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Subgroup analyses of CASTOR
A
B
Figure 3. PFS survival based on (A) cytogenetic risk and (B) MRD status. (A) Kaplan-Meier estimates of PFS among patients evaluated for cytogenetic risk. High-risk patients had any of t(4;14), t(14;16), or del17p cytogenetic abnormal- ities as determined by central next-generation sequencing. Standard-risk patients had an absence of high-risk abnormalities. (B) Kaplan-Meier estimates of PFS among patients in the ITT population population. MRD-negative status was evaluated at a sensitivity threshold of 10–5 using bone marrow aspirate samples that were prepared using Ficoll and analyzed by the clonoSEQ® assay. MRD: minimal residual disease; D-Vd: daratumumab plus bortezomib and dex- amethasone; Vd: bortezomib and dexamethasone.
observed solely at Week 21 in favor of D-Vd for the Visual Analog Scale Score (P=0.0185). No significant differences in EORTC QLQ-C30 global health status were observed for median time to improvement (5.0 versus 5.1 months; HR, 0.99; 95% CI, 0.76-1.29; P=0.9163). Similarly, no sig- nificant differences in median time to improvement were observed for either the EQ-5D-5L Utility Score (7.7 versus 3.5 months; HR, 0.82; 95% CI, 0.62-1.08; P=0.1469) or the Visual Analog Scale Score (5.0 versus 5.0 months; HR, 1.03; 95% CI, 0.79-1.35; P=0.8072).
Discussion
These data confirm that D-Vd provides significant clini- cal benefit to patients with RRMM. D-Vd prolonged PFS, resulting in a 69% reduction in the risk of disease progres- sion or death versus Vd. With an additional 12 months of follow up, responses to daratumumab deepened over time
Figure 4. Time to MRD negativity in the ITT population. MRD-negative status was evaluated over time at a sensitivity threshold of 10–5 using bone marrow aspirate samples that were prepared using Ficoll and analyzed by the clonoSEQ® assay. MRD: minimal residual disease; D-Vd: daratumumab plus bortezomib and dexamethasone; Vd: bortezomib and dexamethasone.
(≥CR: 28.8%) compared with the primary analysis (19.2%).13 Deeper responses to D-Vd were associated with significantly higher (>4 fold) MRD-negative rates at sensi- tivities of 10–5 and 10–6 versus Vd. We hypothesize that, as previous studies have demonstrated a correlation between MRD negativity and OS,21,22 this may translate into improved OS outcomes after longer follow up for patients treated with D-Vd. Analysis of OS is ongoing.
There were consistent clinical benefits with D-Vd versus Vd across subgroups based on prior lines of therapy, treat- ment exposure, or refractory status. These were also observed in patients regardless of time since last therapy or cytogenetic risk, as those patient subgroups were not evaluated in the primary analysis. Importantly, the benefit of D-Vd was maintained in patients who received prior bortezomib (including as their sole prior line of therapy) and those refractory to lenalidomide at their last prior line of therapy. Bortezomib- and lenalidomide-based combi- nations are common MM first-line and maintenance regi- mens. Thus D-Vd can be considered after bortezomib (if patients are not PI-refractory) or in lenalidomide-refracto- ry patients, which is of particular importance considering the increased lenalidomide use as maintenance therapy in newly diagnosed MM regardless of transplant eligibili- ty.23,24 D-Vd significantly prolonged PFS versus Vd across all lines of therapy with the greatest benefit achieved in patients who received 1 prior line in comparison to those who received 2 to 3 or >3 prior lines of therapy. Response rates, including the rates of MRD-negativity, were also highest in patients who received 1 prior line of therapy. As D-Vd showed the greatest benefit at first relapse, it may represent an optimal second-line treatment for patients after frontline lenalidomide or bortezomib.
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