A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma

A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ?3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38-85), 5 (2-14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ?10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ?2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ?2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ?10 mg/kg

Beyond the horizon : New treatment strategies for relapsed/refractory multiple myeloma

Multiple myeloma is the second most common hematologic malignancy in the Western world. Each year approximately 1100 new patients are diagnosed in The Netherlands. Most of these myeloma patients respond initially well to therapy, but the vast majority of patients eventually develop multi-drug resistant disease. In particular, patients refractory to lenalidomide and bortezomib have a very poor prognosis. A recent analysis of lenalidomide- and bortezomib-resistant myeloma patients showed a median overall survival of only 9 months and an event free survival of only 5 months. This clearly indicates the need for new treatment options, especially for this category of patients. There is no standard treatment for this group of patients. An important addition to the arsenal of new therapeutic possibilities is the development of the monoclonal antibody daratumumab directed against CD38, uniformly expressed on multiple myeloma cells. Rational combination strategies with daratumumab are expected to be more effective. Also combinations with existing regimens may work synergistic, so that they can be effective in myeloma patients, even despite their multi-refractory status. In my thesis, we performed translational research searching for factors that are important for response to daratumumab and factors important in the development of refractory disease to daratumumab. This has given direction to promising new rational combinations of therapy with daratumumab in this multi-drug refractory patient group. Our research has led to several new clinical trials testing these rational combination strategies. In addition, we performed a clinical trial in lenalidomide-refractory myeloma patients in which we have shown that the combination lenalidomide-cyclophosphamide-prednisone (the REP-regimen) can be very effective and is a well-tolerated regimen in this extended pretreated group of multi-drug resistant multiple myeloma patients

Beyond the horizon : New treatment strategies for relapsed/refractory multiple myeloma

Multiple myeloma is the second most common hematologic malignancy in the Western world. Each year approximately 1100 new patients are diagnosed in The Netherlands. Most of these myeloma patients respond initially well to therapy, but the vast majority of patients eventually develop multi-drug resistant disease. In particular, patients refractory to lenalidomide and bortezomib have a very poor prognosis. A recent analysis of lenalidomide- and bortezomib-resistant myeloma patients showed a median overall survival of only 9 months and an event free survival of only 5 months. This clearly indicates the need for new treatment options, especially for this category of patients. There is no standard treatment for this group of patients. An important addition to the arsenal of new therapeutic possibilities is the development of the monoclonal antibody daratumumab directed against CD38, uniformly expressed on multiple myeloma cells. Rational combination strategies with daratumumab are expected to be more effective. Also combinations with existing regimens may work synergistic, so that they can be effective in myeloma patients, even despite their multi-refractory status. In my thesis, we performed translational research searching for factors that are important for response to daratumumab and factors important in the development of refractory disease to daratumumab. This has given direction to promising new rational combinations of therapy with daratumumab in this multi-drug refractory patient group. Our research has led to several new clinical trials testing these rational combination strategies. In addition, we performed a clinical trial in lenalidomide-refractory myeloma patients in which we have shown that the combination lenalidomide-cyclophosphamide-prednisone (the REP-regimen) can be very effective and is a well-tolerated regimen in this extended pretreated group of multi-drug resistant multiple myeloma patients

Carfilzomib for relapsed and refractory multiple myeloma

K Groen, NWCJ van de Donk, CAM Stege, S Zweegman, IS Nijhof Department of Hematology, VU University Medical Center, Amsterdam, Netherlands Abstract: Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients. Keywords: carfilzomib, relapsed, refractory multiple myeloma, proteasome inhibito