Low-Dose Dexamethasone Does Not Abrogate the Immunomodulatory Effects of Lenalidomide and Both Reactivate the Impaired Immune System of High-Risk Smoldering Multiple Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2955-2955
Author(s):  
Bruno Paiva ◽  
Maria-Victoria Mateos ◽  
Luis Ignacio Sánchez-Abarca ◽  
Maria Belen Vidriales ◽  
Lucia Lopez-Corral ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
High Risk ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Low Dose ◽  
Single Agent ◽  
Immunomodulatory Effects ◽  
Activation Markers ◽  
Cd8 T Lymphocytes

Abstract Introduction: While dexamethasone (Dex) has been commonly used in the treatment of multiple myeloma (MM), its immunosuppressive effect is becoming a matter of concern with the advent of immune-based therapies. One example is the combination of lenalidomide and Dex (LenDex) because it has been reported that Dex abrogates the immunomodulatory effects of Len; however, most of the studies have been performed in vitro, using high-doses of Dex, and in small series of relapsed patients previously exposed to other drugs. Methods: Because the potentially antagonist effect of Dex may represent a dilemma in the design of clinical trials, here we aim to shed light into the question about whether or not low-dose Dex abrogates the immunomodulatory effect of Len by studying the phenotypic profile of T-lymphocytes, NK-cells and dendritic cells (DCs) of 31 previously untreated high-risk smoldering MM (SMM) patients enrolled in the Quiredex trial at baseline, after 3 and 9 cycles of LenDex, and during maintenance with Len as single-agent. Results: Patients with high-risk SMM showed at baseline normal numbers of CD4 and CD8 T-lymphocytes as well as CD56dim and CD56bright NK-cells compared to age-matched healthy individuals. By contrast, they displayed an increment of TCRγδ positive T-lymphocytes (P=.02) and Tregs (P=.04), as well as an altered distribution of BDCA-1 positive myeloid DCs (P=.02) and tissue macrophages (P=.06). Moreover, the expression levels of activation markers (CD25, CD28 and CD54) as well as Th1-related markers (CD195, IFN-γ, TNF-α, or IL-2) were significantly inferior in T-lymphocytes from high-risk SMM patients. A significantdown-regulation of proliferation-related markers (CD119 and CD120b) was also noted. To assess the combined effect of LenDex in T-lymphocytes and NK-cells, we compared the immune status of the 31 high-risk SMM patients at baseline vs. after 3 and 9 cycles of LenDex. Interestingly, TCRγδ positive T-lymphocytes as well as Tregs were further increased with LenDex; conversely, CD4 T-lymphocytes were significantly decreased at the end of induction. There was a marked shift on the distribution of antigen-related maturation subsets induced by LenDex, and reflected by a significant increase of central memory CD4 (P<.001) and effector memory CD8 (P<.001) T-lymphocytes. Accordingly, CD4 and/or CD8 T-lymphocytes showed an increased expression of activation markers (CD69, CD25, CD28, and CD54), together with an up-regulation of the Th1 related chemokine CCR5 (CD195) and increased cytokine production of IFNγ, TNFα, and IL-2. NK-cells showed an up-regulation of the activation marker HLA-DR (P<.001), the ADCC associated receptor CD16 (P≤0.005), and the adhesion molecules CD11a (P≤0.001) and CD11b (P≤0.005) after 3 and 9 courses of LenDex. The percentage of cells in S-phase progressively increased from baseline vs. 3 and 9 cycles of LenDex for CD4 (P<0.001) and CD8 (P<0.001) T-lymphocytes as well as NK-cells (P<0.001). Most interestingly, high-risk SMM patients treated with LenDex and without disease progression showed higher numbers of functionally active T-lymphocytes as compared to those progressing to MM. To address the question whether Dex antagonizes Len, we compared the immune profile of 13 patients with PB samples collected at cycle 9 of induction vs. during maintenance (single-agent Len at least 3 months after Dex discontinuation). No significant differences were observed for the absolute numbers of all cell populations analyzed. From the total 63 phenotypic parameters analyzed, only 7 were found to be differently expressed. Namely, the expression of CD94, CD154 and CD212 positive T-lymphocytes as well as CD11a in T-lymphocytes and NK-cells were down-regulated during maintenance. Conclusions: Our results, obtained from a carefully selected population of patients without previous exposure to anti-MM therapy and with available longitudinal samples after consecutive cycles of LenDex, shed new light on the synergy between lenalidomide and dexamethasone which, at low doses, does not abrogate the immune modulatory effects of lenalidomide here analyzed. Accordingly, high-risk SMM patients have an impaired immune system that could be re-activated with LenDex, and support the value of therapeutic immunomodulation to delay the progression to MM. Disclosures Paiva: Millenium: Consultancy; BD Bioscience: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Binding Site: Consultancy. Mateos:Takeda: Consultancy; Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. San Miguel:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Sanofi-Aventis: Honoraria; Millennium: Honoraria; Novartis: Honoraria; Onyx: Honoraria.

