scholarly journals Prospective Study Reveals Increased Platelet Function Associated with Multiple Myeloma and Its Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Dalia Khan ◽  
Joanne Mitchell ◽  
Rekha Rana ◽  
Neline Kriek ◽  
Amanda Unsworth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Platelet Function ◽  
Research Funding ◽  
Platelet Reactivity ◽  
Immunoblot Analysis ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fibrinogen Binding ◽  
The Impact

Background: Multiple Myeloma (MM) is a rare incurable bone marrow cancer characterised by a malignant proliferation of plasma cells. MM is usually preceded by a premalignant and benign Monoclonal Gammopathy of Undetermined Significance (MGUS). The incidence of arterial and venous thrombosis in MM is substantially higher than in the normal population, however the cause of this increased thrombosis risk and the impact of MM on platelet function is unclear. Treatments for both newly diagnosed and relapsed/refractory patients with MM include Immunomodulatory drugs (IMiDs) such as thalidomide/lenalidomide-based combinations. These treatments improve considerably patient outcomes, however iMiD treatment also increases the risk of thrombotic complications in these patients. Aims: In this prospective study we explored the impact of MM and its treatment on platelet function. Methods: High throughput functional analysis was performed using platelets from normal healthy controls (n=31) and patients with MGUS (n=18), smouldering multiple myeloma (SMM, n= 20), and MM (26). The MM group was further divided into 3 treatment cohorts; (1) no treatment, (2) treatment with proteasome inhibitor (PI) and dexamethasone (Dex), and (3) treatment with PI, Dex, immunomodulatory drug (iMiD) and direct oral anticoagulant. Platelet aggregation and activation (fibrinogen binding and P-selectin exposure) were measured in response to a concentration range of agonists including ADP, the thrombin receptor agonist TRAP-6, collagen, collagen-related peptide (CRP), a thromboxane receptor agonist U46619 and epinephrine. Cereblon protein was detected in platelet protein extracts by immunoblot analysis. Results: Consistent with previous reports, modestly increased VWF and factor VIII levels were detected in MM patients, but no additional differences in coagulation parameters were detected in patient groups compared to normal healthy controls (other than expected due to anticoagulant usage). Platelet aggregation in response to each agonist was increased significantly in the MM patient group compared to the normal healthy controls, suggesting that platelet reactivity is elevated in MM patients through a common mechanism that is shared by different activation pathways or the involvement of multiple mechanisms. P-selectin exposure on platelets from MM patients was not significantly different from normal healthy donors, indicating that enhanced platelet reactivity in MM is specifically through modulation of integrin αIIbβ3 activation, fibrinogen binding and therefore enhanced aggregation. The effects of treatment on platelet function in patients on iMiD vs. non iMiD treatment were assessed. In the iMiD treatment group, patient platelets aggregated in response to lower concentrations of ADP, collagen, epinephrine and CRP in samples taken post-treatment compared to those taken before and during treatment. This demonstrates an increased sensitivity to platelet activation in these patients induced by treatment. Immunoblot analysis revealed that platelets contain cereblon, a therapeutic target of lenalidomide. The potential direct effects of iMiDs on platelets in vitro was therefore explored. Lenalidomide treatment (10mM) increased the ability of platelets to aggregate in response to low concentrations of each agonist tested when compared to normal controls. Conclusions: Platelet reactivity is increased in multiple myeloma and increased further upon iMiD treatment. The presence of the key therapeutic target for iMiDs in platelets and the ability of lenalidomide to modulate platelet function directly, reveals new avenues for investigation to determine the underlying mechanism of action. Disclosures Laffan: CSL: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Roche: Consultancy; LFB: Consultancy; Shire: Consultancy; Octapharma: Consultancy; Bayer: Speakers Bureau; Roche-Chugai: Speakers Bureau; Takeda: Speakers Bureau; Leo-Pharma: Speakers Bureau; Pfizer: Speakers Bureau. Shapiro:Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Chugai/Roche: Consultancy, Speakers Bureau; Shire/Takeda: Consultancy, Speakers Bureau. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ramasamy:Takeda: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Takeda: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers squibb: Membership on an entity's Board of Directors or advisory committees. Gibbins:Bristol Myers Squibb: Research Funding; Arena Pharmaceuticals: Research Funding.

