Quantitative expression of Ikaros, IRF4, and PSMD10 proteins predicts survival in VRD-treated patients with multiple myeloma

Abstract The search for biomarkers based on the mechanism of drug action has not been thoroughly addressed in the therapeutic approaches to multiple myeloma (MM), mainly because of the difficulty in analyzing proteins obtained from purified plasma cells. Here, we investigated the prognostic impact of the expression of 12 proteins involved in the mechanism of action of bortezomib, lenalidomide, and dexamethasone (VRD), quantified by capillary nanoimmunoassay, in CD138-purified samples from 174 patients with newly diagnosed MM treated according to the PETHEMA/GEM2012 study. A high level of expression of 3 out of 5 proteasome components tested (PSMD1, PSMD4, and PSMD10) negatively influenced survival. The 5 analyzed proteins involved in lenalidomide’s mode of action were associated with time to progression (TTP); low levels of cereblon and IRF4 protein and high levels of Ikaros, AGO2, and Aiolos were significantly associated with shorter TTP. Although the glucocorticoid receptor (GCR) level by itself had no significant impact on MM prognosis, a high XPO1 (exportin 1)/GCR ratio was associated with shorter TTP and progression-free survival (PFS). The multivariate Cox model identified high levels of PSMD10 (hazard ratio [HR] TTP, 3.49; P = .036; HR PFS, 5.33; P = .004) and Ikaros (HR TTP, 3.01, P = .014; HR PFS, 2.57; P = .028), and low levels of IRF4 protein expression (HR TTP, 0.33; P = .004; HR PFS, 0.35; P = .004) along with high-risk cytogenetics (HR TTP, 3.13; P < .001; HR PFS, 2.69; P = .002), as independently associated with shorter TTP and PFS. These results highlight the value of assessing proteins related to the mechanism of action of drugs used in MM for predicting treatment outcome.

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Prognostic impact of kinetics of circulating plasma cells before and after induction therapy in newly diagnosed multiple myeloma patients undergoing early transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8020 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8020-8020

Author(s):

Rajshekhar Chakraborty ◽

Eli Muchtar ◽

Angela Dispenzieri ◽

Martha Lacy ◽

Francis Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

Induction Therapy ◽

Plasma Cells ◽

Progression Free Survival ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Color Flow ◽

Course Of Illness ◽

The Impact

8020 Background: Circulating plasma cells (CPCs) at diagnosis, prior to transplant and at relapse have a negative prognostic impact on survival in multiple myeloma (MM). However, the impact of changes in CPCs along the course of illness has not been defined. Methods: We evaluated 247 patients with newly diagnosed MM (NDMM) undergoing early autologous stem cell transplantation (ASCT) in the era of novel agents (2007 to 2015), who had serial evaluation of CPCs at diagnosis and pre-ASCT by 6-color flow cytometry. Results: The median age at transplant was 62 years.A total of 117 (47%) patients had no detectable CPCs at both time points (CPC-/-), 82 (33%) had CPCs at diagnosis followed by complete eradication after induction therapy (CPC+/-) and 48 (19%) had detectable clonal CPCs at transplant, with persistence of cells (CPC+/+; n=45) or emergence of new CPCs (CPC-/+; n=3) after induction. The incidence of t(11;14) by iFISH was lower in the CPC-/- group (19%) compared to CPC+/- (29%) and CPC +/+ or -/+ (39%) groups ( p=0.033). Conversely, the incidence of hyperdiploidy was significantly higher in patients with CPC-/-, compared to those with CPC+/- and CPC+/+ or -/+ (64%, 44% and 39% respectively; p=0.005). The rate of post-ASCT stringent complete response was 32% in the CPC-/- group, 30% in CPC+/- group and 12% in CPC+/+ or -/+ group ( p=0.018). At a median follow-up of 58 months from ASCT, the median progression-free survival (PFS) from transplant in the 3 respective groups was 30, 24 and 14 months and the 5-year overall survival (OS) rates were 83%, 70% and 43% ( p<0.001 for both comparisons). On a multivariate analysis, using CPC-/- group as the comparator, PFS and OS was significantly inferior in CPC+/- (RR 1.6; p=0.020 and RR 2.7; p=0.008 for PFS and OS respectively) and CPC +/+ or -/+ groups (RR 2.9; p<0.001 and RR 5.8; p<0.001 for PFS and OS respectively). Conclusions: Clonal CPCs are detectable in more than 50% of newly diagnosed MM patients undergoing upfront ASCT. Monitoring for CPCs before initiation of induction therapy and before ASCT by 6-color flow cytometry is highly predictive of outcome in NDMM and should be incorporated into prospective clinical trials.