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8039-8039
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Paolo Fabrizio Caimi ◽  
Leland L. Metheny ◽  
Benjamin Kent Tomlinson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Immune System ◽  
Transforming Growth Factor ◽  
Single Agent ◽  
Cell Activity ◽  
Type I ◽  
Phase Ib ◽  
Progression Of Disease ◽  
Grade Iii

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]

scholarly journals NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 768 ◽  
Author(s):  
Renato Zambello ◽  
Gregorio Barilà ◽  
Sabrina Manni ◽  
Francesco Piazza ◽  
Gianpietro Semenzato
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
Nk Cells ◽  
Plasma Cell ◽  
Potential Role ◽  
Myeloma Cell ◽  
Initial Reduction ◽  
Plasma Cell Dyscrasias

Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.

Dihydroartemisinin regulates the immune system by promotion of CD8+ T lymphocytes and suppression of B cell responses

2019 ◽  
Vol 63 (5) ◽  
pp. 737-749 ◽  
Author(s):  
Ting Zhang ◽  
Yiwei Zhang ◽  
Ning Jiang ◽  
Xu Zhao ◽  
Xiaoyu Sang ◽  
...  
Keyword(s):  
Immune System ◽  
T Lymphocytes ◽  
B Cell ◽  
Cell Responses ◽  
Cd8 T Lymphocytes ◽  
B Cell Responses

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1168-1171 ◽  
Author(s):  
Maurizio Zangari ◽  
Eric Siegel ◽  
Bart Barlogie ◽  
Elias Anaissie ◽  
Fariba Saghafifar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Doppler Ultrasonography ◽  
Standard Dose ◽  
Single Agent ◽  
Cytotoxic Chemotherapy ◽  
Newly Diagnosed ◽  
Statistical Association ◽  
Increased Risk

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos- phanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P = .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing DVT.

