scholarly journals Updated Meta-Analysis of Randomized Controlled Trials to Evaluate the Incidence of Infection and Pneumonia in Patients with Multiple Myeloma Treated with Daratumumab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4771-4771
Author(s):  
Thura Win Htut ◽  
Aung M Tun ◽  
Anita Sultan ◽  
Myint Aung Win ◽  
Sriman Swarup ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Randomized Controlled Trials ◽  
Phase Iii ◽  
Control Group ◽  
Controlled Trials ◽  
Study Group ◽  
High Grade ◽  
Newly Diagnosed ◽  
Antitumor Effects ◽  
Randomized Controlled

Introduction: Multiple myeloma is a hematologic cancer of plasma cell, a blood cell which normally produce antibodies, and accounts for approximately 13% of all hematologic malignancies. Daratumumab is a human anti CD38 IgGκ monoclonal antibody with a well characterized mechanism of action via direct antitumor effects and an immunomodulatory component and the incorporation of daratumumab to standard multiple myeloma regimen has shown to significantly improve response rates and survival, with notable toxicities. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of infection and pneumonia in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention infection including pneumonia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 35, suggesting some heterogeneity among RCT. The incidence of any-grade infection was 58.01% in study group vs 48.06 % in control group (RR, 1.21; 95% CI: 1.12 - 1.31; P < 0.0001). High-grade infection rate was 5.46% higher in daratumumab group compared to control arm (RR, 1.27; 95% CI: 1.13 - 1.44; P = 0.0001). Any-grade pneumonia was reported in 12.58% in study arm versus 7.72%% in control group with RR of 1.63 (95% CI: 1.08 - 2.45; P = 0.02). High-grade pneumonia was 8.47% in study group versus 5.52% in control arm (RR, 1.51; 95% CI: 0.97 - 2.35; P = 0.07). The RR for high-grade pneumonia was statistically significant at 2.07 (95% CI: 1.50 - 2.85; P < 0.0001) in a subset of newly diagnosed multiple myeloma patients treated with daratumumab (n= 2503). Conclusions: The addition of daratumumab to standard multiple myeloma regimen contributed to higher incidence of all grades of infection and any-grade pneumonia, with RR of 1.27 for high-grade infection and RR of 1.63 for any-grade pneumonia. However, high-grade pneumonia was only found to be significant in a subset of patients with newly diagnosed multiple myeloma treated with daratumumab, with RR of 2.07. Timely intervention with proper supportive care is required. Disclosures No relevant conflicts of interest to declare.

scholarly journals Daratumumab-Related Hematological Toxicities in Patients with Multiple Myeloma: A Combined Analysis of Five Phase III Randomized Controlled Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3485-3485
Author(s):  
Thura Win Htut ◽  
Kyaw Zin Thein ◽  
Anita Sultan ◽  
Sriman Swarup ◽  
Myint Aung Win ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Effects ◽  
Randomized Controlled Trials ◽  
Conflicts Of Interest ◽  
Phase Iii ◽  
Immunomodulatory Activity ◽  
Controlled Trials ◽  
High Grade ◽  
Antitumor Effects ◽  
Randomized Controlled

Introduction: Multiple myeloma is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Daratumumab is a humanized IgGκ monoclonal antibody that targets CD38 with direct antitumor effects along with immunomodulatory activity, resulting in depletion of immunosuppressive cells and clonal expansion of cytotoxic T cells. Addition of daratumumab to standard multiple myeloma regimens has recently shown to improve survival in patients with multiple myeloma with considerable safety profile. We undertook a meta- analysis of randomized controlled trials (RCT) to determine the risk of hematological toxicities in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. The RR of all-grade side effects were as follows: anemia, 0.85 (95% CI: 0.76 - 0.95; p = 0.005); neutropenia, 1.38 (95% CI: 1.09 - 1.74; p = 0.008); thrombocytopenia, 1.15 (95% CI: 0.90 - 1.47; p = 0.27); and leukopenia, 1.60 (95% CI: 1.16 - 2.20; p = 0.004). The RR of high-grade adverse effects were as follows: anemia, 0.72 (95% CI: 0.60 - 0.86; p = 0.0004); neutropenia, 1.48 (95% CI: 1.17 - 1.88; p = 0.001); thrombocytopenia, 1.15 (95% CI: 0.88 - 1.49; p = 0.31); and leukopenia, 1.72 (95% CI: 1.28 - 2.30; p = 0.0003). Conclusions: Our study demonstrated that patients on daratumumab combination regimens experienced higher risk of all grades of neutropenia and leukopenia, with RR of 1.48 and 1.72 for high-grade neutropenia and leukopenia. However, there was lower incidence of all grades of anemia in daratumumab containing group compared to control arm, favoring daratumumab-based regimens. Disclosures No relevant conflicts of interest to declare.