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Impact of acquired del(17p) in multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018028530 ◽

2019 ◽

Vol 3 (13) ◽

pp. 1930-1938 ◽

Cited By ~ 4

Author(s):

Arjun Lakshman ◽

Utkarsh Painuly ◽

S. Vincent Rajkumar ◽

Rhett P. Ketterling ◽

Prashant Kapoor ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Plasma Cells ◽

Progression Free Survival ◽

Lactate Dehydrogenase Level ◽

Data Sets ◽

Prognostic Impact ◽

Disease Characteristics ◽

Baseline Factors

Abstract The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

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Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.4120 ◽

2008 ◽

Vol 26 (16) ◽

pp. 2737-2744 ◽

Cited By ~ 136

Author(s):

Gema Mateo ◽

M. Angeles Montalbán ◽

Maria-Belén Vidriales ◽

Juan J. Lahuerta ◽

Maria V. Mateos ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Progression Free Survival ◽

Study Groups ◽

High Dose ◽

Prognostic Impact ◽

Free Survival ◽

Multiparametric Flow Cytometry ◽

Risk Of Progression ◽

Bone Marrow Plasma

Purpose To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM). Patients and Methods We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol. Results Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001). Conclusion To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.

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PTEN Gene Deletions in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.4889.4889 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4889-4889

Author(s):

Xiao Ying Qi ◽

A. Keith Stewart ◽

Hong Chang

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Progression Free Survival ◽

Myeloma Cell ◽

Suppressor Gene ◽

High Dose Chemotherapy ◽

Pten Gene ◽

Allelic Loss ◽

High Dose ◽

13Q Deletion

Abstract PTEN, a tumor suppressor gene, negatively regulates the anti-apoptotic action of akt phosphorylation. Allelic loss or mutation of this gene has been detected in many solid tumors and more recently in human myeloma cell lines (HMCLs). Expression of PTEN has resulted in growth inhibition and apoptosis of a HMCL, suggesting that it may play a role in the pathogenesis of multiple myeloma (MM). However, the PTEN status in tumor cells from patients with MM has not been determined. Using a triple staining method combining staining for cytoplasmic light chains and fluorescence in situ hybridization (FISH) with chromosome 10-centromere and PTEN-gene specific probes, we analyzed clonal plasma cells from 71 patients with MM, 10 with plasma cell leukemia (PCL) and 10 HMCLs. Hemizygous PTEN deletions were detected in 4 of 71 (5.6%) MM patients, 2 of 10 (20%) PCLs, and 2 of 10 (20%) HMCLs. The percentages of clonal plasma cells containing PTEN deletions ranged from 21–90% (median, 56%). Three of the 4 patients with PTEN deletions were detected at diagnosis with stage III disease (Duire-Salmon) and 1 was detected at relapse. Two patients had IgG kappa, 1 IgG lambda and 1 free lambda light chain. To correlate the PTEN status with other known genetic abnormalities in MM, we investigated 4 MM and 2 PCLs with PTEN deletions using FISH for chromosome13q, p53 status, translocations t(11;14), t(4;14) and t(14;16). One MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. All 4 MM patients with hemizygous PTEN deletions received melphalan based high-dose chemotherapy and autologous stem cell support. Their median overall survival (OS) was 48.1months, and progression free survival (PFS) was 42.8 months as compared to patients without PTEN deletions (OS, not reached, PFS, 25.8 months) (p=0.51 for OS, p=0.67 for PFS). Our results indicate that PTEN deletions are uncommon in MM patients and therefore unlikely represent a primary event for MM. PTEN deletions appear to occur in the advance stage of the disease, and are more frequently involved in PCL or HMCLs suggesting that deletions of PTEN may be associated with disease progression in a subset of MM.

