Page 212 - Haematologica Vol. 109 - July 2024

ARTICLE - S-DVd in RRMM patients
V. González-Calle et al.
in part 2; P=0.2) and discontinued in eight (14%) patients (5 in part 1 and 3 in part 2; P= 0.2). Bortezomib was the second drug most commonly modified and was reduced in 15 (26.3%) and withdrawn in four (7.0%) (3 in part 1 and 1 in part 2; P=0.3), patients. Dexamethasone was reduced in ten (17.5%) patients (5 in each part) and withdrawn in two (3.5%) patients belonging to part 1 of the study. No patient discontinued daratumumab permanently. Only one patient discontinued daratumumab treatment temporarily due to a grade 4 cytopenia and restarted therapy after recovery (Table 4).
Discussion
The addition of selinexor to DVd (S-DVd) resulted in en- couraging clinical efficacy with a safety profile generally consistent with known safety profile of selinexor. Higher efficacy was observed when S-DVd was administrated in earlier lines of treatment and, also in len-refractory patients. The primary endpoint of the study was CR rate. If we analyze the ITT population, as a whole, the CR rate was 22%, although, it is important to acknowledge that 22 of 57 patients enrolled were heavily pretreated and 52% previously exposed to bortezomib. Thus, although the trial did not meet its primary endpoint potentially due to the changes in the study design and mixed patient populations, the CR rate in part 2 here presented seems encouraging. In part 1, the population included was consistent with the population enrolled in the pivotal studies that the led to the approval of daratumumab monotherapy (mostly double re- fractory and daratumumab-naïve).16,17 In this trial, increased efficacy was observed with the addition of selinexor plus bortezomib to daratumumab (median PFS 7,2 months as compared with the 3.7 months PFS reported for daratu- mumab single agent). However, the major interest of our trial regards part 2 since the clinical characteristics of the patients were closer to those treated with DVd in the phase III CASTOR trial (almost half [49%] of patients received only 1 PL of therapy, and one third were refractory to last line of treatment).18,19 In this context, the addition of selinexor to the backbone DVd in the present trial may have led to a deepening in the responses as compared to CASTOR in terms of MRD-negative rate in the ITT population (27% vs. 15%,20 respectively), translating into potentially longer PFS for S-DVd compared to the DVd-treated population in the CASTOR trial (median PFS of 25.1 vs. 16.7 months, respectively, or 18 months for patients with one or more PL in the CASTOR trial).19,21
Furthermore, 45% of the S-DVd-treated patients were len-refractory, whereas only 24% in the DVd arm of the CASTOR trial, and interestingly, in these subsets the PFS also appeared to be longer with S-DVd versus DVd (medi- an PFS of 22.8 vs. 7.8 months).21 As previously mentioned, len-refractory patients remained a difficult to treat pop-
ulation and carfilzomib + anti-CD38 monclonal antibodies (MoAb) are becoming standard of care in this setting based on positive results of the phase III CANDOR and IKEMA studies, respectively. These studies were also conducted in a similar RRMM population after one to three PL of therapy, apparently obtaining a similar ORR (84-87%) and CR rates (29-40%) as in part 2 of GEM Selibordara trial, but with a slightly underrepresented population of len-refractory patients in both CANDOR and IKEMA studies (33%).22–25 Still, PFS was longer in both IKEMA and CANDOR trial as compared to the trial here presented. The safety profile is different, and the intravenous formulation of carfilzomib has its drawbacks. In this sense, the availability of regimens such as S-DVd could be an alternative for patients with cardiovascular comorbidities, when there is a preference for subcutaneous and oral administration or in places where the combination of anti-CD38 plus carfilzomib and dexamethasone is not yet available.
In addition, it is worth mentioning that in the phase III BOSTON trial the SVd combination was investigated for patients with RRMM after one PL based.6 In this scenario, the addition of daratumumab to SVd may also appear to improve the depth of responses compared to SVd alone (CR or better: 33% vs. 17%; MRD negativity: 82% vs. 17%), and, as a result, also to prolong PFS (median PFS: 25.1 months vs. 13.9 months), despite a high proportion of prior bortezomib-exposed patients in part 2 of GEM Selibordara (91%) as compared to the BOSTON trial (69%). Moreover, focusing on len-refractory patients, deeper responses were also seen in the current trial as compared to the BOSTON study (ORR: 73% vs. 68%, and CR or better: 27% vs. 9%,), as well as longer PFS (median 22.8 vs. 10.2 months), sug- gesting a potential role of this quadruplet combination in this setting.
Regarding safety, incidence of treatment related AE were generally consistent with other studies with regimens containing selinexor, daratumumab, bortezomib and dexa- methasone, such as SVd and DVd. A similar incidence of hematological AE such as thrombocytopenia or anemia was observed, although a higher incidence of neutropenia was reported in this trial compared to the BOSTON trial, likely related to the addition of daratumumab, but overall grades 3-4 were similar.6,11 With regard to non-hematological AE, infections were the most frequently observed with S-DVd, although it is true that not only respiratory infections have been considered, which in the BOSTON and CASTOR stud- ies reached an incidence of 48-68%. Asthenia or fatigue were similar to that reported in the BOSTON trial. Regard- ing gastrointestinal toxicity, it was consistent with what was reported with SVd in the BOSTON trial, and, of note, loss of appetite was observed in only 5.3% of participants, probably due to the prophylactic measures implemented in the GEM Selibordara protocol. Importantly the discon- tinuation rate due to AE was lower although a significant proportion of patients did require dose modifications to
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