22 results on '"Usmani, Saad Z"'
Search Results
2. Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study
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Iida, Shinsuke, Ishikawa, Takayuki, Min, Chang Ki, Kim, Kihyun, Yeh, Su Peng, Usmani, Saad Z., Mateos, Maria-Victoria, Nahi, Hareth, Heuck, Christoph, Qin, Xiang, Parasrampuria, Dolly A., Gries, Katharine S., Qi, Ming, Bahlis, Nizar, and Ito, Shigeki
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- 2021
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3. Greater treatment satisfaction in patients receiving daratumumab subcutaneous vs. intravenous for relapsed or refractory multiple myeloma: COLUMBA clinical trial results
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Usmani, Saad Z., Mateos, Maria-Victoria, Hungria, Vania, Iida, Shinsuke, Bahlis, Nizar J., Nahi, Hareth, Magen, Hila, Cavo, Michele, Hulin, Cyrille, White, Darrell, De Stefano, Valerio, Fastenau, John, Slavcev, Mary, Heuck, Christoph, Qin, Xiang, Pei, Huiling, Masterson, Tara, Lantz, Kristen, and Gries, Katharine S.
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- 2021
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4. Post hoc analysis of daratumumab plus lenalidomide, bortezomib and dexamethasone in Black patients from final data of the GRIFFIN study.
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Nooka, Ajay K., Kaufman, Jonathan L., Rodriguez, Cesar, Jakubowiak, Andrzej, Efebera, Yvonne, Reeves, Brandi, Wildes, Tanya M., Holstein, Sarah A., Anderson, Larry D., Badros, Ashraf, Shune, Leyla, Chari, Ajai, Pei, Huiling, Cortoos, Annelore, Patel, Sharmila, Lin, Thomas S., Voorhees, Peter M., Usmani, Saad Z., and Richardson, Paul G.
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BLACK people ,DARATUMUMAB ,LENALIDOMIDE ,BORTEZOMIB ,HEALTH services accessibility - Abstract
Summary: Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant‐eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment‐emergent adverse events. In summary, these findings suggest a benefit of D‐RVd front‐line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses
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Xu, Xu Steven, Moreau, Philippe, Usmani, Saad Z., Lonial, Sagar, Jakubowiak, Andrzej, Oriol, Albert, Krishnan, Amrita, Bladé, Joan, Luo, Man, Sun, Yu-Nien, Zhou, Honghui, Nnane, Ivo, Deraedt, William, Qi, Ming, Ukropec, Jon, and Clemens, Pamela L.
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- 2020
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6. Corticosteroid tapering is a safe approach in patients with relapsed or refractory multiple myeloma receiving subcutaneous daratumumab: part 3 of the open-label, multicenter, phase 1b PAVO study.
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Nahi, Hareth, Usmani, Saad Z., Mateos, Maria-Victoria, van de Donk, Niels W. C. J., Oriol, Albert, Plesner, Torben, Bandyopadhyay, Nibedita, Hellemans, Peter, Tromp, Brenda, Nnane, Ivo, Zemlickis, Donna, Chari, Ajai, and Moreau, Philippe
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STEM cell transplantation , *MULTIPLE myeloma , *DARATUMUMAB , *PAVO , *PATIENT safety - Abstract
These results indicate that corticosteroid tapering does not diminish DARA SC monotherapy efficacy, as patients who received DARA SC with/without tapering achieved similar efficacy [[3], [15]]. No patients evaluable for daratumumab immunogenicity were positive for anti-daratumumab antibodies, indicating a low risk for immunogenicity for DARA SC with corticosteroid tapering. All patients experienced >=1 TEAE; 21 (50.0%) patients reported a grade >=3 TEAE, and 16 (38.1%) patients experienced a serious TEAE. [Extracted from the article]
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- 2023
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7. A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma.
