Symptoms of Multiple Myeloma: Results of Hybrid Concept Elicitation/Cognitive Debriefing Interviews

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5973-5973 ◽  
Author(s):  
Peter C. Trask ◽  
Bhumi Trivedi ◽  
Andrew Palsgrove ◽  
William Benton Jones ◽  
Colleen McHorney
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Plasma Cells ◽  
Qualitative Interviews ◽  
Cognitive Debriefing ◽  
Symptom Scale ◽  
Sleep Difficulty ◽  
Novel Treatments ◽  
Third Line ◽  
The Impact

Abstract Aims: Multiple myeloma (MM) is a malignant plasma cell disease that is characterized by clonal proliferation of plasma cells in the bone marrow and the production of excessive amounts of a monoclonal immunoglobulin (usually of the IgG or IgA type or free urinary light chain [paraprotein, M protein, or M-component]). Hallmark symptoms of MM include bone disease, which contributes to pain, and anemia, which manifests itself as tiredness and fatigue. Recently, we developed a new MM Symptom Scale based on a systematic literature review and previously conducted qualitative interviews with MM patients. The instrument presents a set of symptoms and evaluates their frequency and severity over the last seven days. In this study, we conducted one-on-one interviews with third-line plus relapsed or refractory (RR) MM patients to: (1) elicit and confirm key disease symptoms that patients describe in response to MM using open-ended questions; and (2) assess the clarity, understanding, and content validity of the newly-developed draft MM Symptom Scale. Methods: Third-line plus RR MM patients were recruited for one-on-one interviews in San Diego, CA and Fort Lauderdale, FL. All participants had to be adult, symptomatic RR MM patients who had previously been treated with an immunomodulary drug and a proteasome inhibitor. They also had to have evidence of disease progression or be currently on treatment to qualify for the study. The first half of the interview focused on open-ended questions regarding important symptoms that patients had experienced. In the second half of the interview, the MM Symptom Scale was introduced, the patient completed the scale in a think-aloud cognitive-debriefing interview, and each question was evaluated for clarity and understanding. Results: A total of nine patients participated in the hybrid interviews of whom four were female and five were male. The average age of the participants was 61.6 years. The average severity of MM symptoms across the nine participants was 6.2 on a scale of 1-10. The average report of the worst level of pain experienced in the last week was 5.2 on a scale of 1-10. The average report on the worst level of tiredness experienced in the last week was 6.2 on a scale of 1-10. The most frequently-reported symptoms were pain (specifically back pain) and tiredness (100% of participants). Other commonly-reported symptoms include swelling of the extremities, itching, feeling depressed, and diarrhea. During the cognitive-debriefing portion of the interview, most participants did not find difficulty in understanding any of the items. Some symptoms, however, were deemed not particularly relevant for the nine MM patients. For example, all of the nine MM patients believed that the symptoms “loss of bladder control” and “loss of bowel control” did not apply to them. These and other symptoms will be evaluated more closely for potential exclusion from the MM Symptom Scale. Some symptoms – such as neuropathy, sleep difficulty, constipation, and weight gain − were endorsed by at least three patients and will be considered for inclusion in the MM Symptom Scale. Conclusions: Health-related quality of life (HRQoL) in MM patients is characterized largely by the burden of pain and tiredness in addition to a few other key symptoms. These can be reliably and validly quantified using HRQoL instruments. The MM Symptom Scale is currently being refined to provide a standardized way through which clinician investigators can assess the impact of novel treatments on patients’ HRQoL. Disclosures Trask: Sanofi: Employment. Trivedi:Sanofi: Research Funding. Palsgrove:Sanofi: Research Funding. Jones:Sanofi: Employment. McHorney:Sanofi: Research Funding.

scholarly journals Targeting Cancer Associated Fibroblasts in the Bone Marrow Prevents Resistance to Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 865-865 ◽  
Author(s):  
Reona Sakemura ◽  
Michelle J. Cox ◽  
Michael J. Hansen ◽  
Mehrdad Hefazi ◽  
Claudia Manriquez Roman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Therapy ◽  
Cell Line ◽  
Research Funding ◽  
Plasma Cells ◽  
Flow Cytometric Analysis ◽  
Data Safety Monitoring Board ◽  
Nsg Mice ◽  
Dual Targeting ◽  
The Impact