scholarly journals Multiple Myeloma Treatment Is Associated with Enhanced Platelet Reactivity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3300-3300
Author(s):  
Jonathan Gibbins ◽  
Rekha Rana ◽  
Dalia Khan ◽  
Susie Shapiro ◽  
Henri Grech ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Platelet Function ◽  
Research Funding ◽  
Platelet Reactivity ◽  
Immunomodulatory Drugs ◽  
Advisory Committees ◽  
Blood Samples ◽  
Fibrinogen Binding ◽  
Smoldering Myeloma

Abstract Multiple myeloma (MM) is associated with elevated levels of thrombotic disease. Poor mobility due to bone disease and older age are contributory factors but a satisfactory molecular or cellular explanation for this has not been established. Furthermore, the treatment of newly-diagnosed or relapsed MM patients with immunomodulatory drugs increases thrombosis risk. In this study, we therefore sought to determine whether platelet function and/or haemostasis is altered during the clinical progression from the benign monoclonal gammopathy of underdetermined significance (MGUS) to the smouldering myeloma (SM, untreated) state, and to establish the impact of lenalidomide therapy in MM patients on platelet reactivity. Patients (MGUS (N=10), SM (N=10) MM (N=4), healthy volunteer/control (N=10)) were recruited at the myeloma clinics at the Royal Berkshire and Oxford University Hospital Trusts. Single blood samples were obtained from controls, MGUS and smoldering myeloma participants. For patients undergoing therapy (lenalidomide, dexamethasone and anti-coagulant or anti-platelet therapy), samples were taken at predose Cy1, Cy1 D14, Cy1 D28 (a week free from lenalidomide administration), and Cy4 D14. All blood samples were taken less than 12 hours from Lenalidomide dosing, and analysis performed within 4 hours. High throughput platelet function analysis was performed on platelet-rich plasma and washed platelets to measure platelet aggregation, secretion and fibrinogen binding in response collagen, collagen-related peptide (a collagen receptor GPVI-selective ligand), ADP, thrombin receptor activatory peptide (TRAP), the thromboxane mimetic U46619 and epinephrine, and full concentration-response profiles obtained for each. The levels of key platelet receptors including GPVI, CD61, CD41b, CD36 and CD31, were also measured by flow cytometry and remained unaltered between groups. In comparison with control samples, platelet functional responses (maximal response, maximal gain and EC50) from MGUS and smoldering myeloma patients were unaltered (EC50: ADP 1µM, collagen-related peptide (CRP-XL) 0.1µg/ml, U46619 1µM, TRAP 1.6µM, epinephrine 1.3µM). Similarly circulating levels of platelet-bound fibrinogen and P-selectin exposure were unaltered (control: 709±194 AU, MGUS: 581±129 AU, SM: 655±148 AU 9 (Mean±SD)). In MM patients during therapy, the levels of these platelet responses (aggregation, fibrinogen binding and P-selectin exposure - a marker for a-granule secretion) were increased 2-4 fold. In most patients this was notable at week 2 and had declined approximately 50% by week 4 of cycle 1 but remained above predose levels, and remained elevated to a similar level in drug cycle 4. The study of further patients (including Bortezomib treated patients as controls) will be required in order to validate these findings which suggest that (1) baseline platelet function is not substantially compromised in MM and SM, (2) lenalidomide and other immunomodulatory drugs may be able to modulate platelets in patients causing increased platelet reactivity, and (3) effects noted are lenalidomide-dependent and not related to inflammatory state secondary to disease response. The effects of exposure of platelets to lenalidomide in vitro in the presence or absence of dexamethasone and a proteasome inhibitor are being tested to explore potential direct effects of the drugs on circulating platelets. Results from these experiments will also be presented. Disclosures Gibbins: Celgene Corporation: Research Funding. Rana:Celgene Corporation: Research Funding. Khan:Celgene Corporation: Research Funding. Shapiro:Freeline Therapeutics Ltd: Consultancy. Grech:Novartis: Other: sponsorship for scientific meetings. Ramasamy:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3132-3132
Author(s):  
Bryce Manso ◽  
Kimberly Gwin ◽  
Charla R Secreto ◽  
Henan Zhang ◽  
Wei Ding ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
Advisory Committees ◽  
The Impact