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Paul, Barry, Liedtke, Michaela, Khouri, Jack, Rifkin, Robert, Gandhi, Mitul D, Kin, Andrew, Levy, Moshe Y, Silbermann, Rebecca, Cottini, Francesca, Sborov, Douglas W, Sandhu, Irwindeep, Villarreal, Lyssa, Murphy, Michael, Gu, Lin, Chen, Ann, Rajakumaraswamy, Nishanthan, and Usmani, Saad Z
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Magrolimab is a monoclonal antibody that blocks CD47, a 'do not eat me' signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion). Magrolimab is a therapy that blocks a 'do not eat me' signal overexpressed by certain cancers, including multiple myeloma (MM) cells. Studies have shown that blocking this signal leads to destruction of myeloma cells and that this cancer-killing effect may be increased by combining magrolimab with certain additional anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This study is investigating magrolimab in combination with commonly used myeloma therapies in patients with MM who have persistent disease despite prior treatment. Goals of the trial include assessing safety and response to treatment. Clinical Trial Registration:NCT04892446 (ClinicalTrials.gov) This phase II study investigates safety and treatment response to #magrolimab, an antibody that enhances phagocytosis of cancer cells, combined with commonly used therapies in patients with #multiplemyeloma. [ABSTRACT FROM AUTHOR]
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- 2023
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8. A short course of daratumumab in patients with multiple myeloma and minimal residual disease after induction therapy.
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Nath, Karthik, Shekarkhand, Tala, Salcedo, Meghan, Derkach, Andriy, Rueda, Siobhan, Chansakul, Aisara, Hulcrantz, Malin, Korde, Neha, Shah, Urvi A., Tan, Carlyn, Chung, David J., Lahoud, Oscar B., Hassoun, Hani, Lesokhin, Alexander M., Landau, Heather J., Shah, Gunjan, Scordo, Michael, Giralt, Sergio A., Usmani, Saad Z., and Roshal, Mikhail
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MULTIPLE myeloma ,DARATUMUMAB ,DISEASE remission ,CLINICAL trials ,BONE marrow examination ,PLASMACYTOMA - Abstract
At last follow-up, 5 (50%) patients remained on maintenance lenalidomide, and 5 (50%) patients received a subsequent line of therapy (note: three patients, in the absence of PD, continued on daratumumab beyond the six cycles). It is plausible that in standard-risk patients there may be a stable MRD clone without clinical consequence, leading to clinician and patient preferences to avoid interventions in the absence of a clinical relapse. Despite the improved complete response (CR) rates in multiple myeloma with newer therapies, most patients still relapse [[1]]. Although there was a third patient that converted to bone marrow MRD-negativity, this patient had serologic progressive disease (PD) at the time of response assessment and was deemed not to have achieved the primary end point. [Extracted from the article]
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- 2022
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9. Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma
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Chari, Ajai, Lonial, Sagar, Mark, Tomer M., Krishnan, Amrita Y., Stockerl‐Goldstein, Keith E., Usmani, Saad Z., Londhe, Anil, Etheredge, Delores, Fleming, Sarah, Liu, Baolian, Ukropec, Jon, Lin, Thomas S., Jagannath, Sundar, and Nooka, Ajay K.
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Adult ,Cyclopropanes ,Male ,Acetates ,Sulfides ,Drug Administration Schedule ,Discipline ,Antineoplastic Agents, Immunological ,Humans ,Clinical Trials ,Infusions, Intravenous ,Drug Approval ,Aged ,Aged, 80 and over ,Antibodies, Monoclonal ,Original Articles ,Middle Aged ,daratumumab ,Survival Analysis ,United States ,Injection Site Reaction ,multiple myeloma ,Treatment Outcome ,montelukast ,Quinolines ,Original Article ,Female ,monoclonal antibodies ,Neoplasm Recurrence, Local ,CD38 - Abstract
Background Daratumumab is a human CD38‐directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). Methods A multicenter, open‐label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment‐emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. Results Three hundred forty‐eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03‐6.0 months). Fifty‐two percent of patients transitioned to commercially‐available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug‐related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. Conclusions The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000‐000., An early access treatment protocol confirms the safety profile of daratumumab in patients with relapsed or refractory myeloma. Findings from 2 study sites (60 patients) that used montelukast premedication indicate reduced infusion reactions and infusion time associated with the first dose of daratumumab.
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- 2018
10. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study.