Cellular immunotherapy is a rapidly progressing field in multiple myeloma (MM). Multiple clinical trials have reported impressive efficacy of B cell maturation antigen (BCMA) directed chimeric antigen receptor cell therapy (BCMA CART) in MM. While trials demonstrated an overall response rate of 70-90% in patients with relapsed/refractory MM, the durable response rate is around 30%. Most patients lose their CART cells and the disease relapses within the first year, suggesting an inhibition by the MM tumor microenvironment (TME). Therefore strategies to overcome this inhibition would represent a major advance in CART cell therapy for MM. Cancer associated fibroblasts (CAFs) within the TME play a critical role in promoting tumor growth and in the generation of an immunosuppressive microenvironment. We hypothesized that CAFs from bone marrows of patients with MM (MM-CAFs) inhibit BCMA CART cells and contribute to their failure and that targeting both the malignant plasma cells and CAFs can overcome this resistance. To test this hypothesis, we isolated MM-CAFs and studied their interaction with BCMA CART cells generated from normal donors (41BB costimulated, lentivirally transduced). Our initial findings suggest that MM-CAFs inhibit BCMA CART cell antigen specific proliferation in the presence of the BCMA+ MM cell line OPM2, and this inhibition is predominantly mediated through the secretion of TGF-β (Fig A). MM-CAFs also promoted MM tumor growth in an MM-TME xenograft model established in the laboratory (Fig B). Here, immunocompromised NOD-SCID-γ-/- (NSG) mice were engrafted with 1x106 luciferase+ BCMA+ OPM2, in combination with either 1x106 CAFs or vehicle control intraveneously (IV). Subsequent tumor burden was monitored by bioluminescent imaging of these mice. The presence of CAFs in this model significantly accelerated MM progression (Fig B). Based on these findings, we aimed to develop CART cell therapy targeting both malignant MM cells and their CAFs and to determine whether this strategy can reverse MM-CAF induced CART cell inhibition. To identify targets for these CART cells, we first verified the expression of Fibroblast Associated Protein (FAP), an established CAF target, on MM-CAFs. Flow cytometric analysis of MM-CAFs showed significantly higher expression of FAP, compared to fibroblasts derived from normal bone marrow (Fig C). In addition, our screening flow cytometric analysis identified CS1 as another protein overexpressed by MM-CAFs (Fig C). We therefore designed and generated FAP CART cells (41BB costimulated, lentivirally transduced) and CS1 CART cells (CD28 costimulated, lentivirally transduced). We also generated dual CART cells for both BCMA-FAP CART cells and BCMA-CS1 CART cells. These dual CART cells were generated through the dual transduction of two lentiviral vectors during CART manufacturing. Next, we evaluated the impact of CAFs on effector functions of BCMA CART cells compared to dual targeting CART cells. When CART cells were stimulated with the BCMA+ MM cell line MM1S, in the presence of MM-CAFs, the antigen specific proliferation of BCMA CART cells, but not the dual targeting CART cells was significantly inhibited (Fig A). Similarly, in the presence of MM-CAFs, production of key effector cytokines by BCMA CART cells, but not the dual CART cells was reduced (Fig D). Finally, to verify the significance of our laboratory findings, we investigated the impact of CAFs on CART cell functions in vivo. First, using OPM2 xenografts, treatment with BCMA CART cells were able to completely eradicate MM (Fig E). However, to determine the effect of targeting CAFs, we used our MM-TME model. Here, NSG mice were engrafted with the luciferase+ MM cell line OPM2, along with MM-CAFs, as described in Fig 1B. Mice were then imaged for engraftment and randomized to treatment with 1) untransduced control T cells, 2) BCMA CART cells, 3) BCMA-FAP CART cells, or 4) BCMA-CS1 CART cells. A lower dose (1x106 IV) of CART cell was used to induce relapse post BCMA CART cells. Treatment with BCMA CART cells led to a transient antitumor activity in this MM-TME model (mice died within 2 weeks), while dual targeting CART cells resulted in durable remissions and long term survival of these mice (Fig F). In summary, we demonstrate for the first time that dual targeting both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART cell therapy in multiple myeloma. Figure Disclosures Sakemura: Humanigen: Patents & Royalties. Cox:Humanigen: Patents & Royalties. Parikh:Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AstraZeneca: Honoraria, Research Funding. Kay:Celgene: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Kenderian:Lentigen: Research Funding; Kite/Gilead: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Tolero: Research Funding; Novartis: Patents & Royalties, Research Funding; Morphosys: Research Funding.

scholarly journals Comparison of Minimal Residual Disease Detection between the Manual and Automated Gating Strategies of Euroflow Next-Generation Flow in Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3083-3083
Author(s):  
Hiroyuki Takamatsu ◽  
Takeshi Yoroidaka ◽  
Takeshi Yamashita ◽  
Ryoichi Murata ◽  
Mikio Ueda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Pharmaceutical Company ◽  
Research Funding ◽  
Plasma Cells ◽  
Residual Disease ◽  
Next Generation ◽  
Chugai Pharmaceutical ◽  
Company Limited ◽  
Minimal Residual