Abstract Peripheral immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) is well-studied and likely relates to the incidence of serious recurrent infections and second malignancies that plague CLL patients. However, the current paradigms of known immune abnormalities are not able to consistently explain these complications and it is not easy to correct CLL patient immune status. Here, we expand on our preliminary reports that demonstrate bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced short-term functional capacity of hematopoietic progenitors in BM using colony forming unit assays (Figure 1A-C) and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations (exemplified by Lin-CD34+ HSPCs, Figure 1D). We further report that protein levels of the transcriptional regulators HIF-1α, GATA-1, PU.1, and GATA-2 are overexpressed in distinct HSPC subsets from CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Interestingly, sustained myelopoiesis, evaluated by limiting dilution analysis in long-term culture-initiating cell (LTC-IC) assays maintained for five weeks, revealed no difference between healthy controls and CLL patients. These new data indicate that when HSPCs are removed from the leukemic microenvironment for ample in vitro culture time, they recover the ability to sustain myelopoiesis. To further assess the impact of the CLL microenvironment on HSPC biology, isolated HSPCs (CD34+ BM cells) from healthy controls were exposed in vitro to known leukemic microenvironment constituents. Exposure to TNFα, a cytokine constitutively produced by CLL B cells, resulted in rapid increases in PU.1 and GATA-2 proteins (Figure 2A-D). Similarly, addition of TNFα to the LTC-IC assay resulted in a striking ablation of myelopoiesis, even at the highest input cell concentration. Further, overexpression of PU.1 and GATA-2 were observed in HSPCs following co-culture with CLL B cells, a result that was not recapitulated when cells were exposed to IL-10, another cytokine constitutively produced by CLL B cells. These findings indicate specific components of the leukemic microenvironment are involved in HSPC modulation. Together, these findings expand on our previous observations of BM hematopoietic dysfunction in untreated CLL patients and offer new molecular insights into the contribution of the leukemic microenvironment on immunodeficiency in CLL. Disclosures Ding: Merck: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Impact of Renal Impairment (RI) on Outcomes after Treatment (Tx) with Lenalidomide and Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): First Trial Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2112-2112
Author(s):  
Meletios A. Dimopoulos ◽  
Matthew C Cheung ◽  
Murielle Roussel ◽  
Ting Liu ◽  
Barbara Gamberi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Board Of Directors ◽  
Normal Renal Function ◽  
Research Funding ◽  
Failure Time ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Of Death ◽  
The Impact

Abstract Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P < 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes. Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and < 80 mL/min), 23% had moderate RI (≥ 30 and < 50 mL/min), and 9% had severe RI (< 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484). Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P < 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P < 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl < 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, < 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3). Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. Disclosures Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma – Subgroup Analysis from the GMMG-MM5 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3475-3475 ◽  
Author(s):  
Maximilian Merz ◽  
Hans Salwender ◽  
Mathias Hänel ◽  
Uta Bertsch ◽  
Christina Kunz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Group Iv ◽  
Route Of Administration ◽  
Prolonged Treatment ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
The Impact