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Landgren, Ola, Weisel, Katja, Rosinol, Laura, Touzeau, Cyrille, Turgut, Mehmet, Hajek, Roman, Mollee, Peter, Kim, Jin Seok, Shu, Natalie, Hu, Xuguang, Li, Chuang, and Usmani, Saad Z.
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MULTIPLE myeloma ,SUBGROUP analysis (Experimental design) ,DARATUMUMAB ,PROGRESSION-free survival ,CYTOGENETICS - Abstract
CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high‐risk and 87% versus 79% in standard‐risk groups. Median progression‐free survival was 11.2 versus 7.4 months in high‐risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard‐risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high‐risk cytogenetics. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study.
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Usmani, Saad Z, Quach, Hang, Mateos, Maria-Victoria, Landgren, Ola, Leleu, Xavier, Siegel, David, Weisel, Katja, Gavriatopoulou, Maria, Oriol, Albert, Rabin, Neil, Nooka, Ajay, Qi, Ming, Beksac, Meral, Jakubowiak, Andrzej, Ding, Bifeng, Zahlten-Kumeli, Anita, Yusuf, Akeem, and Dimopoulos, Meletios
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MULTIPLE myeloma , *DARATUMUMAB , *PROGRESSION-free survival , *SURVIVAL analysis (Biometry) , *SEPTIC shock , *THERAPEUTIC use of antineoplastic agents , *RESEARCH , *OLIGOPEPTIDES , *DEXAMETHASONE , *MONOCLONAL antibodies , *EVALUATION research , *DISEASE relapse , *COMPARATIVE studies - Abstract
Background: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma.Methods: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting.Findings: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis.Interpretation: A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma.Funding: Amgen and Janssen. [ABSTRACT FROM AUTHOR]- Published
- 2022
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12. Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma.
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Weisel, Katja, Martin, Thomas, Krishnan, Amrita, Jagannath, Sundar, Londhe, Anil, Nair, Sandhya, Diels, Joris, Vogel, Martin, Schecter, Jordan M., Banerjee, Arnob, Berdeja, Jesus G., Nesheiwat, Tonia, Garrett, Ashraf, Qi, Keqin, Valluri, Satish, Usmani, Saad Z., and Yong, Kwee
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MULTIPLE myeloma ,BORTEZOMIB ,PROTEASOME inhibitors ,PHYSICIANS ,CLINICAL trials ,TERMINATION of treatment ,DARATUMUMAB ,CD38 antigen - Abstract
Background and Objective: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted. Methods: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1. These patients received physician's choice of treatment following the discontinuation of study drugs. Inverse probability of treatment weighting was used to align the external control and CARTITUDE-1 populations on important baseline characteristics. Overall response rate, complete response or better rate, progression-free survival, time to next treatment, and overall survival were assessed. Several sensitivity analyses were conducted. Results: After propensity score weighting, baseline characteristics were comparable between cohorts. Patients showed improved results with cilta-cel vs physician's choice of treatment: overall response rate (relative risk: 2.95 [95% confidence interval (CI) 2.27, 3.84; p < 0.0001]), complete response or better (relative risk: 111.70 [95% CI 29.08, 429.06; p < 0.0001]), progression-free survival (hazard ratio [HR]: 0.24 [95% CI 0.15, 0.37; p < 0.0001]), time to next treatment (HR: 0.14 [95% CI 0.09, 0.22; p < 0.0001]), and overall survival (HR: 0.21 [95% CI 0.13, 0.35; p < 0.0001]). Results were consistent across all sensitivity analyses. Conclusions: Cilta-cel showed superior efficacy compared with physician's choice of treatment, making it a promising new treatment option for patients with triple-class exposed relapsed or refractory multiple myeloma. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Carfilzomib, dexamethasone and daratumumab in relapsed or refractory multiple myeloma: results of the phase III study CANDOR by prior lines of therapy.