Background: The rate of complete response (CR) in multiple myeloma (MM) has dramatically increased because of the development of novel agents. In addition, the development of methods for measuring minimal residual disease (MRD), such as multiparameter flow cytometry and next-generation sequencing, has made it possible to stratify CR patients according to the MRD extent. EuroFlow next-generation flow (EuroFlow-NGF) is considered one of the gold standard methods for evaluating the negative status of MRD in MM. The automated gating strategy of EuroFlow-NGF has been shown to detect MRD as accurately as the manual gating strategy by experts. Oberle et al. (Haematologica, 2017) have found that daratumumab persisted on the surface of myeloma cells treated with it and that the anti-CD38 multi-epitope antibody used in EuroFlow-NGF has partial cross-reactivity with daratumumab, leading to generally lower mean fluorescence intensities of CD38. Therefore, MRD levels may have been underestimated in patients who were treated with anti-CD38 monoclonal antibodies (mAbs) using the automated gating strategy, leading to inappropriate management of the patients. Because no studies have examined the correlation of MRD extent between the manual and automated gating strategies in patients with MM who have received anti-CD38 mAbs, we compared MRD detection between the two gating strategies of EuroFlow-NGF in patients with MM. Methods: The study included bone marrow samples from 51 patients with MM (27 male and 24 female patients), including 13 patients treated with anti-CD38 mAb (12 treated with daratumumab and 1 treated with isatuximab). The median patient age was 70 years (range, 32-92 years) at MRD assessment. The disease statuses at MRD assessment were stringent CR in 26 patients (51%), CR in 7 (14%), very good partial response in 13 (26%), partial response in 1 (2%), and progressive disease in 4 (8%). The sample preparation protocol, Ab panel, and automated gating strategy of EuroFlow-NGF have been reported previously (Flores-Montero et al. Leukemia 2017). Briefly, we performed the EuroFlow-NGF method, which involved ammonium chloride-based bulk lysis, followed by surface staining using antibodies against CD138-BV421, CD27-BV510, CD38 multiepitope (ME)-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, and CD81-APC C750 in tube 1 and surface/intracellular staining using antibodies against CD138-BV421, CD27-BV510, CD38 ME-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, CD81-APC C750, cytoplasmic (cy) Igκ-APC, and cyIgλ-APC C750 after permeabilization in tube 2. For data analysis, events from both eight-color tubes (tubes 1 and 2) were merged, and the values of all parameters per tube were mathematically calculated using the merge and calculation functions of Infinicyt software (Cytognos SL, Salamanca, Spain). Automatic identification and enumeration of total plasma cells (tPCs) and abnormal plasma cells (MRD) were performed using the automatic gating function of Infinicyt software as described previously (Flores-Montero et al. Leukemia 2017). We compared the total nucleated cell number, tPC ratio, and MRD ratio between the manual (by experts) and automated gating strategies of EuroFlow-NGF. Results: In patients with MM who did not receive any anti-CD38 mAb therapy, we observed high correlations for both the tPC (r = 0.959, P < 0.0001) (Figure A) and MRD (r = 0.974, P < 0.0001) (Figure B) ratios between the manual and automated gating strategies of EuroFlow-NGF. On the other hand, in patients with MM who received anti-CD38 mAb therapy, we did not observe good correlations for both the tPC (r = 0.349, P = 0.2) (Figure A) and MRD (r = 0.292, P = 0.3) (Figure B) ratios between the two strategies owing to a lower fluorescence intensity of CD38 on PCs. In addition, when the MRD threshold was set to 10-5, the discordance of MRD positivity/negativity between the two strategies was significantly higher in patients who received anti-CD38 mAb therapy than in those who did not receive anti-CD38 mAb therapy [4/13 (31%) vs. 1/38 (3%), P = 0.012]. Conclusion: Although the automated gating strategy of EuroFlow-NGF could be a viable alternative to the manual strategy for the assessment of MRD in MM, we may have to utilize the manual strategy to obtain precise MRD results for patients with MM who received anti-CD38 mAbs. Figure Disclosures Takamatsu: Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Becton, Dickinson and Company: Honoraria; Abbvie: Consultancy; Daiichi-Sankyo Company: Honoraria. Yoroidaka:Ono Pharmaceutical: Honoraria. Yamashita:Janssen Pharmaceutical K.K.: Honoraria; Daiichi-Sankyo Company: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; TEIJIN PHARMA LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria. Murata:Celgene: Honoraria; Ono pharmaceutical: Honoraria. Nakao:Daiichi-Sankyo Company, Limited: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; SynBio Pharmaceuticals: Consultancy; Ohtsuka Pharmaceutical: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Alaxion Pharmaceuticals: Honoraria. Matsue:Novartis Pharma K.K: Honoraria; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria.

