Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10(5) white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. Conclusions The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
Background Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. Methods In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. Results A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. Conclusions Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134 .).
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 4 years ago
Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.
Background Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. Methods In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. Results Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. Conclusions Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797 .).
Context: Curcumin is a yellow-orange polyphenol derived from turmeric [Curcuma longa L. (Zingiberaceaerhizomes)]. Turmeric is a main ingredient of Indian, Persian, and Thai dishes. Extensive studies within the last half a century have demonstrated the protective action of curcumin in many disorders of the body. Objective: This study evaluated the protective effect of curcumin on dexamethasone-induced spermatogenesis defects in mice. Materials and methods: Thirty-two NMRI mice were randomly divided into 4 groups. The first (control) group received 1 mL/day of distilled water by intraperitoneal (i.p.) injection for 7 days. The second group received 200 mg/kg/day of curcumin (Cur) for 10 days. Third group received 7 mg/kg/day of dexamethasone (Dex) for 7 days. Forth group received 200 mg/kg of curcumin for 10 days after dexamethasone treatment. Testicular histopathology, morphometric analysis, head sperm counting, and immunohistochemistry assessments were performed for evaluation of the dexamethasone and curcumin effects. Results: Expression of Bcl-2 was significantly increased in the curcumin + dexamethasone group compared with dexamethasone-treated animals (p < 0.05). Dexamethasone induced spermatogenesis defects including epithelial vacuolizations, sloughing of germ cells, reduction of seminiferous tubule diameter, reduction in the number of sperm heads and significant maturation arrest (p < 0.001). Curcumin + dexamethasone treatment significantly prevented these changes (p < 0.05). Discussion and conclusion: The results of this study demonstrate that curcumin increases the expression of Bcl-2 protein, an important anti-apoptotic factor, and improves the spermatogenesis defects in dexamethasone treated mice. Curcumin has a potent protective effect against the testicular toxicity and might be clinically useful.
The combination of lenalidomide, bortezomib and dexamethasone (RVD) has shown excellent efficacy in patients with relapsed or refractory multiple myeloma (RRMM). The aim of our study was to assess the efficacy and toxicity profile of RVD for patients with advanced RRMM. We retrospectively reviewed the records of all patients with RRMM treated with RVD between March 2009 and December 2011. Thirty patients received ≥1 full cycle of RVD. Primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). After a median of 5 cycles (1-16), a very good partial response (VGPR) was seen in 10%, partial response (PR) in 36.7% and stable disease (SD) in 13.3% (ORR of 46.7%). Disease progression occurred in 21 patients at a median of 3 months (range 1.41-4.59). Eight patients (26%) experienced grade ¾ adverse events, including anemia, neutropenia, muscle weakness and pneumonia. No patient experienced worsening peripheral neuropathy. Although RVD has been previously shown to be effective in RRMM, the ORR and PFS we observed were affected by very advanced disease status and heavy prior exposure to novel agents. Nevertheless, six of these patients with RRMM experienced a benefit of ≥6 months, suggesting synergism of this immunomodulatory derivative/proteasome inhibitor combination and/or re-establishment of drug sensitivity by an emergent myeloma clone.
Renal impairment (RI) is a common complication affecting patients with multiple myeloma (MM). Timely identification of MM-related RI and early treatment with novel antimyeloma agents can reverse renal damage in a high proportion of patients and improve outcomes. The IMiDs® immunomodulatory compound lenalidomide (Len) in combination with dexamethasone (Dex) is an effective and well-tolerated regimen for patients with relapsed or refractory (RR) MM. A retrospective analysis of Phase III data has shown that Len/Dex remains effective and well-tolerated in patients with moderate or severe RI, albeit with an increase in myelosuppression. This analysis demonstrated that in a high proportion of patients Len/Dex treatment can reverse MM-related RI and restore normal function. Lenalidomide has a predominantly renal route of excretion and in patients with RI the plasma concentration and half-life of the drug are significantly increased. As a consequence, lower starting doses are required in patients with RI to avoid over-exposure and an increased risk of adverse events, while maintaining good therapeutic index. A prospective cohort study in 50 patients with RRMM has reported that when Len/Dex dosing was adjusted according to renal function, response rates and survival outcomes were similar in patients with and without RI, and there was no increase in adverse events in patients with RI. Further clinical studies are required to confirm the efficacy and tolerability of Len/Dex regimens in MM patients with RI, and to evaluate the impact of reversing renal damage in terms of patient survival.
To evaluate the efficacy, safety, and reinjection interval of dexamethasone intravitreal implant (DEX implant) in branch retinal vein occlusion and central retinal vein occlusion patients receiving ≥2 DEX implant treatments.
Objective: To describe that Topiramate may well be a cause of false positive in Overnight 1 mg dexamethasone suppression test (DST) for hypercortisolism screening.Methods: We present a case in which topiramate induced dexamethasone metabolism showing a false positive in DST.Results: A 44 year-old woman, with an incidentally found adenoma in the right adrenal gland, underwent a DST for hypercortisolism screening. The patient was taking topiramate prescribed by a psychiatrist for an affective disorder and insufficient suppression of cortisol (11.9 mcg/dl) was observed. Free cortisol in 24-hour urine was normal and insufficient suppression was established in a second determination (9.3 mcg/dl). Finally, her psychiatrist switched her treatment from topiramate to bupropion and measures were repeated. When she was not taking topiramate correct suppression with 1 mg of dexamethasone was obtained (1.7 mcg/dl) and free cortisol in 24 hour urine was again normal, thereby excluding the presence of hypercortisolism. On reviewing the literature, topiramate was not found to have been previously described as a cause of a false positive in DST, but it was proposed as a cause of hypoadrenalism in a patient taking oral corticosteroid replacement because its capacity to induce dexamethasone metabolism.Conclusion: Topiramate treatment may well be a cause of false positive in dexamethasone suppression tests and its presence should be taken into consideration when performing DST.
In the last decade, one of the major advances in the management of patients with symptomatic newly diagnosed multiple myeloma has been the introduction of novel agents, thalidomide, bortezomib and lenalidomide, as part of frontline treatment in both transplant and non transplant candidates. These drugs have markedly improved the rate of complete remission, and time to progression, progression-free survival and overall survival have significantly increased. This manuscript focuses on more recent frontline therapeutic approaches both in older patients, not eligible for high-dose therapy and autologous stem cell transplantation (ASCT), and in younger patients eligible for early ASCT.