SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Spinal cord compression

182

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 .).

Concepts: Spinal cord compression, Hematology, Proteasome, Dexamethasone, Bortezomib, Lenalidomide, Thalidomide, Multiple myeloma

28

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.

Concepts: Bone marrow, Spinal cord compression, Proteasome, Dexamethasone, Bortezomib, Lenalidomide, Multiple myeloma, Thalidomide

28

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.

Concepts: Nephrology, Spinal cord compression, Renal failure, Lenalidomide, Thalidomide, Multiple myeloma, Dexamethasone, Clinical trial

11

We describe a system to deliver drugs to selected tissues continuously, if required, for weeks. Drugs can be released remotely inside the small animals using pre-implanted, novel vertically aligned electromagnetically-sensitive polypyrrole nanowires (PpyNWs). Approximately 1-2mm(2) dexamethasone (DEX) doped PpyNWs was lifted on a single drop of sterile water by surface tension, and deposited onto a spinal cord lesion in glial fibrillary acidic protein-luc transgenic mice (GFAP-luc mice). Overexpression of GFAP is an indicator of astrogliosis/neuroinflammation in CNS injury. The corticosteroid DEX, a powerful ameliorator of inflammation, was released from the polymer by external application of an electromagnetic field for 2h/day for a week. The GFAP signal, revealed by bioluminescent imaging in the living animal, was significantly reduced in treated animals. At 1week, GFAP was at the edge of detection, and in some experimental animals, completely eradicated. We conclude that the administration of drugs can be controlled locally and non-invasively, opening the door to many other known therapies, such as the cases that dexamethasone cannot be safely applied systemically in large concentrations.

Concepts: Genetically modified organism, Dexamethasone, Field, Electromagnetic field, Gene expression, Water, Cortisol, Spinal cord compression

8

Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone in an open-label, multicenter, phase 1, dose-escalation study. Patients that relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib intravenously on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m(2)), pomalidomide once daily on days 1-21 (4 mg as the initial dose level) and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m(2), pomalidomide 4 mg, dexamethasone 40 mg). Hematological adverse events occurred in ≥60% of all patients, including eleven patients with grade ≥3 anemia. Dyspnea was limited to grade ½ in ten patients. Peripheral neuropathy was uncommon and limited to grade ½. Eight patients had dose reductions during therapy, and seven patients discontinued treatment due to adverse events. Two deaths were noted on study due to pneumonia and pulmonary embolism (n=1 each). The combination of carfilzomib, pomalidomide, and dexamethasone is well-tolerated and highly active in patients with RRMM. This study was funded by Onyx Pharmaceuticals, Inc., an Amgen subsidiary, and Celgene Corporation. The trial was registered with www.Clinicaltrials.gov: identifier NCT01464034.

Concepts: Spinal cord compression, Bone marrow, Celgene, Dexamethasone, Multiple myeloma, Hematology, Lenalidomide, Thalidomide

6

Background For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. Results After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Conclusions Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363 .).

Concepts: Spinal cord compression, Bortezomib, Hematology, Dexamethasone, Smoldering myeloma, Lenalidomide, Thalidomide, Multiple myeloma

4

We previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m(2) Days 1 and 2 of Cycle 1, 27 mg/m(2) Days 8, 9, 15, 16 and thereafter; lenalidomide 25 mg Days 1-21, dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade ¾ AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses. This study is registered at clinicaltrials.gov, identifier: NCT00603447.

Concepts: Bone marrow, Spinal cord compression, Clinical trial, Bortezomib, Dexamethasone, Lenalidomide, Thalidomide, Multiple myeloma

2

2

To compare short-course radiotherapy (RT) (4 Gy × 5) to longer-course RT (3 Gy × 10) for metastatic epidural spinal cord compression (MESCC).

Concepts: Spinal cord compression, Oncology

1

Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing.

Concepts: Monoclonal antibodies, Patient, Paraprotein, Spinal cord compression, Lenalidomide, Dexamethasone, Multiple myeloma, Thalidomide