Melphalan and Prednisone (MP) Versus Melphalan, Prednisone and Thalidomide (MPT) as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 615-615 ◽  
Author(s):  
Prashant Kapoor ◽  
S. Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
David Dingli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Randomized Controlled Trials ◽  
Research Funding ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
The Impact

Abstract Abstract 615 Background: Trials comparing efficacy of standard melphalan prednisone (MP) therapy with MP plus thalidomide (T) in the transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. While there is greater agreement with regard to superior response rates (RR) with the addition of T to MP in elderly patients, the impact on progression free survival (PFS) and overall survival (OS) is less clear with some trials showing an improvement in PFS and/or OS with MPT and others demonstrating no difference in outcomes. We performed a systematic review to integrate the existing outcome data related to the efficacy of MP vs. MPT using a meta-analytic approach. Methods: A comprehensive search of electronic database through July 31st, 2009 was performed for publications, abstracts and presentations to identify randomized controlled trials (RCTs) comparing MP with MPT. A meta-analysis was performed by pooling results on clinical endpoints of RR, PFS and OS reported in all the identified RCTs under a random effects model. We did not have access to individual patient data from these trials. Results: Overall, five prospective RCTs (3 published articles and 2 abstracts) comparing MP with MPT regimen and comprising a total of 1571 patients were identified. For the endpoints of OS and PFS, data were extractable only from 4 RCTs (abstract by Gulbrandsen et al. was excluded). The Bregg and Egger funnel plot for OS demonstrated a symmetric distribution (P = 0.6) indicating no significant publication bias. The test of heterogeneity among all RCTs was statistically significant in the estimate of RR (tau2=0.21; chi2=16.33; p=0.003 (df=4); I2 = 75.5%), but not significant for the estimates of PFS (tau2=0.01; chi2=4.61; p=0.2 (df=3); I2 = 34.9%), and OS (tau2=0.02; chi2=5.53; p=0.14 (df=3); I2 = 45.8%). As expected, the pooled odds ratio of responding to treatment with MP versus MPT was 0.307 (P&lt;0.001) indicating that MP was worse than MPT in achieving at least a partial response. The pooled hazard ratios (HR) for PFS and OS were 1.59 (p&lt;0.001) and 1.34 (p=0.006), respectively (see table for forest plots) in favor of MPT. Conclusion: Our meta-analysis implies that in previously untreated, transplant ineligible elderly patients with multiple myeloma, the addition of thalidomide to melphalan-prednisone demonstrates improved RR, PFS and OS compared with the use of melphalan-prednisone alone. Although the results from a comprehensive individual patient data pooled analysis would give a more precise estimate, our analysis suggests that MPT is superior to MP in terms of response and survival. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Frequent Dysregulation of Fc Gamma Receptor IIb (Fc γRIIb) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) Signaling Occurs in Multiple Myeloma (MM) Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2917-2917
Author(s):  
Jennifer Li ◽  
Andrew Leu ◽  
Mingjie Li ◽  
Ethan D Hobel ◽  
Kevin Delijani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Cell Lines ◽  
Research Funding ◽  
Plasma Cells ◽  
Critical Role ◽  
Rt Pcr ◽  
Binding Ability ◽  
Downstream Signaling

Abstract Abstract 2917 The inhibitory Fc receptor, Fc γRIIb, is expressed on plasma cells, controls their persistence in the bone marrow (BM) and their ability to produce serum Ig. Activation of Fc γRIIb leads to the phosphorylation of ITIM and recruitment of SH2-containing inositol 5'-phosphatase (SHIP) in plasma cells. Immunoreceptor tyrosine-based activation motif (ITAM) and ITIM provide the basis for two opposing signaling modules that duel for control of plasma cell activation. Fc γRIIb-mediated SHIP phosphorylation activates downstream ITAM or ITIM signaling. To determine whether multiple myeloma (MM) cells express Fc γRIIb, we performed immunohistochemical staining on bone marrow mononuclear cells from MM patients and controls. We found that not only CD20+ B cells expressed Fc γRIIb but more importantly CD138+ cells from MM patients also showed expression of this receptor. Next, we examined whether Fc γRIIb was present and expressed in CD138+ primary MM cells purified from fresh MM BM and the MM cell lines MM1s, RPMI8226, and U266 using PCR and RT-PCR on DNA and mRNA, respectively. We focused on the transmembrane domain of the Fc γRIIb gene with four primers from different parts of this domain since this portion plays a critical role in this receptor's function. The MM cell lines expressed different amounts of Fc γRIIb. Notably, we found that 17% (5/30) of MM patients showed absence of Fc γRIIb both using RT-PCR for mRNA and PCR for DNA. Moreover, use of these same primers on nonmalignant PBMCs from the MM patients also showed absence of this gene in the same five patients. As a result of these findings, we are currently sequencing Fc γRIIb in MM patients to determine if additional patients show mutational changes that affect the function of this receptor. We also further determined SHIP-1 phosphorylation using Western blot analysis since this protein mediates downstream signaling of Fc γRIIb. Following stimulation with Fc complexes, phosphorylation of SHIP-1 was markedly reduced in MM tumor cells compared to normal CD20+ B cells. Interestingly, the patients with missing Fc γRIIb expressed higher levels of SHIP-1 gene expression compared to patients with normal Fc γRIIb expression. We investigated the IgG-binding ability of MM patients (n=33) and normal donors (n=33) to Fc γRIIb. Each serum sample was incubated with cells from MHC1, a cell line that specifically expresses Fc γRIIb but not Fc γRI and Fc γRIIa. The results showed MM patients' serum IgG have much lower Fc γRIIb-binding ability than normal human IgG (P<0.05) by using both flow cytometric and immunofluorescence assays. Our findings suggest that the monoclonal protein produced by MM patients has a very low Fc γRIIb-binding ability and is incapable of signaling through the inhibitory ITIM pathway. Germline loss of Fc γRIIb in MM patients with variation in its expression level and its downstream signaling molecule SHIP and its phosphorylation as well as the inability of MM IgG to bind cells containing this receptor is a potential new mechanism that contributes to the uncontrolled growth of MM. Disclosures: Berenson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.