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Quach, Hang, Nooka, Ajay, Samoylova, Olga, Venner, Christopher P., Kim, Kihyun, Facon, Thierry, Spencer, Andrew, Usmani, Saad Z., Grosicki, Sebastian, Suzuki, Kenshi, Delimpasi, Sosana, Weisel, Katja, Obreja, Mihaela, Zahlten‐Kumeli, Anita, and Mateos, Maria‐Victoria
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DARATUMUMAB ,MULTIPLE myeloma ,INTERACTIVE voice response (Telecommunication) - Abstract
For patients with one prior LOT, the PFS HR (95% CI) was 0-90 (0-48-1-70) for lenalidomide-naive patients, 0-30 (0-10-0-86) for lenalidomide-exposed patients and 0-11 (0-02-0-52) for lenalidomide-refractory patients. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Keywords: cancer; clinical studies; clinical trials; multiple myeloma EN cancer clinical studies clinical trials multiple myeloma 784 788 5 08/18/21 20210815 NES 210815 Bortezomib- and lenalidomide-based therapies have become standard front-line treatment for multiple myeloma (MM),1 resulting in many patients being refractory to bortezomib or lenalidomide at first relapse.2,3 This may negatively impact the efficacy of later lines of therapy (LOT)4 and makes optimal sequencing of MM therapies challenging. [Extracted from the article]
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- 2021
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14. Exposure‐Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.
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Luo, Man (Melody), Usmani, Saad Z., Mateos, Maria‐Victoria, Nahi, Hareth, Chari, Ajai, San‐Miguel, Jesus, Touzeau, Cyrille, Suzuki, Kenshi, Kaiser, Martin, Carson, Robin, Heuck, Christoph, Qi, Ming, Zhou, Honghui, Sun, Yu‐Nien, and Parasrampuria, Dolly A.
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DARATUMUMAB , *THERAPEUTIC use of monoclonal antibodies , *THERAPEUTIC use of antineoplastic agents , *DRUG efficacy , *INVESTIGATIONAL drugs , *DISEASE incidence , *CANCER patients , *TREATMENT effectiveness , *MULTIPLE myeloma , *SUBCUTANEOUS infusions , *PATIENT safety - Abstract
We report the population pharmacokinetic (PK) and exposure‐response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33‐92 years; weight, 28.6‐147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1‐2, once every 2 weeks for cycles 3‐6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard‐of‐care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak‐to‐trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure‐response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65‐kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800‐mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma.
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Hussain, M. Junaid, Robinson, Myra M., Hamadeh, Issam, Arnall, Justin, Bhutani, Manisha, Atrash, Shebli, Friend, Reed, Pineda‐Roman, Mauricio, Symanowski, James T., Usmani, Saad Z., and Voorhees, Peter M.
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MULTIPLE myeloma ,THALIDOMIDE ,BORTEZOMIB ,T helper cells ,CYTOTOXIC T cells ,KILLER cells - Abstract
The article focuses on the role of Daratumumab, pomalidomide and dexamethasone (Pd) combination therapy for the treatment of relapsed and refractory multiple myeloma. It mentions the addition of daratumumab to the Pd backbone (DaraPd) for the patients with relapsed and refractory multiple myelom and also discussions on daratumumab that depletes levels of CD38 (cluster of differentiation 38).
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- 2019
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16. Daratumumab, pomalidomide, and dexamethasone as a bridging therapy to autologous stem cell transplantation in a case of systemic light-chain amyloidosis with advanced cardiac involvement.