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Clarithromycin (Biaxin®), Low Dose Thalidomide and Dexamethasone (BLT-D) in Newly Diagnosed and Previously Treated African American Patients with Multiple Myeloma: A Retrospective, Single Institution Experience.

Blood ◽

10.1182/blood.v106.11.3501.3501 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3501-3501

Author(s):

Jack Jacoub ◽

Joao L. Ascensao ◽

Boyer James ◽

Thomas O’Connor ◽

Reema Batra ◽

...

Keyword(s):

Multiple Myeloma ◽

African American ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

Staging System ◽

Stage I ◽

M Protein ◽

Duration Of Treatment ◽

Previously Treated

Abstract Introduction : African-Americans (AA) are twice as likely to develop multiple myeloma (MM) than Caucasians but are largely underrepresented in clinical trials. Thalidmode plus dexamethasone is an established therapy in MM. Biaxin® may augment the efficacy of this combination possibly via potentiating steroid activity (M. Coleman, et al. Leuk Lymphoma 2002, R. Niesvizky, et al. Blood 2003, Abs #832). Methods : We conducted a retrospective review of all AA patients (pts) with symptomatic MM treated with BLT-D from 2002-present. Treatment consisted of Thalidomide 50–200mg daily, Biaxin 500mg twice daily and dexamethasone 40mg weekly. All pts received monthly bisphosphonate therapy and aspirin 81–325mg daily. Response criteria was defined as follows: complete response (CR) = no detectable M-protein, marrow plasma cells <5%; very good partial response (VGPR) = decrease in M-protein by >90%; partial response (PR) = decrease in M-protein by >50%; stable disease (SD) = M-protein decrease by <50% without clinical progression; no response (NR)= progression with no change or increase in M-protein or response <4wks. Progression free survival (PFS) was defined from the start of BLT-D until discontinuation or change in therapy due to progressive disease as clinically indicated. Toxicity was graded according to WHO criteria. Results :15 pts received BLT-D and their characteristics were as follows: all were males; median age 66 (range 30–78); IgG=53%, IgA=20%, light chain only=27%; Durie-Salmon stage I=20%, II=33%, III=47%; International Staging System stage I=20%, II=47%, III=13%, undefined = 20%; 7 were previously treated (5 pts had 1 prior regimen, 2 pts had ≥2 prior regimens). In previously treated pts (n=7) responses were as follows: no CR, 2 VGPR (28%), 3 PR (43%), 1 SD (14%) and 1 NR (14%) for an overall response rate (ORR) of 87%. Their duration of treatment ranged from 4–32 mos and median PFS in responders (VGPR+PR+SD) was 29.5 mos (range 23–35). 3 pts had BLT-D discontinued after 12–15 months of therapy and remained in stable plateau phase off therapy for > 1 year; one was referred for ASCT after 14 mo; one continues stable at 15 mo and the third relapsed at 12 months but failed to respond again to BLT-D. Responses in treatment naive pts (n=8) were as follows: no CR, 3 VGPR (38%), 1 PR (13%) and 2 SD (25%), 2 NR (25%) for an ORR of 75%. Their duration of therapy ranged from 3–20 mos and median PFS in responding patients was 11 mos (range 7–20). The longest survivor in this group (37 mos) received an ASCT after 12 mos of therapy. 13 pts (87%) remain alive at a median follow-up of 24 mos (range 8–37). Grade 3–4 toxicity consisted of 3 DVTs + 1 PE (27%), 5 hypergycemias (33%), 2 infections (13%) and 1 peripheral neuropathy (7%). Additionally, 1 pt developed superficial thrombophlebitis; 1 QT prolongation resolving with Biaxin discontinuation; 5 others with neuropathy; and 2 others with hyperglycemia. Conclusion : BLT-D is feasible and effective therapy in African-American patients with MM and is capable of inducing durable responses. However, we encountered significant thrombotic and endocrine toxicity that appears out of proportion to what has been previously reported with thalidomide plus dexamethasone alone. Furthermore, aspirin thromboprophylaxis at daily doses of 81–325 mg appears suboptimal in preventing thromboembolic events in this group of patients when prescribed this regimen.