A Retrospective Comparison of Matched Elderly Patients Treated with Laromustine (Cloretazine®) or Best Supportive Care or Low Dose Ara-C in the LRF AML14 Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2960-2960 ◽  
Author(s):  
Robert Hills ◽  
Susan O’Brien ◽  
Verena Karsten ◽  
Alan K. Burnett ◽  
Francis Giles
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Low Dose ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Best Supportive Care ◽  
Cell Counts ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Background : A substantial proportion of older patients with AML are considered unlikely to benefit from an intensive treatment approach. They often receive either best supportive care (BSC), low dose treatment such as Low Dose Ara-C (LDAC), or clinical trials of novel agents. In one of the few randomised studies where patients were prospectively considered likely to be unfit for intensive therapy, LDAC was superior to BSC with 18% v 1% patients achieving CR. No patients with high risk cytogenetics (Grimwade 1998), achieved CR (Burnett 2007). Laromustine (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Laromustine has previously shown clinical activity in patients with de novo AML and high risk MDS (Giles et al. JCO 2007). A confirmatory phase II study of single agent laromustine was conducted in previously untreated patients ≥ 60 years old with de novo AML, prospectively considered likely to be unfit for intensive chemotherapy. Patients had at least one poor risk factor, defined by age ≥70, performance status 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Eighty-five patients received induction therapy with 600 mg/m2 laromustine. Second induction cycles were administered in 14 patients after partial response or hematologic improvement. Eighteen patients received at least one consolidation cycle of cytarabine 400 mg/m2/day CIV for 5 days. Methods: A retrospective non-randomised comparison was performed between the 85 patients treated with laromustine, and 121 patients satisfying the same entry criteria, treated in the AML 14 trial with either BSC or LDAC. Outcomes were compared using Mantel-Haenszel and logrank methods for unadjusted comparisons, and regression methods for adjusted analyses. Results : Patients in AML14 were slightly older than those treated with laromustine (median age 75 v 73), and tended to have higher white blood cell counts; by contrast, there were significantly fewer cardiac or respiratory comorbidities reported in the AML14 population. Other important risk factors such as performance status and cytogenetics were similar between the groups. Responses overall (CR/CRp) were seen in 33% (28/85) of patients treated with laromustine, compared with 2% (1/60) and 23% (14/61) in patients treated with BSC and LDAC (p&lt;0.0001, p=0.2, respectively). In particular, 1 patient with −5/del(5q), and 3 patients with −7/del(7q) cytogenetics experienced a CR with laromustine; patients in AML 14 with adverse cytogenetics saw no remissions. Survival was significantly improved in the laromustine group compared to BSC (1 year survival 20% v 8%, unadjusted HR 0.58 [0.40–0.84] p=0.004), and roughly comparable to that of LDAC (1 year survival 20% v 25%, HR 1.04 [0.73–1.49] p=0.8). Analyses adjusted for differences in baseline demographics, and using propensity scores gave consistent figures. Conclusions: Retrospective comparison of unrandomised data has significant limitations even though care has been taken to match for factors known to be predictive for survival. Laromustine was able to achieve a higher CR rate than LDAC or BSC, and produced remissions in groups where no remissions have previously been seen with LDAC or BSC. Laromustine gave significantly better survival than BSC, and demonstrated similar survival to LDAC.

Lenalidomide IS Able to Restore Immune SYSTEM IN MULTIPLE MYELOMA PATIENTS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4909-4909 ◽  
Author(s):  
Annalisa Chiarenza ◽  
Nunziatina Parrinello ◽  
Piera La Cava ◽  
Eleonora Spina ◽  
Daniele Tibullo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
T Cell ◽  
T Lymphocytes ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Gradient Centrifugation ◽  
Target Cells ◽  
First Line ◽  
Number Of Patients