CLO19-053: Incidence of Cabozantinib-Associated Palmar-Plantar Erythrodysesthesia and Hypertension in Patients With Metastatic Solid Tumors: A Combined Analysis of 4 Phase III Randomized Controlled Trials

2019 ◽  
Vol 17 (3.5) ◽  
pp. CLO19-053
Author(s):  
Kyaw Z. Thein ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Subhanudh Thavaraputta ◽  
Myo H. Zaw ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Phase Iii ◽  
Control Group ◽  
Controlled Trials ◽  
High Grade ◽  
Randomized Controlled

Background: Tyrosine kinases such as VEGFR, KIT, RET, MET are implicated in development and progression of several solid tumors. Cabozantinib is an oral multiple tyrosine kinase inhibitor and has shown survival benefits in several solid tumors. Yet, there are notable toxicities. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of palmar-plantar erythrodysesthesia (PPE) and hypertension in patients with metastatic solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention PPE and hypertension as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% CI. Random effects model was applied. Heterogeneity was assessed using I2 statistic. Results: 4 phase III RCTs with total of 2,703 patients, comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone, were included. I2 statistic was 70.70, suggesting some heterogeneity among RCTs. All grade-PPE incidence was 666 (39.3%) in cabozantinib arm vs 38 (3.76%) in control arm with a RR of 11.378 (95% CI: 6.545–19.782; P<.0001). The absolute RD was 0.383 (95% CI: 0.294–0.473; P<.0001). High-grade PPE was reported in 172 (10.15%) in cabozantinib group vs 3 (0.29%) in control group with a RR of 19.077 (95% CI: 5.733–63.476; P<.0001). The RD was 0.105 (95% CI: 0.049–0.160; P<.0001). The overall incidence of hypertension was noted at 524 (30.95%) in cabozantinib arm vs 84 (8.31%) in control arm. The pooled RR of hypertension was 4.131 (95% CI: 2.656–6.425; P<.0001) and RD was 0.240 (95% CI: 0.186–0.295; P<.0001). High-grade hypertension was reported in 276 (16.30%) in cabozantinib group vs 41 (4.05%) in control group with a RR of 4.324 (95% CI: 2.484–7.525; P<.0001) and RD was 0.115 (95% CI: 0.085–0.144; P<.0001). Conclusion: Our meta-analysis demonstrated that cabozantinib contributed to significant toxicity of any-grade and high-grade PPE as well as hypertension, with a RR of 19.07 for grade 3 and 4 PPE. Recognizing these toxicities and prompt intervention with proper supportive care may enhance patients’ quality of life, ultimately leading to better compliance.

Thromboprophylaxis In Multiple Myeloma Patients Undergoing Immunomodulatory Therapy with Thalidomide and Lenalidomide: A Systematic Review and Meta-Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1090-1090
Author(s):  
Marc Carrier ◽  
Gregoire Le Gal ◽  
Jason Tay ◽  
Cynthia M. Wu ◽  
Agnes Y. Lee
Keyword(s):  
Multiple Myeloma ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Newly Diagnosed ◽  
Bleeding Events ◽  
Randomized Controlled ◽  
Literature Search Strategy ◽  
Previously Treated ◽  
Data Source