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Dual Targeting of -TORC1 and -TORC2 as a New Strategy In the Treatment of Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.133.133 ◽

2010 ◽

Vol 116 (21) ◽

pp. 133-133 ◽

Cited By ~ 2

Author(s):

Patricia Maiso ◽

AbdelKareem Azab ◽

Yang Liu ◽

Yong Zhang ◽

Feda Azab ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Cell Lines ◽

Mechanism Of Action ◽

Plasma Cells ◽

Bone Marrow Microenvironment ◽

Advisory Committees

Abstract Abstract 133 Introduction: Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment such as cytokines and growth factors, nutrients and stresses to regulate multiple cellular processes, including translation, autophagy, metabolism, growth, motility and survival. Mechanistically, mTOR operates in two distinct multi-protein complexes, TORC1 and TORC2. Activation of TORC1 leads to the phosphorylation of p70S6 kinase and 4E-BP1, while activation of TORC2 regulates phosphorylation of Akt and other AGC kinases. In multiple myeloma (MM), PI3K/Akt plays an essential role enhancing cell growth and survival and is activated by the loss of the tumor suppressor gene PTEN and by the bone marrow microenvironment. Rapamycin analogues such as RAD001 and CCI-779 have been tested in clinical trials in MM. Their efficacy as single agents is modest, but when used in combination, they show higher responses. However, total inhibition of Akt and 4E-BP1 signaling requires inactivation of both complexes TORC1 and TORC2. Consequently, there is a need for novel inhibitors that can target mTOR in both signaling complexes. In this study we have evaluated the role of TORC1 and TORC2 in MM and the activity and mechanism of action of INK128, a novel, potent, selective and orally active small molecule TORC1/2 kinase inhibitor. Methods: Nine different MM cell lines and BM samples from MM patients were used in the study. The mechanism of action was investigated by MTT, Annexin V, cell cycle analysis, Western-blotting and siRNA assays. For the in vivo analyses, Luc+/GFP+ MM.1S cells (2 × 106/mouse) were injected into the tail vein of 30 SCID mice and tumor progression was detected by bioluminescence imaging. Nanofluidic proteomic immunoassays were performed in selected tumors. Results: To examine activation of the mTOR pathway in MM, we performed kinase activity assays and protein analyses of mTOR complexes and its downstream targets in nine MM cell lines. We found mTOR, Akt, pS6R and 4E-BP1 are constitutively activated in all cell lines tested independently of the status of Deptor, PTEN, and PI3K. All cell lines expressed either Raptor, Rictor or both; excepting H929 and U266LR7 which were negative for both of them. Moreover, primary plasma cells from several MM patients highly expressed pS6R while normal cells were negative for this protein. We found that INK128 and rapamycin effectively suppressed phosphorylation of p6SR, but only INK128 was able to decrease phosphorylation of 4E-BP1. We observed that INK128 fully suppressed cell viability in a dose and time dependent manner, but rapamycin reached a plateau in efficacy at ± 60%. The IC50 of INK128 was in the range of 7.5–30 nM in the eight cell lines tested. Similar results were observed in freshly isolated plasma cells from MM patients. Besides the induction of apoptosis and cell cycle arrest, INK128 was more potent than rapamycin to induce autophagy, and only INK128 was able to induce PARP and Caspases 3, 8 and 9 cleavage. In the bone marrow microenvironment context, INK128 inhibited the proliferation of MM cells and decreased the p4E-BP1 induction. Importantly, treatment with rapamycin under such conditions did not affect cell proliferation. INK128 also showed a significantly greater effect inhibiting cell adhesion to fibronectin OPM2 MM1S, BMSCs and HUVECs compared to rapamycin. These results were confirmed in vivo. Oral daily treatment of NK128 (1.0 mg/kg) decreased tumor growth and improved survival of mice implanted with MM1S. Conclusion: Dual inhibition of TORC1 and TORC2 represent a new and promising approach in the treatment of MM and its microenvironment. The ability of INK128 to inhibit both TORC1 and TORC2 strongly supports the potential use of this compound in MM patients. Disclosures: Anderson: Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Final Results from the Phase IIa Study of the Anti-CXCL12 Spiegelmer® Olaptesed Pegol (NOX-A12) in Combination with Bortezomib and Dexamethasone in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2111.2111 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2111-2111 ◽