Abstract Background: In patients with relapsed multiple myeloma (MM), Moreau and colleagues (Lancet Oncol, 2011) demonstrated that subcutaneous (SC) administration of bortezomib (BTZ) significantly reduced rates of adverse events (AE) compared to the intravenous (IV) formulation without loss of efficacy. Prospective data on SC BTZ in newly diagnosed MM are limited. We investigated the impact of SC versus IV BTZ in two different induction therapies for patients with newly diagnosed MM treated within the multicenter, prospective randomized MM5 trial of the German Myeloma Multicenter Group (GMMG). Methods: From 06/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12 and 17-20) or 3 cycles VCD (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Cyclophosphamide 900 mg/m2IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9 and 11-12) for induction therapy. In the MM5 trial, induction therapy is followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. Primary end points of the ongoing study are response to treatment after induction therapy and progression-free survival. Due to improved AE profile of SC compared to IV BTZ reported by Moreau, the administration of BTZ was changed from IV to SC in 02/2012. Therefore, we were able to perform an explorative analysis of 598 patients who received at least one dose of trial medication (PAd: n=150 IV / 140 SC; VCD: n=154 IV / 140 SC). 14 patients were excluded from the analysis because administration of BTZ was changed after start of induction therapy. We analyzed whether the route of administration influenced the applied cumulative BTZ dose, toxicity and efficacy of PAd and VCD. Results: The cumulative applied BTZ dose was significantly higher in patients treated with SC BTZ (PAd: 28.9 mg; VCD: 28.8 mg) compared to IV-treated patients (PAd: 27.6 mg; VCD: 27.9 mg; p = 0.007). Analysis of reported AEs associated to induction therapy revealed a significantly higher rate in patients treated with IV BTZ (65.1%) compared to SC-treated patients (55.7%, p = 0.02). AE > °II were reported more frequently in the IV group (IV: 52.0%; SC: 43.9%, p = 0.004). In detail, abnormal laboratory findings including leucopenia and thrombocytopenia (IV: 23.0%; SC: 16.4%, p = 0.05), metabolism and nutrition disorders (IV: 12.5%; SC: 5.4%, p = 0.004) and gastrointestinal disorders (IV: 9.9%; SC: 3.9%, p = 0.006) occurred more often in IV-treated patients. Analysis of peripheral neuropathy (PN) ≥ °II revealed no significant differences between IV and SC BTZ during the first two cycles of induction therapy (cycle 1: IV: 1.6%; SC: 2.5%; cycle 2: IV: 2.3%; SC: 3.6%) but PN occurred more often in IV-treated patients during the third cycle of induction therapy compared to the SC group (IV: 7.6%; SC: 1.8%, p = 0.001). Overall response rates (partial response or better) were not influenced by the route of administration in patients treated with PAd (IV: 72.7%; SC: 70.7%; p = 0.79) or VCD (IV: 77.9%; SC: 82.1%; p = 0.39). Analysis of the VCD arm showed that rates of VGPR or better were significantly higher in patients treated with IV BTZ compared to SC-treated patients (IV: 41.6%; SC: 28.6%, p = 0.02). Rates of VGPR or better were also higher for IV-treated patients in the PAd arm but did not reach statistical significance (IV: 36.7%; SC: 31.4%, p=0.39). Patient characteristics including baseline creatinine levels > 2 mg/dl, obesity or age at inclusion > 65 years did not influence efficacy of IV or SC BTZ in both arms. Conclusion: Last year we reported on the favorable toxicity profile and equal efficacy of VCD compared to PAd. With the current analysis we demonstrate that toxicity is further reduced with SC BTZ compared to IV. We therefore recommend VCD as induction therapy. However, we show for the first time a possible loss of efficacy in SC-treated patients. Therefore it remains unclear whether the reduced toxicity justifies the general application of SC BTZ in newly diagnosed, transplant-eligible patients or whether a prolonged treatment (4 x VCD SC) may reduce toxicity while achieving similar efficacy. Further studies are warranted since our results are partially in contrast with the previously presented data in relapsed MM and the ongoing MM5 trial was initially not designed to prospectively investigate the effect of SC or IV BTZ. Disclosures Salwender: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Celgene: Honoraria; Janssen: Honoraria. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Schmidt-Wolf:Janssen: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

scholarly journals The Impact of Fractures on Survival in Multiple Myeloma: Results from a Population-Based Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4490-4490
Author(s):  
Sigrun Thorsteinsdottir ◽  
Ingigerdur S Sverrisdottir ◽  
Gauti Gislason ◽  
Ola Landgren ◽  
Ingemar Turesson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Population Based ◽  
Advisory Committees ◽  
Population Based Study ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Impact