CD38-Targeted Immunochemotherapy Of Multiple Myeloma: Preclinical Evidence For Its Combinatorial Use In Lenalidomide and Bortezomib Refractory/Intolerant MM Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 277-277 ◽  
Author(s):  
Inger S. Nijhof ◽  
Willy A. Noort ◽  
Jeroen Lammerts van Bueren ◽  
Berris van Kessel ◽  
Joost M. Bakker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lysis ◽  
In Vitro Assays ◽  
Human Antibody ◽  
Myeloma Cells ◽  
Clinical Phase

Abstract Multiple myeloma (MM) remains an incurable malignancy of clonal plasma cells. Although the new generation of immunomodulatory agents, such as lenalidomide (LEN), and the potent proteasome inhibitor bortezomib (BORT) have significantly improved the overall survival of MM patients, all chemotherapy strategies are eventually hampered by the development of drug-resistance. The outcome of patients who are refractory to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor. Set out with the idea that targeted immunotherapy with human antibodies may offer new perspectives for MM patients, we have recently developed daratumumab (DARA), a CD38 human antibody with broad-spectrum killing activity, mainly via ADCC (antibody dependent cellular cytotoxicity) and CDC (complement dependent cytotoxicity). In our previous preclinical studies and in current clinical phase I/II trials, DARA induces marked anti-MM activity. Based on these encouraging results, we now explored the potential activity of DARA for patients who are refractory to LEN- and/or BORT. In a recently developed human-mouse hybrid model that allows the in vivo engraftment and outgrowth of patient-derived primary myeloma cells in immune deficient Rag2-/-gc-/- mice, single dose DARA treatment appeared to effectively inhibit the malignant expansion of primary MM cells derived from a LEN- and BORT-refractory patient, indicating the potential efficacy of DARA even in LEN/BORT refractory patients. To substantiate the conclusions of these in vivo data, we conducted in vitro assays, in which full BM-MNCs from LEN (n=11) and LEN/BORT (n=8) refractory patients were treated with DARA alone or the combination of DARA with LEN or BORT to induce MM cell lysis. As expected, LEN alone induced no or little lysis of MM cells in the LEN-refractory patients and also BORT was not able to induce any lysis in the BORT-refractory patients. On the contrary, DARA induced substantial levels of MM cell lysis in all LEN and LEN/BORT-refractory patients. This lysis was significantly enhanced by combination with LEN or BORT. The combination of DARA and BORT improved MM lysis by additive mechanisms. However, LEN improved DARA-mediated lysis of MM cells in a synergistic manner through the activation of effector cells involved in DARA-mediated ADCC. In conclusion, our results demonstrate that DARA is also effective against multiple myeloma cells derived from LEN- and BORT-refractory patients. Especially LEN seems to improve responses in a synergistic manner. Our results provide a rationale for clinical evaluation of DARA in combination with LEN to achieve more effective results in LEN- and BORT-refractory patients. Disclosures: Lammerts van Bueren: Genmab: Employment. Bakker:Genmab: Employment. Parren:Genmab: Employment. van de Donk:Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

Meta-Analytic Summary of the Burden of Pain and Fatigue in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5967-5967
Author(s):  
Peter C. Trask ◽  
Mark Atkinson ◽  
Bhumi Trivedi ◽  
Andrew Palsgrove ◽  
William Benton Jones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Sensitivity Analysis ◽  
Research Funding ◽  
Meta Analysis ◽  
Clinical Group ◽  
Common Symptom ◽  
Newly Diagnosed ◽  
Eortc Qlq C30 ◽  
Eortc Qlq ◽  
The Impact