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Arnall, Justin R, Usmani, Saad Z, Adamu, Hawawu, Mishkin, Joseph, and Bhutani, Manisha
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THERAPEUTIC use of monoclonal antibodies , *DEXAMETHASONE , *ABDOMINAL pain , *COMBINATION drug therapy , *HEMATOPOIETIC stem cell transplantation , *MULTIPLE myeloma , *THALIDOMIDE , *CARDIAC amyloidosis - Abstract
Systemic light-chain (AL) amyloidosis is a rare hematologic disorder where proteins infiltrate tissues leading to organ failure and death. Cardiac involvement, present in ∼70% of patients, determines stage and prognosis of the disease, with advanced involvement having a median survival of six months. The treatment of light-chain amyloidosis is directed at recovering organ function with therapeutic strategies following those of multiple myeloma with plasma cell-directed therapies. The use of single agent daratumumab has been reported in light-chain amyloidosis achieving rapid and deep responses. The combination of daratumumab, pomalidomide, and dexamethasone (DaraPomD) is particularly interesting for severe AL based on success in multiple myeloma. A 43-year-old female with light-chain amyloidosis and concomitant multiple myeloma presented with severe bowel dysmotility causing abdominal pain, anemia, and a 100-pound unintentional weight loss. A combination of cyclophosphamide, bortezomib, and dexamethasone was initiated but after five cycles her symptoms were progressing and therapy was switched to DaraPomD to optimize response. At the conclusion of two cycles she had achieved an amyloid complete-hematologic response, with her recurring ileus and abdominal pain significantly improved. Additionally, cardiac markers also suggested a rapid response without a common paradoxical worsening of congestive heart failure, and was overall well tolerated. Given the severe symptoms and refractory nature of our patient's disease DaraPomD was reasonable. With the tolerability and response seen, this patient experience supports a formal clinical trial evaluating the safety and efficacy of DaraPomD in light-chain amyloidosis. [ABSTRACT FROM AUTHOR]
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- 2019
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17. Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma.
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Donk, Niels W. C. J., Casneuf, Tineke, Di Cara, Alessandro, Parren, Paul W., Zweegman, Sonja, Kessel, Berris, Lokhorst, Henk M., Usmani, Saad Z., Lonial, Sagar, Richardson, Paul G., Chiu, Christopher, Mutis, Tuna, Nijhof, Inger S., and Sasser, A. Kate
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The article informs on a study for analysing the impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma. It examines effect of Fc portion of IgG polymorphisms on response, survival, and infusion-related reactions in multiple myeloma patients treated with daratumumab drug as single agent in the GEN501 and SIRIUS studies.
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- 2019
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18. CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance.
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van de Donk, Niels W.C.J. and Usmani, Saad Z.
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MULTIPLE myeloma ,BIOCHEMICAL mechanism of action ,CD38 antigen - Abstract
MM cells express high levels of CD38, while CD38 is expressed at relatively low levels on normal lymphoid and myeloid cells, and in some non-hematopoietic tissues. This expression profile, together with the role of CD38 in adhesion and as ectoenzyme, resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM). At this moment several CD38 antibodies are at different phases of clinical testing, with daratumumab already approved for various indications both as monotherapy and in combination with standards of care in MM. CD38 antibodies have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Inhibition of ectoenzymatic function and direct apoptosis induction may also contribute to the efficacy of the antibodies to kill MM cells. The CD38 antibodies also improve host-anti-tumor immunity by the elimination of regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Mechanisms of primary and/or acquired resistance include tumor-related factors, such as reduced cell surface expression levels of the target antigen and high levels of complement inhibitors (CD55 and CD59). Differences in frequency or activity of effector cells may also contribute to differences in outcome. Furthermore, the microenvironment protects MM cells to CD38 antibody-induced ADCC by upregulation of anti-apoptotic molecules, such as survivin. Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients. [ABSTRACT FROM AUTHOR]
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- 2018
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19. Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma.