Abstract Abstract 1090 Background: The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) is high in patients treated with thalidomide (T)- and lenalidomide (L)-based regimens containing dexamethasone (D) and/or cytotoxic chemotherapy (C). Consensus guidelines recommend routine thromboprophylaxis but reliable data from randomized controlled trials are lacking. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. Purpose: To determine the absolute rates of VTE with and without different thromboprophylactic agents (ASA, warfarin, low-molecular-weight-heparin [LMWH]) in patients with newly diagnosed or previously treated MM receiving T- or L-based regimens. Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to Jan 2010. Results: A total of 66 studies were included in the analyses. Of these, 61 (4264 patients) and 5 (1119 patients) assessed T- and L-based regimens, respectively. Thalidomide-based regimens The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with T-based regimens: The rates of VTE (per 100 patient-months) in patients with previously treated MM managed with T-based regimens: Lenalidomide-based regimens The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with L-based regimens: The rate VTE (per 100 patient-months) in patients with previously treated MM managed with L-based regimens: None of the studies reported major bleeding events. Limitations: The definition for VTE varied across studies. Most studies did not outline the diagnostic criteria for VTE. Data are not available (NA) for all prophylaxis regimens. Conclusion: Patients with newly diagnosed or previously treated MM receiving T- or L-based regimens are at high risk of VTE. It is uncertain whether thromboprophylaxis provides a clear benefit, especially in those receiving L-based therapy or have previously treated disease. Randomized controlled trials are needed to address this important clinical need. Disclosures: Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.

Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients: Meta-analysis of Efficacy in Pivotal Randomized Controlled Trials

2019 ◽  
Vol 19 (10) ◽  
pp. e9-e10
Author(s):  
Salomon Manier ◽  
Suzanne Robinson ◽  
Melody Owen ◽  
Sujith Dhanasiri ◽  
Andrew Frederickson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Newly Diagnosed ◽  
Randomized Controlled

Risk of secondary hematologic malignancies in patients with ovarian cancer treated with PARP inhibitors: A combined meta-analysis of seven phase III randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12076-12076
Author(s):  
Thura Htut ◽  
Somedeb Ball ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Control Group ◽  
Controlled Trials ◽  
Strand Breaks ◽  
Randomized Controlled

12076 Background: Ovarian cancer (OC) is a leading cause of death from gynecologic cancers in women worldwide. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors prevent the repair of single-strand breaks and generate double-strand breaks in tumor cells and have recently shown survival benefits in OC. Yet, the impact on the risk of secondary hematologic malignancies (SHM) remains uncertain. We performed a combined meta-analysis of randomized controlled trials (RCT) to determine the risk of SHM in patients with advanced OC treated with PARP inhibitors. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2020 were queried. Phase III RCTs utilizing PARP inhibitors maintenance in advanced OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 and Cochran's Q- statistic. Fixed effects model was applied. Results: A total of 4,445 patients with advanced OC from seven phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib or veliparib or olaparib +bevacizumab while the control arm utilized placebo or bevacizumab. Randomization ratio was 2:1 in all studies. The I2 statistic for heterogeneity was 0, suggesting some heterogeneity among RCTs. The overall SHM incidence was 0.80% in PARP inhibitors group vs 0.47% in control group (RR 1.45; 95% CI: 0.68 – 3.07, P = 0.34). In patients with newly diagnosed OC (n = 3,044), the incidence was 0.59% vs 0.09% in control group (RR 2.7; 95% CI: 0.7—10.37, P = 0.15). In recurrent OC subset (n = 1,401), 1.28% were reported in both study and control arms (RR 0.96; 95% CI: 0.38-2.46, P = 0.94). SHM was noted in 1.3% in the olaparib subgroup compared to 1% in the control with RR of 1.24 (95% CI: 0.46 –3.31, P = 0.67). SHM occurred in 0.7% in the niraparib subgroup compared to 0.47% in the control with RR of 1.28 (95% CI: 0.30-5.45, P = 0.74). Conclusions: Our study demonstrated that the risk of SHM was not significantly increased in patients who received PARP inhibitors compared to control arm, despite attaining survival benefits. Further studies and long term follow up are necessary to define the actual relation and definitive incidence.

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