Abstract Introduction Multiple myeloma (MM) causes lytic bone lesions, osteopenia, and fractures, which increase the morbidity of MM patients. Results from small previous studies have indicated that fractures in MM have a negative effect on survival. Aims The aim of the study was to evaluate the impact of fractures on survival in MM patients diagnosed in Sweden in the years 1990-2013. Furthermore, to analyze the effect of bone fractures at MM diagnosis on subsequent survival. Methods Patients diagnosed with MM in 1990-2013 were identified from the Swedish Cancer Registry. Information on date of birth, diagnosis, and death were collected from the Registry of Total Population. Information on all fractures were retrieved from the Swedish Patient Registry. Cox regression model was used with fractures as time-dependent variables. The effect of fractures on survival was assessed for any fracture or a subtype of fracture (a specific bone fracture or ICD-coded pathologic fracture). Either first fracture or the first subtype of fracture was used in the analysis. The effect of a fracture at MM diagnosis (within 30 days before or 30 days after MM diagnosis) on survival was also estimated using a Cox regression model. All models were adjusted for age, sex, time of diagnosis, and previous fractures. Results A total of 14,008 patients were diagnosed with MM in the study period. A total of 4,141 (29.6%) patients developed a fracture including fractures that occurred within a year before MM diagnosis and thereafter. Hereof 2,893 (20.7%) patients developed a fracture after MM diagnosis. The risk of death was significantly increased for patients that developed a fracture after the time of MM diagnosis with a hazard ratio (HR) of 2.00 (95% confidence interval (CI) 1.91-2.10) for all fractures combined. The risk of death was significantly increased for patients that developed all subtypes of fractures after MM diagnosis except ankle fractures. The risk of death was significantly increased for patients that developed pathologic fractures (HR=2.17; 95% CI 2.03-2.32), vertebral fractures (HR=1.73; 95% CI 1.61-1.87), hip fractures (HR=1.99; 95% CI 1.82-2.18), femoral fractures (HR=2.62; 95% CI 2.32-2.98), humerus fractures (HR=2.57; 95% CI 2.32-2.86), forearm fractures (HR=1.24; 95% CI 1.05-1.46), and rib fractures (HR=1.52; 95% CI 1.31-1.77), but not for ankle fractures (HR 1.07; 95% CI 0.79-1.44). A total of 942 (6.7%) of all MM patients were diagnosed with a fracture within 30 days before or 30 days after MM diagnosis. The patients with a fracture at diagnosis were at a significantly increased risk of death compared to those without (HR 1.31; 95% CI 1.21-1.41; Figure) Conclusions Our large population-based study, including over 14,000 patients diagnosed with MM in Sweden in the years 1990-2013, showed that MM patients that developed a fracture after the time of diagnosis were at twofold increased risk of dying compared to MM patients without a fracture. Furthermore, MM patients with a fracture at diagnosis had a 30% higher risk of dying compared to patients without a fracture. Our results indicate that fractures in MM reflect a more advanced disease at diagnosis and stress the importance of managing MM bone disease in all MM patients. Figure. Figure. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

scholarly journals A Novel Approach to Risk Stratification in Multiple Myeloma Using ISS Stage and FISH

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1800-1800 ◽  
Author(s):  
Shaji K. Kumar ◽  
Patricia Greipp ◽  
Morie A Gertz ◽  
Angela Dispenzieri ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Final Model ◽  
Survival Table ◽  
The Impact ◽  
1Q Gain

Background: A variety of risk factors have been described in multiple myeloma and current risk assessment incorporates ISS stage with specific FISH results and serum LDH (R-ISS). However, this model does not include all the current abnormalities described as prognostic for survival in multiple myeloma. Importantly, the impact of many of these high-risk abnormalities are not uniform. We examined if we can better integrate FISH results into a risk assessment tool to better predict the outcomes of newly diagnosed MM. Patients and methods: We studied a cohort of 1316 patients with FISH done within 6 months of diagnosis of MM, in whom results for commonly observed abnormalities were available. We specifically examined the individual impact of common translocations involving chromosome 14, MYC rearrangements, chromosome 1q gain (single or multiple duplication) and del13q/monosomy 13. A risk assessment system was developed, weighting each abnormality according to their Risk Ratio and integrating ISS stage and serum LDH into the final model construction. Overall survival was calculated from diagnosis, with those alive at last follow up being censored. Results: We first examined the impact of each of the above FISH abnormalities: 1) high risk translocations [t(4;14), t(14;16), or t(14,20)], 2) trisomies, 3) t(11;14), 4) MYCrearrangements, 5) del13q/monosomy 13, and 6) 1q gain . Each of the abnormalities, except for t(11;14), was prognostic for survival (Table 1 with the risk ratios). For 1q gain, the median OS was NR, 105 mos and 79 mos respectively for no abnormality, duplication of 1 copy and duplication of multiple copies, (p<0.001). On multivariate analysis, t(11;14) and trisomies were no longer prognostic for overall survival (Table 1). The cumulative impact of abnormalities demonstrated worsening survival in the presence of increasing numbers of abnormalities (Figure 1). Including ISS stage 3 and LDH > ULN as additional variables for prognostication indicated both were individually prognostic for OS. In a multivariate analysis, including these two and FISH abnormalities, 1q gain and LDH were not independently prognostic. The final model consisted of HR translocations, MYCrearrangements, del17p/monosomy 17, del13q/monosomy 13, and ISS stage 3. Each of these variables was weighted using their risk ratio and a composite score was developed using 998 patients for whom all variables were available (range: 0-7.9; median 1.8). Three patient groups were characterized: group 1 (0; 32%), group 2 (1-4; 58%) and group 3 (>4; 10%) with a median OS of 53 mos, 106 mos, and NR, respectively, p <0.001 (Figure 2). Conclusion: Using the most relevant FISH and laboratory factors, in a large cohort of patients, we refined the current system to develop a risk stratification system that predicts survival in patients with newly diagnosed MM treated with contemporary treatment regimens. This needs validation in future studies. Disclosures Kumar: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Gertz:International Waldenstrom Foundation: Research Funding; Annexon: Consultancy; Medscape: Consultancy, Speakers Bureau; Amyloidosis Foundation: Research Funding; Abbvie: Other: personal fees for Data Safety Monitoring board; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Consultancy. Dispenzieri:Akcea: Consultancy; Janssen: Consultancy; Intellia: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Cellectar: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

