I am going to discuss a bit about the role of selinexor in combination with bortezomib and dexamethasone in some specific subgroups of patients with multiple myeloma in the relapsed and refractory setting but specifically after just one prior line of therapy. The rationale for these two presentations is based on the BOSTON study, it is a phase III clinical study in which selinexor, bortezomib and dexamethasone was compared with bortezomib and dexamethasone in 400 relapsed and refractory myeloma. The study met its primary endpoint – benefit in progression free survival for selinexor, bortezomib and dexamethasone with a hazard ratio of 0.7 and a median progression free survival of 14 months for SVd versus 9.4 months for Vd alone.
When we evaluate how the treatment landscape is evolving in multiple myeloma, and especially in the first line of therapy, we are going to be faced more and more at the moment of relapse with patients refractory to lenalidomide as well as also with patients refractory to daratumumab and lenalidomide. We are going to be faced with some patients even naïve for proteasome inhibitors. These two abstracts are basically focussed on relapsed and refractory myeloma after just one prior line of therapy, focussing on patients naïve for proteasome inhibitors as well as refractory to lenalidomide. These are the two abstracts I would like to discuss.
What was the design of the study?
The trial design was a randomised phase III clinical study in 402 relapsed and refractory myeloma patients after at least one and not more than three prior lines of therapy. Selinexor, bortezomib and dexamethasone as continuous therapy was compared with bortezomib and dexamethasone also as continuous therapy. The primary endpoint for this study was progression free survival and key secondary endpoints included overall response rate, VGPR rate or better, as well as grade 2 or more peripheral neuropathy.
This is the study design for the BOSTON study but if we are concerned with the sub-analysis presented at the EHA 2023, I would like to say that the first abstract is focussed on the updated results for this BOSTON study by the number of prior lines of therapy.
What were the key results?
According to my previous answer, if we focus specifically on patients treated with just one prior line of therapy, in the BOSTON study approximately 200 patients were treated after just one prior line of therapy. Baseline characteristics for SVd and Vd were comparable, and the majority of the patients did present an optimal performance status. Approximately 50% of the patients in both arms presented with high-risk cytogenetic abnormalities. Important to note, approximately 30% of the patients had been previously treated with autologous stem cell transplantation, indicating that the majority of the patients will be not eligible for autologous stem cell transplantation. This is important because this is a specific subgroup of patients in which we plan selinexor, bortezomib and dexamethasone as the first choice.
In this sub-analysis when we evaluated the outcomes in terms of progression free survival for patients treated with selinexor, bortezomib and dexamethasone over bortezomib and dexamethasone, treated with just one prior line of therapy, the benefit is quite consistent. The hazard ratio for progression free survival is 0.62 and the median progression free survival is 21 months for SVd versus 10.7 for bortezomib and dexamethasone. This benefit is derived also from a significant benefit in terms of overall response rate – 81% for SVd, including almost one-third of the patients achieving complete response.
In addition, in this specific sub-analysis we decided to focus on patients naïve for proteasome inhibitor because if we consider that the first line of therapy, especially in the [inaudible] population is daratumumab in combination with lenalidomide and dexamethasone, this means that the majority of the patients at first relapse will be naïve for bortezomib and naïve for proteasome inhibitor. This sub-analysis has been also conducted in the BOSTON study and there are approximately almost 100 patients treated with SVd and proteasome inhibitor naïve after just one prior line of therapy. What we can see is how the hazard ratio for progression free survival does continue being very significant for selinexor, bortezomib and dexamethasone, 0.29, and the median progression free survival for SVd was almost 30 months versus 9.7 months for bortezomib and dexamethasone.
The same data were observed when we focussed not only on patients after one prior line of therapy and naïve for proteasome inhibitors but, in addition, bortezomib naïve. The median progression free survival for SVd was also approximately 30 months.
What were the findings from the lenalidomide-refractory subgroup?
In addition, with the great benefit observed for SVd in patients after one prior line of therapy and proteasome inhibitor naïve, the other challenging situation is the lenalidomide-refractory population because basically the majority of the patients after just one prior line of therapy will be refractory to lenalidomide. This is the second sub-analysis presented at the European Haematology Association Congress – how is the outcome for patients treated with selinexor, bortezomib and dexamethasone if they are refractory to lenalidomide?
I have to say that 106 patients included in the phase III BOSTON study were refractory to lenalidomide. No significant differences, according to the baseline characteristics, between both arms but it’s important to note that the majority of the lenalidomide-refractory patients included in the BOSTON study had received two or three prior lines of therapy and only approximately one-third of the patients had received only one prior line of therapy. This is related with the standard of care at the moment in which the BOSTON study was conducted but, in spite of this fact, selinexor added to bortezomib and dexamethasone resulted in a longer median progression free survival in comparison with bortezomib and dexamethasone alone – 10.2 months versus 7.1 months. This benefit was also observed in terms of overall response rate as well as complete response rate and VGPR rate or better. This means that whilst selinexor, bortezomib and dexamethasone is also superior to Vd in the lenalidomide-refractory population, although it’s true that more data will be required from the lenalidomide-refractory population after just one prior line of therapy. But maybe this data will be generated in real life.
How can these results impact the future treatment of MM?
Selinexor, bortezomib and dexamethasone is a new standard of care already approved by the authorities for relapsed and refractory myeloma patients after just one prior line of therapy. Now, according to the treatment landscape for newly diagnosed myeloma patients, we are going to basically be faced at first relapse with patients with daratumumab and lenalidomide refractoriness, and in some cases even naïve for proteasome inhibitors. From my point of view, his means that this combination could be a good option for these patients just relapsing or progressing after one prior line of therapy. Of course, beyond the first relapse it is also possible to utilise selinexor, bortezomib and dexamethasone based on the efficacy and safety data reported in the BOSTON study.