02 Dec ASH18: CENTAURUS Study Evaluates Dosing Schedule of DARZALEX® (daratumumab) for High Risk Smoldering Multiple Myeloma
MedicalResearch.com Interview with:
Dr. Vorhees
Peter Voorhees, MD
Plasma Cell Disorders Program
Department of Hematologic Oncology and Blood Disorders
Levine Cancer Institute
Atrium Health
MedicalResearch.com: What is the background for this study?
Response: All multiple myeloma arises from its precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although the rate of progression to multiple myeloma for patients with MGUS is low (~5% over 5 years), patients with SMM have a ~50% likelihood of requiring therapy for their multiple myeloma within the first 5 years of diagnosis. For those at intermediate to high risk of disease progression, early intervention to delay progression of disease, thereby averting disease-related morbidities related and potentially changing the natural course of the disease, is highly desirable.
On the other hand, given the fact that these patients are by definition asymptomatic and would otherwise be monitored off treatment, it is critical that any intervention applied in this group of patients is well tolerated. Daratumumab is a highly attractive candidate in this particular space, because it has single agent activity in heavily-pretreated relapsed/refractory multiple myeloma and a favorable side effect profile relative to many other myeloma therapeutics. Additionally, given the importance of impaired immune surveillance in multiple myeloma, the immuno-stimulatory effects of daratumumab in the bone marrow microenvironment could potentially reawaken robust T cell responses to the disease.
MedicalResearch.com: What are the main findings?
Response: The CENTAURUS study was a randomized phase II trial evaluating 3 different dosing schedules of daratumumab for the treatment of smoldering multiple myeloma at intermediate to high risk of progression to active disease. Patients either received 8 weekly doses (short arm), 8 weekly doses followed by once every 8-week dosing for 19 additional 8-week cycles (intermediate arm) or 8 weekly doses followed by every 2-week dosing for 16 weeks, every 4-week dosing for 32 weeks and then once every 8-week dosing for an additional 13 8-week cycles (intense arm). Importantly, the overall response rate was 56% (27% PRs, 24% VGPRs, 5% CRs/sCRs) and the 24-month progression free survival (progression from SLiM – CRAB criteria of multiple myeloma) was 90% in the intense arm compared with 75% in the short arm. When considering biochemical progression and SLiM – CRAB criteria, the 24-month progression-free survival was 78% for the intense arm, 27% for the short arm. Serious adverse events related to daratumumab occurred in only 2 of 142 patients and only 2 patients discontinued treatment due to daratumumab-related adverse events. Hematologic treatment-emergent adverse events occurred in <10% of patients and the rate of grade 3 / 4 infections was <5% in all arms of the study.
MedicalResearch.com: What should readers take away from your report?
Response: Although the rate of deep responses (CRs) was lower than anticipated, there was a clear signal of disease control for patients treated with the more intense schedule of daratumumab. Importantly, daratumumab was well tolerated in patients with SMM, particularly when considering the toxicity profiles of other therapeutic interventions that have been tested in this group of patients.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The safety and early efficacy results of this trial clearly support pursuit of a phase III study of daratumumab monotherapy for patients with SMM at intermediate – high risk of disease progression. To this end, the AQUILA trial is an international, randomized phase III comparing active monitoring / surveillance to subcutaneous daratumumab for patients with SMM at intermediate to high risk of progression.
MedicalResearch.com: Is there anything else you would like to add?
Response: The definition of intermediate / high risk SMM is in a state of flux, and the risk profile of SMM patients in various published and ongoing studies is heterogeneous. It will be important that we evaluate and interpret the results of CENTAURUS, AQUILA and other studies with this in mind.
Disclosures: Amgen, Janssen: Speakers Bureau activities. Adaptive, BMS, Celgene, Janssen, Novartis, Oncopeptides, Takeda, TeneoBio: Consulting
Citation: ASH 18
Ola Landgren, MD, PhD1, Michele Cavo, MD2*, Ajai Chari, MD3, Yael C Cohen, MD4, Andrew Spencer, MBBS, FRACP, FRCPA, DM5, Peter M. Voorhees, MD6, Jane Estell, FRACP7, Irwindeep Sandhu, MD, FRCPC8, Matthew Jenner9*, Catherine Williams10*, Niels W. C. J. van de Donk11, Meral Beksac, MD12, Hartmut Goldschmidt, MD13, Philippe Moreau14*, Steven Kuppens15*, Rajesh Bandekar16*, Tobias Neff17, Annelore Cortoos, MD18*, Pamela L Clemens, PhD16*, Ming Qi16*, Homer Adams III, PhD16* and Craig C Hofmeister, MD, MPH19
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Last Updated on December 2, 2018 by Marie Benz MD FAAD