scholarly journals Characterization of Rare Germline Variants in Familial Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Calogerina Catalano ◽  
Joanna Blocka ◽  
Stefanie Huhn ◽  
Nagarajan Paramasivam ◽  
Matthias Schlesner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Medicinal Product ◽  
Board Of Directors ◽  
Research Funding ◽  
High Impact ◽  
Investigational Medicinal Product ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Advisory Committees ◽  
The Impact

Introduction: The risk of developing Multiple Myeloma (MM) is 2-4 fold higher in first-degree relatives of patients with MM compared to the general population, suggesting genetic predisposition to this cancer. Indeed, recent genome-wide association studies have identified common risk alleles that predispose for MM. Yet, the impact of these variants on MM risk is too low to explain familial aggregation of MM. High-impact alleles have been identified for other cancers such as ovarian and breast cancer (BRCA1,-2) and melanoma (CDKN2A) but the search for such alleles in MM is still in its infancy. In order to identify high-impact alleles in MM we have performed whole genome/exon sequencing (WGS/WES) in members of MM high risk families. Methods: We included 21 families with multiple cases of MM/MGUS. Whole genome/exome sequencing was performed on a total of 46 affected and 20 unaffected family members. Filtering and prioritization of the variants were performed in accordance with the criteria of our in-house familial cancer variant prioritization pipeline version 2 (FCVPPv2). Loss-of-function variants were further screened using MutPred-LOF, Translate tool and IntOGen/c-BioPortal in order to discriminate pathogenic and neutral variants, to translate a nucleotide sequence to a protein sequence and to visualize the domain affected by the variant and the portion of the protein lost after the newly formed stop codon. Variants were analyzed for predicted effects on splicing by using Human Splicing Finder. Results: We found a total of 148 potentially pathogenic variants, 109 non-synonymous and 39 LOF, in 18 out of 21 MM families. Among our genes, many affect protein metabolism, immune system, and other have known links to carcinogenesis. Additionally, some of them are known to interact with key signaling pathways in MM, including PI3K/Akt/mTOR, Ras/Raf/MEK/MAPK, JAK/STAT, NF-κB, Wnt/β-catenin, and RANK/RANKL/OPG, showing congruency with previously reported literature. Interestingly, we also found different missense variants in the same two genes in two unrelated families. Conclusions: We have identified potentially pathogenic gene variants in 85% of MM/MGUS families. Our results can offer a useful reference to gene finding efforts by others in order to improve screening, early diagnosis and personalized therapy of individuals at risk of developing MM. Disclosures Durie: Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Goldschmidt:Merck Sharp and Dohme (MSD): Research Funding; Molecular Partners: Research Funding; Incyte: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Sequential Use of Carfilzomib and Pomalidomide in Relapsed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-7
Author(s):  
Arleigh McCurdy ◽  
Christopher P. Venner ◽  
Martha L Louzada ◽  
Richard LeBlanc ◽  
Michael Sebag ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Observational Study ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Treatment Initiation ◽  
Median Line ◽  
Advisory Committees ◽  
Two Agents ◽  
The Impact