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Usmani, Saad Z., Khan, Imran, Chiu, Christopher, Foureau, David, Druhan, Lawrence J., Rigby, Katherine, Casneuf, Tineke, and Sasser, A. Kate
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MULTIPLE myeloma treatment , *MONOCLONAL antibodies , *T cells - Abstract
Background: Daratumumab, a human CD38 monoclonal antibody that has direct on-tumor and immunomodulatory mechanisms of action, demonstrated clinical benefit as monotherapy or in combination with established regimens in patients with multiple myeloma with one or more prior lines of therapy. Case presentation: A male patient, who was 70 years of age at the time of diagnosis of multiple myeloma in 2011, relapsed after five lines of therapy, including autologous stem cell transplantation. The patient's disease, which was considered high risk with a deletion of chromosome 17p, advanced quickly and was triple refractory 2 years after diagnosis leaving few treatment options. He was treated with daratumumab monotherapy in the SIRIUS clinical trial resulting in a stringent complete response and clearance of minimal residual disease. The duration of the patient's clinical response is now over 3.5 years without relapse, compared with a median of 7.6 months for similarly treated patients. The patient's immunophenotype revealed CD8+ T-cell expansion, clonal expansion of the T-cell receptor repertoire and decreases in regulatory T cells during daratumumab therapy, suggesting a robust adaptive immune response. This immune response was still present 32 months into daratumumab therapy. Conclusions: The results from this case report showed that a patient with advanced multiple myeloma, who had exhausted all treatment options with existing regimens, mounted an ongoing, deep and durable response to daratumumab monotherapy. Further investigation of the immunologic profile provided additional patient-level evidence of an immunomodulatory mechanism of action of daratumumab. [ABSTRACT FROM AUTHOR]
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- 2018
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20. Treatment of Patients in First or Second Relapse
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Yee, Andrew J., Raje, Noopur S., Usmani, Saad Z., editor, and Nooka, Ajay K., editor
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- 2018
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21. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study.
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Dimopoulos, Meletios, Quach, Hang, Mateos, Maria-Victoria, Landgren, Ola, Leleu, Xavier, Siegel, David, Weisel, Katja, Yang, Hui, Klippel, Zandra, Zahlten-Kumeli, Anita, and Usmani, Saad Z
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MULTIPLE myeloma , *DEXAMETHASONE , *TERMINATION of treatment , *PROGRESSION-free survival , *TREATMENT duration , *DARATUMUMAB , *THERAPEUTIC use of antineoplastic agents , *RESEARCH , *INTRAVENOUS therapy , *CLINICAL trials , *OLIGOPEPTIDES , *CHRONIC diseases , *RESEARCH methodology , *CANCER relapse , *MONOCLONAL antibodies , *EVALUATION research , *MEDICAL cooperation , *TREATMENT effectiveness , *COMPARATIVE studies , *RANDOMIZED controlled trials - Abstract
Background: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.Methods: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting.Findings: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]).Interpretation: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile.Funding: Amgen. [ABSTRACT FROM AUTHOR]- Published
- 2020
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22. Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies
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Lotfi Benboubker, Saad Z. Usmani, Shinsuke Iida, Jordan M. Schecter, Maria-Victoria Mateos, Christopher Chiu, Lisa O'Rourke, Ludek Pour, Michele Cavo, Nizar J. Bahlis, Gordon Cook, Jacob P. Laubach, Katja Weisel, Andrew Spencer, Sung-Soo Yoon, Ajay K. Nooka, Meletios A. Dimopoulos, Xiang Qin, Jon Ukropec, Mateos, Maria-Victoria, Spencer, Andrew, Nooka, Ajay K, Pour, Ludek, Weisel, Katja, Cavo, Michele, Laubach, Jacob P, Cook, Gordon, Iida, Shinsuke, Benboubker, Lotfi, Usmani, Saad Z, Yoon, Sung-Soo, Bahlis, Nizar J, Chiu, Christopher, Ukropec, Jon, Schecter, Jordan M, Qin, Xiang, O'Rourke, Lisa, and Dimopoulos, Meletios A
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medicine.medical_specialty ,Neutropenia ,Gastroenterology ,Dexamethasone ,Article ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Adverse effect ,Lenalidomide ,Aged ,multiple myeloma, Daratumumab, POLLUX, CASTOR, lenalidomide/dexamethasone, bortezomib/dexamethasone, relapsed/refractory multiple myeloma ,business.industry ,Hazard ratio ,Antibodies, Monoclonal ,Daratumumab ,Hematology ,medicine.disease ,Confidence interval ,3. Good health ,Plasma Cell DIsorders ,Multiple Myeloma ,business ,030215 immunology ,medicine.drug - Abstract
The phase 3 POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival versus lenalido-mide/dexamethasone (median: 28.9 versus 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; P=0.0042) and increased overall response rate (93.1% versus 76.5%; P=0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 versus 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; P=0.0022) and increased overall response rate (95.0% versus 78.8%; P=0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of daratumumab was largely consistent with the overall populations.
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- 2019
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