Clinical trials in multiple myeloma

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In chapter 2 and 3 the results of the Carthadex trial were described. In this trial patients with newly diagnosed MM (NDMM) were treated with different dose levels of carfilzomib combined with thalidomide and dexamethasone (KTd) as induction and consolidation treatment. This is the only clinical trial evaluating different dose levels of carfilzomib. This trial demonstrated that higher doses of carfilzomib (minimal 36 mg/m2 twice a week) had better efficacy with similar toxicity in patients with NDMM. However, due to the limited number of patients and the absence of randomization, a definitive answer about the optimum dose level remains unclear. Currently, carfilzomib is not yet approved as first line treatment in NDMM due to lack of randomized trials using carfilzomib in this patient population.
In Chapter 4 we showed the results of the HOVON 95/EMN02 trial. This trial randomized patients between continuous therapy and HDM with ASCT, followed by randomization between consolidation and no consolidation, with all patients receiving lenalidomide maintenance. Patients who received consolidation therapy after HDM and ASCT experienced an improvement in progression-free survival (PFS) compared to those who did not receive consolidation, which is considered the standard of care nowedays.
In chapter 5 a registry study with pomalidomide was presented. In this chapter we emphasize the importance of performing registry studies due to strict inclusion criteria for patients included in clinical trials. We demonstrated that response and survival in patients treated with pomalidomide and dexamethasone (Pd) in real world is comparable to survival shown in clinical trials. Pomalidomide is effective in treating patients with MM, however preferably a third drug is added. Which drug is depended on previous therapy, development of resistance and patients choice.
In chapter 6 the results of a correlative study regarding IMiDs and the effect on the CRBN pathway were demonstrated, by analyzing bone marrow biopsies of patients treated in the HOVON87. In this study protein expression of cereblon (CRBN) and its downstream targets (Ikaros, Aiolos, c-Myc and IRF-4) were analyzed with the aim to investigate if one of these targets may act as a practical clinical marker to predict which patient will have a durable response and improvement of survival with IMiD treatment. The study found that higher CRBN protein levels were associated with an improvement in survival, and if used as a predictive marker, it is best to use a standardized technique for staining and scoring. However, the technique is time-consuming and may not be used in clinical practice. The study also discusses the development of resistance to IMiDs, where IRF4 may play an important role, and higher levels of IRF-4 in combination with higher levels of CRBN were associated with better survival. However, other factors such as genetic and chromosomal changes may have a larger impact on the development of resistance.
In chapter 7 and 8 the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was described. This is a validated tool used to evaluate the clinical benefit of new treatments in solid tumors. However, its applicability in hematological diseases (HM) is being questioned due to the differences in behavior between oncological and HM. Despite this, the ESMO-MCBS is still applicable in most analyzed studies of HM, with some shortcomings that need to be addressed. EHA and ESMO will work together to develop a new version of the scale that is validated for HM, taking into account the shortcomings found. A critical appraisal of clinical trials is necessary to use this tool effectively, as it can play an important role in decision making regarding the effect of new treatments on survival and quality of life.
Original languageEnglish
Awarding Institution
  • Erasmus University Rotterdam
  • Sonneveld, Pieter, Supervisor
  • Broijl, A., Co-supervisor
Award date6 Mar 2024
Place of PublicationRotterdam
Print ISBNs978-94-6361-959-2
Publication statusPublished - 6 Mar 2023


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