Introduction: The treatment of multiple myeloma (MM) has dramatically improved due to the availability of immunotherapies such as daratumumab (Dara). However, in Canada, myeloma treatments now account for up to 20% of some provincial drug budgets. As Dara may be effective for a prolonged period and is quickly moving into first-line therapy, the Canadian body which provides guidelines to the provincial ministries of health recommended in 2019 against open sequencing of drugs in relapsed MM. Specifically, patients who receive Dara are now only eligible for public funding for either carfilzomib (CAR) or pomalidomide (POM)--but not both-- for relapsed MM. Given the known heterogeneity of myeloma, data gaps regarding the optimal sequencing of the available agents and uncertainly regarding the impact of this new restriction on patient outcomes, we utilized our Canadian national myeloma database to assess the sequencing of these two agents. The goal of our study was to understand the efficacy of these two commonly used treatments in the relapsed setting: 1) POM- after CAR-based therapy and 2) CAR- after POM-based therapy. Methods: We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), analyzed up to 30/06/2020. The CMRG-DB (formerly Myeloma Canada Research Network Database/MCRN-DB) is a prospectively maintained disease-specific database with over 7000 patients enrolled from 14 academic sites across Canada and includes legacy data collected from 2007. All patients with MM who were treated for relapsed disease with approved regimens using POM after CAR, or CAR after POM were included. Our primary outcomes were overall response rates (ORR) in each respective cohort. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and a landmark OS analysis from treatment initiation with the first of the two agents. Survival was estimated using Kaplan-Meier methods and compared between groups using log rank test. Results: A total of 121 patients were included: 49 treated with POM after CAR, and 72 with CAR after POM. In the POM after CAR group, the median line of treatment was 4th for POM and 3rd for CAR. In the CAR after POM group, the median line of treatment was 4th for POM and 5th for CAR. In 79/121 patients (65%), the two therapies were directly sequential, 40/49 (82%) for the POM after CAR group, and 38/72 (54%) in the CAR after POM group. Baseline characteristics and treatment details are shown in Table 1. The ORR was 51% for patients treated with POM after CAR, and 49% for patients treated with CAR after POM. The median PFS for POM after CAR was 4.93 months (95% CI, 2.76-7.07), and for CAR after POM was 5.36 months (95% CI, 3.75-6.94). The median OS for patients treated POM after CAR was 11.01 months (95% CI, 4.50-19.13), and for patients treated with CAR after POM the median OS was 10.98 months (95% CI, 8.98-19.17) (Figure 1). In a landmark analysis using the time of the treatment initiation with the first of the two agents, the median OS of patients treated with CAR after POM was 37.61 months (95% CI 26.66-46.52) and 25.32 months (95% CI 14.56-41.19) for patients treated with POM after CAR (p=0.1270) (Figure 2). Conclusion: In this real-world observational study we demonstrated that both CAR- and POM-based therapies were effective treatment options for patients with advanced relapsed MM as each produced responses in approximately 50% of patients with a median PFS of about 5 months and median OS of 11 months. These results are comparable to those noted in prospective clinical trials leading to the approval of these agents in this setting. Further, a landmark analysis showed that using both agents sequentially late in the disease course provided reasonable OS outcomes, regardless of the order in which they are sequenced. Finally, as the cost of MM therapy increases, the use of real-world data can help determine the impact of funding decisions on the outcome of patients treated in a publicly funded universal health care system such the one in Canada. Disclosures McCurdy: GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Consultancy, Honoraria. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Kotb:Takeda: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Karyopharm: Current equity holder in publicly-traded company; Amgen: Honoraria. Mian:Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Stakiw:Roche: Research Funding; Lundbeck: Honoraria; BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Research Funding. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding.

scholarly journals Oncogene Induced Senescence As a Potential Breakpoint Mechanism Against Malignant Transformation in Plasma Cell Disorders