Abstract Abstract 4909 LENALIDOMIDE IS ABLE TO RESTORE IMMUNE SYSTEM IN MULTIPLE MYELOMA PATIENTS Annalisa Chiarenza, Nunziatina Parrinello, Piera La Cava, Eleonora Spina, Daniele Tibullo, Cesarina Giallongo, Maide Cavalli, Alessandra Romano, Paolo Fiumara, Giuseppe A. Palumbo, Francesco Di Raimondo Background Multiple myeloma (MM) is a malignant plasma-cell proliferative disorder associated with dysfunctional T-cell responses. The immunomodulatory Thal derivative (IMiD) CC-5013 (lenalidomide) appears to be a promising agent for the treatment of myeloma. Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated to be responsible for it's activity (inhibition of angiogenesis, direct antiproliferative and proapoptotic effects on MM cells, suppression of pro-inflammatory cytokines, modulation of myeloma-stromal cells adhesive interactions). In addition, it has been demonstrated that lenalidomide in vitro is able to enhance T cell proliferation and to promotes ADCC. In this study we evaluated if MM patients have a deficit of T-reg (CD4+, CD25+, and FOXP3+) and of T lymphocytes bearing CD200 (a tolerogenic molecule) and the effect of lenalidomide treatment on these parameters. In addition, we investigated whether lenalidomide could improve ex vivo the ADCC against myeloma cells. Materials and methods Eight patients with previously untreated MM (median age 56 years) were treated with lenalidomide plus dexamethasone as first line therapy. Lenalidomide was given orally 25 mg daily on days 1 to 21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1, 8, 15, 22 of each cycle. All patients were evaluable for response and toxicity. Peripheral blood mononuclear cells (PBMNc) were obtained from MM patients using density gradient centrifugation (Fycoll) under sterile condictions, at the beginning of treatment and after 4 cycles of therapy. The percentage of T-reg (CD4+CD25+FOXP3+) and the expression of CD200 on T- lymphocytes were evaluated by cytometry. Twelve healthy subjects were used as control. Moreover, PBMNc (effector cells, E) were incubated with MM cells line ARH-77 (target cells, T), previously labelled with CFDA,SE (carboxyfluorescein diacetate, succinimidyl ester) as a tracing fluorescent marker, in culture medium (RPMI-1640, 10%FCS, 1%penicillin/streptomycin) at different concentration (T/E ratio 1:20, 1:40). After 18-24 h co-colture cells were analyzed by flow cytometry and MM plasma cells cytotoxicity was calculated as the percentage of positive CFDA,SE/propidium cells. Myeloma cell viability was determined by tripan blue esclusion and apoptosis was also evaluated using Annexin V/propidium assay. Two MM patients treated in first line with a combination of Velcade, Thalidomide and Dexamethasone (VTD) were used as control and the experiments were performed in duplicate. Results MM patients have a significantly lower rate of CD4+/CD25+/FOXP3+ and CD200+/CD3+ than normal (28,3±14,9/mmc and 37,8±24,7 /mmc vs 79,3±27,8 and 79,5± 48,9)(p=0,0001 and p=0,01 respectively). In our study, lenalidomide treatment resulted in an increase both of Treg cells and T-lymphocytes espressing CD200. This improvement is not statistically significant probably due to the low number of patients examined (tab I). More important, we observed that PBMC derived from patients treated with lenalidomide showed an increase ability to kill a target MM cell line compared to PBMC collected at diagnosis (CFDA,SE/propidium cells 11% vs 68%). This effect was more prominent in patients treated with lenalidomide than in MM patients treated with VTD (CFDA,SE/propidium cells 12% vs 39%), Fig.1. Conclusions Our data emphasize the role of lenalidomide in modulating the endogenous tumor-specific immune response and underline the anti-myeloma activity of these new class of drugs. Disclosures No relevant conflicts of interest to declare.

Influence of Lenalidomide Treatment on Immune Effector Cells From High-Risk Smoldering Multiple Myeloma (SMM) Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3944-3944
Author(s):  
Bruno Paiva ◽  
Maria Victoria Mateos ◽  
Lucía López-Corral ◽  
María-Belén Vidriales ◽  
Miguel T. Hernandez ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Γδ T Cells ◽  
Activation Markers ◽  
Hla Dr ◽  
Activation Profile ◽  
Immunomodulatory Properties