Abstract Aims: Multiple myeloma (MM) is a hematologic malignancy of plasma cells. Bone disease is a characteristic symptom of MM, and pain is one of its most distressing features. Anemia is also a common symptom and is manifested as fatigue and tiredness among MM patients. We conducted a systematic review and meta-analysis of the EORTC QLQ-C30 pain and fatigue scales in two clinical MM populations (one with newly-diagnosed MM and a second undergoing medical management with re-emergent or advanced myeloma) to more precisely quantify the burden of pain and fatigue in MM. Methods: Studies assessing pain and fatigue in MM were identified through a search of specific terms in the medical-subject headings and keywords in PubMed. Inclusion criteria were English-language studies published between January 1, 1996, and July 1, 2014; diagnosis of MM; and availability of data on pain and/or fatigue as measured by the EORTC QLQ-C30. Full-text articles from germane abstracts were retrieved for eligibility assessment, and 27 articles were selected for inclusion in the analysis. Two groups of peer-reviewed articles were created: one consisting of publications that focused on newly-diagnosed MM and the other consisting of articles involving MM patients with advanced conditions, including those who had a disease recurrence or were receiving autologous bone marrow transplantation. The mean values and standard deviations (SDs) were recorded across all publications irrespective of sex, age, and stage of illness. Of the 27 studies, 17 did not report standard error (SE) or SD values associated with EORTC QLQ-C30 pain and fatigue scales. These missing values were estimated using the overall average of SDs for that scale observed across all studies within the publication group (either newly-diagnosed or recurrent/advanced disease). A sensitivity analysis was conducted to compare the pooled mean and SEs associated with results obtained with and without the SD imputation procedure. The means and SDs from the two sets of publications were entered into Comprehensive Meta-analysis™ with both scales (pain or fatigue) and existing or imputed SDs as grouping variables. The summary means and confidence intervals for each scale by clinical group were computed by weighting the individual studies by sample size and were statistically summarized based on a fixed-effect model. Results: The EORTC QLQ-C30 fatigue and pain scales range from 0-100 with higher scores indicating greater symptoms (i.e., more fatigue and pain). The overall mean across the 27 publications was 47.1 for fatigue and 48.2 for pain for MM patients compared to scores of 25.0 and 16.9 for a general population. The results of the sensitivity analysis indicated that estimation of the SDs for those studies missing the statistic did not have a significant effect on the summary mean estimate. In most cases, the inclusion of additional means with estimated SDs reduced the summary SE estimate associated with the summary mean. Overall, the scores for fatigue and pain across research articles involving newly-diagnosed patients (fatigue=48.5 and pain=49.1) were statistically higher (indicating worse pain and fatigue) than among patients who were recurrent or receiving more aggressive treatments (fatigue=39.9 and pain=38.7). Conclusions: The burden of pain and fatigue in MM is substantial and is different between newly-diagnosed and more advanced MM patients. Pain and fatigue can be easily quantified using standardized health-related quality of life instruments. Pivotal clinical trials in MM need to assess the impact of novel treatments on pain and fatigue. Disclosures Trask: Sanofi: Employment. Atkinson:Sanofi: Research Funding. Trivedi:Sanofi: Research Funding. Palsgrove:Sanofi: Research Funding. Jones:Sanofi: Employment. McHorney:Sanofi: Research Funding.

Impact of Lenalidomide Maintenance Therapy on Immune Polarization and Activation in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2966-2966 ◽  
Author(s):  
Manisha Bhutani ◽  
David Foureau ◽  
Tammy Cogdill ◽  
Kyle Madden ◽  
Qing Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Maintenance Therapy ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Lymphoid Cells ◽  
Relative Distribution ◽  
The Impact

