MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Multiple myeloma accounts for approximately 1 percent of all cancers and slightly more than 10 percent of all hematologic malignancies. At present, more than 80,000 new cases are reported worldwide each year, and the disease prevalence is increasing.
Plitidepsin is a synthetic cyclic depsipeptide isolated from the marine tunicate Aplidium albicans targeting the proto-oncogene eEF1A2, which is over-expressed in multiple myeloma cells.
In ADMYRE trial 255 relapsed and refractory multiple myeloma patients with at least three but not more than six prior regimens, including at least bortezomib and lenalidomide/thalidomide, were randomized at 2:1 ratio to receive plitidepsin 5 mg/m2 D1 and 15 plus DXM 40 mg D1, 8, 15 and 22 (P+DXM), or DXM 40 mg D1,8,15 and 22 (DXM) every four weeks.
P+DXM met the primary endpoint, progression-free survival (PFS) assessed by an Independent Review Committee, showing a 35% risk reduction in the probability of progression or death. Indeed, a 20% risk reduction in the probability of death was also observed in spite of the fact that 44% of patients from control arm (DXM) switched to P+DXM arm after progression. Therefore, survival in the control arm might have been extended by the effect of plitidepsin, increasing the post progression survival and overestimating the survival observed in the control arm and consequently underestimating the actual difference between treatment arms.
Several methods were used to assess the impact of crossover and the robustness of the results even when penalizations were applied; PharmaMar believes that strong evidence in terms of survival benefit in favour of P+DXM has been established.
MedicalResearch.com: What should readers take away from your report?
Response: From our point of view, the first and the most important fact is that a clinical trial has to be designed to address the medical need of patients with multiple myeloma, but sometimes, there are practical issues in the conduct of clinical trials that have to be solved or mitigated by means of statistical models.
For example, in ADMYRE trial primary endpoint was PFS and the ‘gold standard’ overall survival (OS) was selected as key secondary endpoint. In this late line with ~75% of patients refractory to their last treatment regime, where few efficacy alternatives were available, investigators asked PharmaMar to allow the crossover to the P+DXM after progression in order to benefit their patients. Although it is not possible to know what would have happened if crossover was not permitted, the two-stage and RPSFT methods allow an estimate of the survival benefit after the effect of crossover is discounted.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our recommendation for the medical community is to use all the methods available from any area (e.g. clinical informatics, genomics, statistics…) in the clinical decision making process. This kind of statistical modelling has been widely used in other fields like pharmacoeconomics, and it is been increasingly used in oncology, so we encourage its use in the development of new compounds when treatment switch is involved.
Disclosures: Of course, we are PharmaMar employees and we work as biostatisticians so we believe in the models we have used. At the end of the day, we measure outcomes in an uncertain environment and work with probabilities but try to help decisions based on high level medical evidence and take into account the clinical relevance of the results.
ASCO 2018 poster abstract
Overall survival (OS) results of randomized phase III study (ADMYRE trial) of plitidepsin and dexamethasone (DXM) vs. DXM alone in patients with relapsed/refractory multiple myeloma (RRMM): Evaluation of the crossover impact
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