Abstract Abstract 3944 Lenalidomide is an immunomodulatory agent that enhances T and NK cell activation, being this consideration as a major player in its anti-myeloma effect. However, in MM lenalidomide is usually combined with the immunosuppressant dexamethasone, which has raised questions regarding a potential abrogation of this immunomodulatory effect. In fact, this may be a dilemma upon treating early stage MM patients with lenalidomide +/− dexamethasone. Moreover, our current knowledge of the immune system in SMM is limited. Herein we evaluated by multiparameter flow cytometry (MFC) immunophenotyping peripheral blood (PB) T and NK cells from high-risk SMM patients (N=33), treated according to the QUIREDEX trial (NCT 00480363): an induction phase of 9 four-week cycles of LenDex followed by maintenance with lenalidomide until disease progression. To evaluate the immune status of T and NK cells of SMM patients, we compared them at baseline vs healthy adults (HA) aged over 60 years (N=10). To assess the effect of LenDex on T and NK cells of SMM patients, we compared baseline samples vs those studied after 3 and 9 cycles of LenDex. To address the question whether dexamethasone antagonizes the immunomodulatory properties of lenalidomide, we compared in 11 of the 33 patients, the PB T and NK cells at the end of induction (9th cycle of LenDex) vs during maintenance (lenalidomide alone and at least 3 months after dexamethasone discontinuation). The percentage of PB T cells in high-risk SMM patients at baseline was increased when compared to HA (23% vs 17%; P=.02), mainly due to expansion of CD8 T cells (P=.03). Of note, γδ T cells were also increased in SMM (0.8% vs 0.3%; P=.003). In turn, no differences (P>.05) were noted for both the CD56dim and CD56bright NK cell compartments. However, when a more detailed immunophenotypic characterization was carried out, CD4 and/or CD8 T cells from SMM patients showed decreased expression of activation markers (CD25, P≤.04; CD54, P<.001 and CD154, P=.002), as well as decreased production of the Th1 related cytokines (IFNγ, P=.03; TNFα, P≤.003; and IL-2, P=.02). We then investigated the effect of LenDex treatment. After 3 and 9 cycles of LenDex both CD4 and/or CD8 T cells showed up-regulation of Th1related chemokines (CCR5; p<.001) and cytokine production (IFNγ, P=.03; TNFα, P=.03 and IL-2, P=.02), as well as increased expression of activation markers (CD69, P≤.005; CD25, P<.001; CD28, P≤.04; CD54, P<.001 and HLA-DR, P<.001). Similarly, CD56dim and CD56bright NK cells showed up-regulation of HLA-DR (P<.001), the antibody-dependent cell-mediated cytotoxicity associated receptor CD16 (p≤.005), and the adhesion molecules CD11a (p≤.001) and CD11b (p≤.005). Concerning cell cycle analysis, the percentage of cells in S-phase was significantly increased from baseline vs. 3 vs. 9 cycles of LenDex for T CD4 (0.04% vs 0.13% vs 0.13%; p<.001), CD8 (0.05% vs 0.13% vs 0.18%; p<.001) and NK cells (0.07% vs 0.16% vs 0.15%; p<.001). Interestingly, an unsupervised cluster analysis of the overall immunophenotypic expression profile obtained after 9 cycles of LenDex was able to discriminate two groups of patients with different activation profiles particularly on T CD8 cells, with differences (P<.05) in both their percentage in PB and expression of activation, Th1 and maturation markers. Patients displaying a higher activation profile showed a trend towards increased depth of response after 9 cycles of LenDex (sCR+CR: 31% vs 15%; p=.229), as well as time-to progression (TTP) to symptomatic MM (TTP at 2-years: 100% vs 79%; P=.177). Finally, we explored whether the immunomodulatory properties of lenalidomide could be increased when dexamethasone was removed for the maintenance phase. Regarding T and NK cell distribution, only an increase in the percentage of CD4 T cells was found (9% vs. 12%, P=.04), whereas no differences (P>.05) were noted regarding the immunophenotypic expression profile of T and NK cells studied. In summary, we show that in high-risk SMM patients at baseline CD8 and γδ T cells are increased but overall T cells show an impaired activation profile. Treatment with LenDex induces an activation and proliferation of T and NK cells which may contribute to disease control. Finally, our results do not show an inhibition of the immunomodulatory effects of lenalidomide by the concomitant use of dexamethasone. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Mateos:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.

A Phase I Trial Of Anti-KIR Monoclonal Antibody IPH2101 and Lenalidomide For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Don M. Benson ◽  
Adam D Cohen ◽  
Craig C Hofmeister ◽  
Munshi C Nikhil ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Low Grade ◽  
Dosing Interval ◽  
Infusion Reactions

Abstract Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

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