Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029.

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).

Functional recovery after open versus laparoscopic colonic resection: a randomized, blinded study.

BACKGROUND: Laparoscopic colonic surgery has been claimed to hasten recovery and reduce hospital stay compared with open operation. Recently, enforced multimodal rehabilitation (fast-track surgery) has improved recovery and reduced hospital stay in both laparoscopic and open colonic surgery. Since no comparative data between laparoscopic and open colonic resection with multimodal rehabilitation are available, the value of laparoscopy per se is unknown. METHODS: In a randomized, observer-and-patient, blinded trial, 60 patients (median age 75 years) underwent elective laparoscopic or open colonic resection with fast-track rehabilitation and planned discharge after 48 hours. Functional recovery was assessed in detail during the first postoperative month. RESULTS: Median postoperative hospital stay was 2 days in both groups, with early and similar recovery to normal activities as assessed by hours of mobilization per day, computerized monitoring of motor activity assessed, pulmonary function, cardiovascular response to treadmill exercise, pain, sleep quality, fatigue, and return to normal gastrointestinal function. There were no significant differences in postoperative morbidity, mortality, or readmissions, although 3 patients died in the open versus nil in the laparoscopic group. CONCLUSION: Functional recovery after colonic resection is rapid with a multimodal rehabilitation regimen and without differences between open and laparoscopic operation. Further large-scale studies are required on potential differences in serious morbidity and mortality.

Colonic surgery with accelerated rehabilitation or conventional care.

BACKGROUND: For patients undergoing colonic surgery, the postoperative hospital stay is usually 6 to 10 days, and the morbidity rate is 15 to 20 percent. Fast-track rehabilitation programs have reduced the hospital stay to 2 to 3 days. The aim of this study was to evaluate the postoperative outcome after colonic resection with conventional care compared with fast-track multimodal rehabilitation. METHODS: One hundred thirty consecutive patients receiving conventional care (group 1) in one hospital were compared with 130 consecutive patients receiving multimodal, fast-track rehabilitation (group 2) in another hospital. Outcomes were time to first defecation after surgery, postoperative hospital stay, and morbidity during the first postoperative month. RESULTS: Median age was 74 years (group 1) and 72 years (group 2). American Society of Anesthesiologists (ASA) score was significantly higher in group 2 ( P < 0.05). Defecation occurred on day 4.5 in group 1 and day 2 in group 2 ( P < 0.05). Median hospital stay was 8 days in group 1 and 2 days in group 2 ( P < 0.05). The use of a nasogastric tube was longer in group 1 ( P < 0.05). The overall complication rate (35 patients) was lower in group 2 ( P < 0.05), especially cardiopulmonary complications (5 patients; P < 0.01). Readmission was necessary in 12 percent of cases for group 1 and 20 percent in group 2 ( P > 0.05). CONCLUSIONS: Time to first defecation, hospital stay, and morbidity may be reduced after colonic resection with fast-track multimodal rehabilitation.

Colostomy closure after Hartmann's procedure with fast-track rehabilitation.

PURPOSE: The aim of this study was to assess the effect of postoperative multimodal rehabilitation after colostomy closure after Hartmann's procedure. METHODS: Twenty-seven consecutive patients scheduled for colostomy closure after Hartmann's procedure received continuous postoperative epidural analgesia, laxative, and enforced oral liquids, protein drinks, and mobilization. RESULTS: Defecation occurred at a median 2 days postoperatively. Mean and median postoperative stay was 3 days, with two readmissions (1 anastomotic dehiscence and 1 social) increasing mean total 1-month hospital stay to 4.3 (median, 3) days. No other complications occurred except three superficial wound infections. CONCLUSION: Postoperative hospital stay and morbidity may be reduced with multimodal rehabilitation after open colostomy closure after Hartmann's resection.

Early recovery after abdominal rectopexy with multimodal rehabilitation.

PURPOSE: Abdominal rectopexy without sigmoid resection is usually associated with a hospital stay of four to ten days. Recent developments have shown that a multimodal rehabilitation program with epidural analgesia and early oral feeding and mobilization will reduce hospital stay after colonic resection. The aim of this study was to describe the results after abdominal rectopexy with a multimodal rehabilitation program. METHODS: Thirty-one consecutive patients with rectal prolapse, median age 69 (range, 24-85) years and including 14 patients of American Society of Anesthesiologists physical status III to IV, were scheduled for abdominal rectopexy with a multimodal rehabilitation program including 48 hours thoracic epidural analgesia or patient-controlled anesthesia (3 patients), early oral nutrition and mobilization, and a planned two-day postoperative hospital stay. Follow-up was done at two months postoperatively. RESULTS: All patients except one tolerated normal diet and were mobilized to the same level as before surgery on the first postoperative day. Bowel movement was reestablished at a median of Day 2, and median postoperative hospital stay was three (mean, 4.4) days. At two months follow-up 16 percent were incontinent vs. 74 percent before surgery. Constipation was noted in 43 percent before surgery vs. 28 percent at two months follow-up. CONCLUSION: Median hospital stay after abdominal rectopexy may be reduced to three days with postoperative multimodal rehabilitation.