Abstract BACKGROUND: Lenalidomide is an immunomodulatory drug (IMiD) with co-stimulatory effects on immune effector cells in vitro and is an approved treatment for multiple myeloma (MM), although its mode of action in patients is not well defined. We studied the impact of lenalidomide maintenance therapy, following autologous stem cell transplant (ASCT), on NK and NK-T polarization (i.e. activating or inhibitory molecules) and, T cell activation (early vs. late activation) in patients with multiple myeloma. PATIENTS AND METHODS: In this ongoing prospective study with a targeted enrollment of 28 newly diagnosed multiple myeloma patients, blood samples are being collected at 2 to 3 months post ASCT, before starting lenalidomide maintenance therapy (baseline), and serially after 1, 3 and 6 months of treatment (T+1mo, T+3mo, T+6mo). Using a 9 color flow cytometry panel, peripheral blood samples were analyzed for expression of CD3 and CD56 to define NK (CD56+ CD3-), NKT (CD56+ CD3+), and T cell (CD56- CD3+) subsets. Killer 'inhibitory' Ig-like receptors, (KiR2DS4, KiR3DL1) natural killer group 2 proteins (NKG2a, NKG2D) and natural killer p46 protein (NKp46) expression were quantified to assess polarization of NK, and NK-T cells. Programmed death receptor 1 (PD-1) and T-cell Ig and mucin receptor 3 (Tim3) expression was quantified to assess T cell activation state. Flow cytometry data were acquired on a BD FACSAria II, and analyzed using FlowJo version X software. RESULTS: Samples from 11 patients have been collected and analyzed so far (11 baseline, 6 T+1mo, 4 T+3mo). At baseline lymphoid cells represent 12-46% of white blood cells (WBC), this heterogeneity being mainly driven by a wide range of T cell relative distribution among patients (30-74 % lymphoid cells). Phenotypically, NK cells at baseline mainly express natural cytotoxicity receptors (NKp46 and NKG2D), whereas NK-T cell also express NKG2D but approximately 1/3 also express PD-1 indicating they may be functionally defective. T cells at baseline express early T cell activation markers NKG2D and approximately 1/3 also stained positive for late T cell activation marker PD-1. Lymphoid cells relative distribution among WBC tends to normalize at T+1mo of treatment (15 to 35 % of WBC) before expanding at T+3mo (35 to 43 % of WBC). Phenotypically, across the 27 immune variables analyzed, each multiple myeloma patient displayed high level of immune homeostasis after 1 or 3 months of lenalidomide treatment. Noticeably, Nkp46 expression by NK cell and PD-1 expression by NK-T cells decreased in 4/6 patients and, NKG2D expression by T cell decreased in all but one patient during lenalidomide therapy. CONCLUSION: To our knowledge, this is the first study examining the influence of lenalidomide maintenance on the comprehensive immune repertoire in the post-ASCT setting in MM patients. The wide heterogeneity of NK, NK-T and T cell distribution observed at baseline among lymphoid cells indicates the potential effect of post-ASCT immune reconstitution and immunomodulatory the impact of lenalidomide. The capacity of lenalidomide to mediate effects on several immune cells raises the question as to which, if any, of these changes correlate with clinical responses. In our study, serially collected data from each patient, when completed would determine the impact of lenalidomide immunomodulatory effect of therapeutic efficacy and PFS duration in relation to immune reconstitution stage. Disclosures Cogdill: Millennium: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ghosh:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Sanofi: Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Celgene: Honoraria, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Array BioPharma: Honoraria, Research Funding.

Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Followed By ASCT with HDM or Bor-HDM Conditioning Regimens: A Single Center Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5492-5492
Author(s):  
Victor H Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Joanne Luider ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Plasma Cells ◽  
High Dose ◽  
Single Center Experience ◽  
Bone Marrow Plasma ◽  
Conventional Cytogenetics ◽  
High Dose Melphalan ◽  
The Impact

Abstract Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve response for MM patients undergoing auto-SCT. In the present study, patients receiving Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) induction followed by ASCT with Bor-HDM and HDM alone were evaluated. Methods All consecutive patients treated with CyBorD induction at our center from 01/2010 to 01/2015 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Definitions of response and progression were used according to the EBMT modified criteria. MRD negativity was assessed by flow cytometry at day-100 post-ASCT. Results Clinical characteristics are shown in Table 1. Among 66 cases receiving CyBorD induction, 42 were conditioned with Bor-HDM and 24 with HDM. At the time of analysis, 90.5% and 91.7% of patients in the Bor-HDM and HDM group are still alive and 4 and 5 patients have already progressed, respectively. At day-100 post ASCT, ORR of 97%, with CR/VGPR rate of 81% was seen in the Bor-HDM group compared to 91% and 70% in the HDM group (p=0.2). MRD negativity was higher in the Bor-HDM group (29.2%) compared to HDM (9%) (p=0.04). Median OS and PFS was similar for Bor-HDM and HDM (p=0.8) with a median follow-up of 12 months. In conclusion, CyBorD is an efficacious regimen for patients with MM and overall seemed to be well tolerated. Our data is one of the first to show the impact of this regimen on MRD negativity rates after receiving HDM or Bor-HDM conditioning, suggesting that higher rates of MRD negativity are seen with Bor-HDM. Further evaluation on a prospective manner and longer follow-up is required to assess the impact of Bor-HDM on OS and PFS. Table 1. Clinical Characteristics of patients with MM undergoing single auto-ASCT treated with CyBorD induction at our Institution Characteristic HDM (n=24) Bor-HDM (42) Age (median) 55 57 GenderMaleFemale 19 (79.1%)5 (20.9%) 25 (59.5%)17 (40.5%) Hb (g/L) 104 (75-157) 106 (76-139) Calcium (µmol/L) 2.3 (1.92-3.28) 2.3 (1.97-3.12) Creatinine (µmol/L) 86 (60-426) 84 (49-950) B2microglobulin (µmol/L) 2.73 (1.55-14.7) 3.41 (1.47-8.47) Albumin (g/L) 32 (21-43) 31 (16-42) Stage IStage IIStage III 7 (29.1%)14 (58.3%)3 (12.5%) 6 (14.2%)25 (59.5%)11 (26.1%) LDH (IU/L) 172 (71-448) 192 (103-669) BMPC (%) 32% (5-84%) 38% (5-90%) Heavy chain:IgGIgAIgDBiclonalIgMFLC oncly 17(70.8%)4 (16.6%)01 (4.1%)0 (1.5%)2 (8.3%) 22 (52.3%)10 (23.8%)01 (2.3%)1 (2.3%)8 (19%) Light chain:KappaLambdaBiclonal 17 (77.2%)5 (20.8%)1 (2%) 21 (50%)20 (47.6%)1 (2.3%) High risk (t(4;14), t(14;16), p53 del, del 13q by CCStandard risk 9 (37.5%)15 (62.5%) 11 (26.1%)31 (73.9%) BMPC: Bone marrow plasma cells; FLC: Free-light chains only; CC: Conventional cytogenetics Disclosures Jimenez-Zepeda: J&J: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Efficacy and Safety of Triplet Versus Doublet Salvage Therapies Among Patients with Multiple Myeloma (MM) Experiencing Early Relapse: Meta-Analysis of Phase III Randomized Controlled Trials (RCTs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5344-5344 ◽  
Author(s):  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
Madhusmita Behera ◽  
Charise Gleason ◽  
Hannah Collins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Mixed Model ◽  
Meta Analysis ◽  
Phase Iii ◽  
P Value ◽  
Serious Adverse Events ◽  
Early Relapse ◽  
The Impact ◽  
Relapsed Myeloma