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4474-4474
Author(s):  
Nicola Lehners ◽  
Elena Ellert ◽  
Jing Xu ◽  
Hartmut Goldschmidt ◽  
Mindaugas Andrulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Malignant Transformation ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Expression Levels ◽  
Plasma Cell Disorders

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

TAK-169, a Novel Recombinant Immunotoxin Specific for CD38, Induces Powerful Preclinical Activity Against Patient-Derived Multiple Myeloma Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Wassilis S.C. Bruins ◽  
Wenrou Zheng ◽  
Jack P. Higgins ◽  
Erin K. Willert ◽  
John Newcomb ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cytotoxic Activity ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cells ◽  
Therapeutic Window ◽  
Target Cells ◽  
Advisory Committees ◽  
Immune Effector ◽  
The Impact

Monoclonal antibodies (daratumumab, anti-CD38; elotuzumab, anti-SLAMF7) and BCMA-targeting T-cell redirecting therapies are highly effective in a large proportion of multiple myeloma (MM) patients. Nonetheless, age, prior (chemo)therapy, and the tumor-microenvironment may impair immune effector cell function and therefore significantly reduce the efficacy of these immunotherapies. Alternatively, an appealing strategy would be the use of targeted therapies, such as immunoconjugates, that directly kill the tumor cells. TAK-169, a novel CD38-specific immunotoxin armed with a deimmunized (DI) Shiga-like toxin A subunit (SLTA) payload, has been designed with this idea. TAK-169 induces irreversible ribosome inactivation of target cells with no dependency on immune effector cells. Prior studies showed that TAK-169 exerts potent cytotoxic activity against CD38-positive human MM cell lines in vitro and in xenograft mouse models (Willert et al. AACR 2019 Abstract 2384). Also, TAK-169 was well tolerated in mice and non-human primates (Willert et al. AACR 2019 Abstract 2384), and deimmunizing the SLTA molecule significantly reduced the in vivo immunogenicity of the payload (Willert et al. AACR 2015 Abstract 2477; Rajagopalan et al. AACR 2016 Abstract 595; Robinson et al. AACR 2017 Abstract 2695). We now assessed the preclinical activity of TAK-169 on a large panel of primary MM cells present in bone marrow (BM) samples from newly diagnosed (ND) (n=13), daratumumab-naive relapsed/refractory (RR) (n=11), and daratumumab-refractory (DR) RR (n=12) patients in flow cytometry-based cytotoxicity assays. In these samples, we also tested the impact of TAK-169 on non-malignant CD38-expressing hematopoietic cells, to gain insight into its on-target off-tumor effects. TAK-169 effectively lysed MM cells present in 36/36 BM samples in a dose-dependent fashion (Figure 1A; median maximal lysis 89%; range 45-100%; EC50: 36pM). Of note, MM cells from ND and daratumumab-naïve RR patients were equally sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 90%; range 76-100% vs. median maximal lysis 91%; range 76-98%). While MM cells from DR RR patients were also effectively killed, a fraction of these samples was less sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 66%, range 45-99%). We are currently exploring the impact of several patient and tumor characteristics, such as previous therapies and surface CD38 expression levels on MM cells, on the cytotoxic activity of TAK-169, and results will be reported. In the BM samples, the cytotoxic activity of TAK-169 was mainly restricted to MM cells - except for limited lysis of NK cells (median maximal lysis: 18%) and monocytes (median maximal lysis: 21%), no other non-malignant hematopoietic cells were lysed (Figure 1D), indicating a favorable therapeutic window generated by targeting CD38 with TAK-169. In conclusion, we show that TAK-169 induces powerful lysis of primary MM cells from both ND and RR MM patients, including those refractory to daratumumab. Our findings support the ongoing phase 1 clinical trial evaluating TAK-169 monotherapy in heavily pretreated MM (NCT04017130), and encourage preclinical evaluation of TAK-169 in other CD38-positive malignancies such as AML and T-ALL. Disclosures Higgins: Molecular Templates, Inc.: Current Employment, Other: Stockholder. Willert:Molecular Templates, Inc.: Current Employment, Other: Stockholder. Newcomb:Takeda Pharmaceuticals International: Current Employment, Other: Stockholder. Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Van De Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Gadeta: Research Funding; Onkimmune: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding; Genmab: Research Funding.

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