNA microarrays that interrogate 33000 genes or ESTs. 109 out of the 33000 genes/ESTs were differentially expressed between TACI[sup+] and TACI[sup-] HMCLs (ratio ≤ 0.5 and ≥ 2, P ≤ 0.05). TACI[sup+] HMCLs have a gene signature indicative of a BM environment dependence close to that of normal bone marrow plasma cells, including genes involved in intercellular communication and signal transduction genes. TACI[sup+] HMCLs with a BM environment dependence signature include the RPMI8226 and LP1 HMCLs that produce BAFF or APRIL as autocrine growth factors, a property of the bone marrow environment in patients with intramedullary MM. The microenvironment dependence signature was also found in 5 HMCLs (XG-2, XG-12, XG-13, XG-19 and XG-20) whose growth requires addition of exogenous IL-6 or BAFF/APRIL in vitro. These data indicate that a high TACI expression and the associated microenvironment dependence gene signature found in primary MMC is kept in HMCLs that have been maintained in culture for 10–30 years, and whose growth does not need anymore interaction with BM environment. One hypothesis is that this gene signature may be a characteristic of the MMC clone at the occurrence of the disease. The MM stem cell could be immortalized at different stages of normal plasma cell differentiation. Transformation at the plasmablastic stage would give rise to a MMC clone with a plasmablastic gene signature. Transformation at a later plasma cell differentiation stage would give rise to a MMC clone with a gene signature of mature BM plasma cells.

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Plasma cell expression of CD28 and CD40 correlates with peripheral T-cell defects in multiple myeloma

Immunology Letters ◽

10.1016/s0165-2478(97)88679-8 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 452

Author(s):

V Redoglia

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Plasma Cell ◽

Cell Expression

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Faculty Opinions recommendation of Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1108297.564322 ◽

2008 ◽

Author(s):

Xavier Leleu

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Plasma Cell ◽

Plasma Cell Disorders

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MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia

BMJ Open ◽

10.1136/bmjopen-2020-046225 ◽

2021 ◽

Vol 11 (3) ◽

pp. e046225

Author(s):

Sarah Brown ◽

Debbie Sherratt ◽

Samantha Hinsley ◽

Louise Flanagan ◽

Sadie Roberts ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Plasma Cell ◽

Phase Ii ◽

Whole Body ◽

Cell Leukaemia ◽

High Dose ◽

Newly Diagnosed ◽

Genetic Changes ◽

Novel Treatment

IntroductionMultiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and disseminationEthics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN16847817, May 2017; Pre-results.

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Monotypic plasma cell interstitial nephritis as the only clinical manifestation in a patient with previously undiagnosed indolent multiple myeloma

Medicine ◽

10.1097/md.0000000000004391 ◽

2016 ◽

Vol 95 (31) ◽

pp. e4391 ◽

Cited By ~ 3

Author(s):

Philippe Attias ◽

Anissa Moktefi ◽

Marie Matignon ◽

Jehan Dupuis ◽

Céline Debiais-Delpech ◽

...

Keyword(s):

Multiple Myeloma ◽

Interstitial Nephritis ◽

Plasma Cell ◽

Clinical Manifestation

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Interphase fluorescence in situ hybridization in multiple myeloma and monoclonal gammopathy of undetermined significance without and with positive plasma cell identification: analysis of 192 cases from the Region of Southern Denmark

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2006.11.015 ◽

2007 ◽

Vol 174 (2) ◽

pp. 89-99 ◽

Cited By ~ 20

Author(s):

Jacob H. Christensen ◽

Niels Abildgaard ◽

Torben Plesner ◽

Anne Nibe ◽

Ole Nielsen ◽

...

Keyword(s):

Multiple Myeloma ◽

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Cell Identification ◽

Identification Analysis ◽

Undetermined Significance

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Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8001 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8001-8001

Author(s):

Martin F. Kaiser ◽

Andrew Hall ◽

Katrina Walker ◽

Ruth De Tute ◽

Sadie Roberts ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Minimal Residual Disease ◽

Plasma Cell ◽

Residual Disease ◽

Cell Leukemia ◽

Ultra High Risk ◽

Grade 3 ◽

Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

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Current Treatment Approaches to Newly Diagnosed Multiple Myeloma

Oncology Research and Treatment ◽

10.1159/000520504 ◽

2021 ◽

Vol 44 (12) ◽

pp. 690-699

Author(s):

Susanne Ghandili ◽

Katja C. Weisel ◽

Carsten Bokemeyer ◽

Lisa Beatrice Leypoldt

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Plasma Cell ◽

Cell Clone ◽

Unmet Need ◽

Continuous Treatment ◽

High Dose ◽

Line Treatment ◽

First Line ◽

First Line Treatment

Background: Multiple myeloma is a so far incurable malignant plasma cell disorder. During the past 2 decades, treatment paradigms substantially changed when novel drugs were introduced initially in treatment of relapsed disease and subsequently also in first-line treatment. Summary: Up to now, first-line treatment differs between patients initially classified as transplant eligible and those who are considered as nontransplant eligible. Transplant-eligible patients receive a primary proteasome inhibitor (PI)-based induction which is being combined with an immunomodulating agent and a CD38-directed monoclonal antibody followed by high-dose melphalan therapy and autologous stem cell transplantation with subsequent maintenance treatment with lenalidomide. Patients who are considered as nontransplant eligible receive upfront treatment preferentially with a continuous combination treatment either with a CD38-directed monoclonal antibody in combination with the immunomodulating agent lenalidomide or a lenalidomide-PI combination followed by lenalidomide maintenance. Key Messages: Primary goal of the initiated treatment is to induce a rapid and deep remission which ideally leads to an eradication of the residual plasma cell clone in sense of a minimal residual disease negativity. Achievement of long-term remission with limited toxicity despite continuous treatment strategies and maintenance or improvement of life-quality is key. Despite successful treatment options, specific difficult-to-treat subgroups, especially patients with high-risk myeloma remain with inferior prognosis and a clear unmet need for novel therapeutic strategies. Future concepts will evaluate cellular treatments and other innovative immunotherapies in first-line treatment in curative intention.

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