Abstract Introduction: Controversy exists regarding the choice of triplet versus doublet salvage therapy among patients with multiple myeloma (MM) experiencing early relapse. Triplet therapies produce deeper responses (CR, ≥VGPR, ORR) and result in prolonged progression free survival (PFS) while doublet therapies demonstrate an improved toxicity profile. We performed a meta-analysis of the RCTs comparing triplet to doublet salvage regimens in early relapsed myeloma patients (1-3 prior lines of therapy). The objective is to test the hypothesis that triplet regimens are tolerable, improve CR, ≥VGPR, ORR rates and would translate to an improved PFS. Methods: We searched Pubmed, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 07/2015 for publications and abstracts to identify the phase III RCTs comparing triplet vs. doublet salvage therapies among patients with relapsed myeloma. A meta-analysis of 4 RCTs (PANORAMA1, MMVAR/IFM 2005-04, ASPIRE, ELOQUENT2 consisting of 2475 patients) was performed using the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the impact of triplets versus doublets (table 1) by evaluating the CR, ≥VGPR, ORR, PFS and toxicities. Mature OS data was not available for the RCTs, hence not included in meta-analysis. The consistency of results (effect sizes) among studies was investigated by means of 2 heterogeneity tests: the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P-value of the Cochran's Q test was <.1 and the I2 statistic was > 50%. Results: The pooled odds ratios of ORR, ≥VGPR and CR with triplets vs. doublets were 1.935 (P <0.000; 95% CI: 1.614-2.321); 2.185 (P <0.000; 95% CI: 1.832-2.606); 2.461 (P <0.000; 95% CI: 1.888-3.207) respectively, indicating that the odds of achieving higher quality responses are improved with triplet regimens compared to the use of a doublet regimens. The pooled hazard ratio (HR) for PFS was 0.661 (95% CI 0.596-0.734; P =0.000) in favor of triplet regimens (Figure 1). The Q-statistic for PFS (P =0.725; df =3; I2 = 0.00) suggests homogeneity across studies. Though the relative risk of selected ≥grade 3 serious adverse events (G3 SAE) was higher with triplet regimens (diarrhea, fatigue, thrombocytopenia 2.288 (95% CI 1.637-3.197; P =0.000), 1.654 (95% CI 1.263-2.166; P =0.000), 2.434 (95% CI 1.934-3.063; P =0.000), respectively), the overall G3 SAE were comparable with RR 1.498 (95% CI 1.176-1.908; P =0.001) favoring doublets. Conclusion: Our mixed model meta-analysis demonstrates that triplet regimens in early relapsed myeloma patients result in improved ORR, ≥VGPR, CR and PFS compared to doublets. G3 SAEs are higher with triplet regimens, however this appears to be influenced by the regimen-related toxicity from the PANORAMA1 trial. Appropriate dose modifications or use of selective HDAC inhibitors in future may mitigate the toxicities of the regimen. The pooled estimates ofresponse and survival strongly favor triplets in the early relapsed setting. Table 1. Triplet vs. doublet regimens in RCTs Trial Triplet regimen Doublet regimen PANORAMA1 Panobinostat, bortezomib, dexamethasone Placebo, bortezomib, dexamethasone MMVAR/IFM 2005-04 Bortezomib, thalidomide, Dexamethasone Thalidomide, Dexamethasone ASPIRE Carfilzomib, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone ELOQUENT 2 Elotuzumab, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Onyx: Research Funding; Merck: Research Funding; Janssen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Gleason:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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