Cited By ~ 1

Author(s):

Heinz Ludwig ◽

Katja Weisel ◽

Maria Teresa Petrucci ◽

Xavier Leleu ◽

Anna Maria Cafro ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Dose ◽

High Risk ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

M Protein ◽

Dose Titration ◽

Free Survival ◽

Protein Change

Abstract Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.

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Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Blood ◽

10.1182/blood-2015-10-646810 ◽

2016 ◽

Vol 127 (6) ◽

pp. 681-695 ◽

Cited By ~ 130

Author(s):

Niels W. C. J. van de Donk ◽

Philippe Moreau ◽

Torben Plesner ◽

Antonio Palumbo ◽

Francesca Gay ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Plasma Cells ◽

Blood Compatibility ◽

Single Agent ◽

Progression Free Survival ◽

Complete Response ◽

Therapeutic Antibody ◽

Drug Discontinuation ◽

Therapeutic Antibodies

AbstractImmunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

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Association of loss of spleen visualization on whole-body diffusion-weighted imaging with prognosis and tumor burden in patients with multiple myeloma

Scientific Reports ◽

10.1038/s41598-021-03496-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Toshiki Terao ◽

Youichi Machida ◽

Ukihide Tateishi ◽

Takafumi Tsushima ◽

Kentaro Narita ◽

...

Keyword(s):

Multiple Myeloma ◽

Diffusion Weighted Imaging ◽

Plasma Cells ◽

Progression Free Survival ◽

Myeloma Cell ◽

Extramedullary Hematopoiesis ◽

Tumor Burden ◽

Whole Body ◽

Diffusion Weighted ◽

Worse Prognosis

AbstractThis study investigated the clinical significance of loss of spleen visualization (LSV) on whole-body diffusion-weighted imaging (WB-DWI) in patients with multiple myeloma (MM). The WB-DWI of 96 patients with newly diagnosed MM (NDMM) and 15 patients with smoldering MM (sMM) were retrospectively reviewed. LSV was observed in 56 patients with NDMM (58.3%) and 1 patient with sMM (6.7%). Patients with NDMM with LSV had a higher median infiltration of bone marrow plasma cells (80.0% vs. 50.0%, p < 0.001) and median total diffusion volume (median; 540.2 vs. 137.0 mL, p = 0.003) than patients without LSV. Patients with LSV had a lower spleen-to-spinal cord ratio (0.36 vs. 0.96, p < 0.001) and worse 2-year overall survival (OS) (84.6% vs. 100%, p = 0.032). Patients who did not recover spleen visualization during treatment had a worse prognosis, even when they obtained very good partial response (median progression-free survival: 13.2 months). Spleen histopathological findings revealed higher cellularity and diffuse myeloma cell infiltration in a patient with LSV and splenic amyloidosis without extramedullary hematopoiesis in a patient without LSV. Therefore, LSV indicates worse prognosis for patients with MM, even when the patient responds to treatment. Further studies are warranted to clarify the immunological role of spleen in MM.

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Defining the Differentiation Stage of Multiple Myeloma Plasma Cells: Biological and Clinical Significance

Blood ◽

10.1182/blood.v124.21.25.25 ◽

2014 ◽

Vol 124 (21) ◽

pp. 25-25

Author(s):

Bruno Paiva ◽

Noemi Puig ◽

María-Belén Vidriales ◽

Norma Carmen Gutierrez ◽

Miguel T Hernandez ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Principal Component ◽

Progression Free Survival ◽

Down Regulation ◽

Phenotypic Data ◽

Cytogenetic Abnormalities ◽

Differentiation Stage ◽

Color Combinations ◽

End Stage

Abstract B-cell lymphopoiesis ends in terminally differentiated bone marrow (BM) plasma cells (PCs). While initially PCs have been viewed mainly as short-lived end-stage B-cells, there is now evidence that this is a heterogeneous cellular compartment in which new-born plasmablasts and long-lived PCs also coexist. The transition between both is characterized by phenotypic modifications, which include higher CD38/CD138 expression alongside HLADR and CD19 down-regulation. CD19 function and expression are regulated by CD81 and accordingly, three normal BM PC subsets can be delineated according to the expression levels of both markers: CD19+/CD81+, CD19-/CD81+, and CD19-/CD81-. However, no additional phenotypic information exists on such normal subsets, nor about how myeloma PC differentiation relates to its normal counterpart. Here, we used 23-color multidimensional flow cytometry (MFC) and principal component analysis (PCA) to phenotypically characterize normal BM PC differentiation in 10 healthy donors and its malignant counterpart in 115 elderly newly-diagnosed multiple myeloma (MM) patients included in the PETHEMA/GEM2010MAS65 study. First, we adopted novel MFC software technology to, after merging and calculating phenotypic data obtained from four 8-color combinations, define the immunophenotypic expression profile (iPEP) of normal BM PCs and characterize their differentiation pathway through PCA. Accordingly, we observed that from the CD19+/CD81+ subset through the CD19-/CD81+ and CD19-/CD81- stages (corresponding to 64%, 32% and 4% of total PCs, respectively) there is a continuous down-regulation on the amount of expression of CD54 (P=.008), CD44 (P=.03) and CD27 (P=.07). By contrast, a trend towards increased levels of CD28 (P=.06), CD38 (P=.05) and CD56 (P=.09) was also observed, suggesting an accumulation of potentially less active and more differentiated PCs from the CD19+/CD81+ to the CD19-/CD81- stages. Using the same approach as described above to determine the iPEP of myeloma PC clones from each individual patient, we then integrated such iPEPs into the normal PC differentiation pathway to investigate, through PCA, the stage and corresponding normal counterpart of each patient myeloma PC clone. From the 115 patients included in this analysis, 3 (3%) had myeloma PCs fitting within the CD19+/CD81+ differentiation stage and 21 (18%) within the CD19-/CD81+ subset, whereas the remaining 91 cases (79%) fitted within potentially more differentiated CD19-/CD81- stages. Virtually no cases with myeloma PC clones corresponding to the CD19+/CD81+ and CD19-/CD81+ differentiation stages had ISS stage I (8%), as compared to 30% in patients with a more differentiated PC CD19-/CD81- signature (P=.03). Furthermore, patients with myeloma PC clones matching the CD19+/CD81+ and CD19-/CD81+ differentiation stages showed a trend for higher incidence of extramedullary plasmacytomas (22% vs 9%; P=.09). Interestingly, almost half of patients with myeloma PC clones in potentially less differentiated stages had no cytogenetic abnormalities [t(IGH), +1q, del(13q), and/or del(17p)] as compared to cases with myeloma PCs matching with the CD19-/CD81- normal PC counterpart (44% vs. 16%, respectively; P=.01). However, whenever present, the type (standard- vs high-risk) of such cytogenetic abnormalities did not differ between both subgroups. Finally, we investigated if the differentiation stage of myeloma PC clones influenced patients’ prognosis, and noted that progression-free survival (PFS) of cases in less and intermediate differentiation stages was significantly inferior PFS as compared to patients with a mature CD19-/CD81- myeloma PC clone (median of 24 months vs not reached, respectively; P=.02). Noteworthy, identical patient prognostication for PFS (P=.02) was observed when the analysis was restricted to cytogenetically-defined standard-risk cases, thus identifying a subgroup of patients with more aggressive MM despite favorable cytogenetic profiles. In summary, we showed that in the vast majority (~80%) of MM patients the PC clone phenotypically matches more differentiated normal PC counterpart subsets. Patients harboring less differentiated clones show a higher incidence of ISS stage II/III and extramedullary disease despite fewer cytogenetic abnormalities, as well as significantly inferior PFS as compared to cases with more differentiated myeloma PC clones. Disclosures Ocio: Array Biopharma: Honoraria, Research Funding.

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