Uttervall, Katarina

Abstract Introduction : Current standard of care for smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), is observation until progression to active MM. Increasing evidence suggests that patients (pts) with SMM at high risk for progression to active MM may benefit from early treatment (tx). In AQUILA, a phase 3 study in pts with high-risk SMM (NCT03301220), daratumumab (Dara) monotherapy significantly reduced risk of progression to active MM or death with a trend of extending overall survival (OS) vs active monitoring (ActMon), with no new safety concerns. Given the evolution in SMM risk stratification, a post hoc analysis was performed to assess outcomes using the IMWG 2020 and IMWG 2020 plus cytogenetic risk models to assess which AQUILA pts benefited most from Dara monotherapy. Safety and efficacy analysis by age and stem cell collection outcomes were also assessed. Methods: Eligible pts with a confirmed diagnosis (≤5 y) of high-risk SMM per IMWG 2014 criteria, defined as clonal bone marrow plasma cells (BMPC) ≥10% and ≥1 risk factor (IgA SMM, serum protein ≥30 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and <100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC >50% to <60%) at study entry, were randomized 1:1 to receive subcutaneous Dara or ActMon for 39 cycles, 36 months, or until confirmed disease progression (PD), whichever came first. Primary endpoint was progression-free survival (PFS) assessed by independent review committee, defined as progression to active MM (based on IMWG SLiM-CRAB diagnostic criteria) or death. Secondary endpoints included time to first-line (1L) MM tx and OS. For this post hoc analysis, we assessed outcomes by age, IMWG 2020 high-risk SMM criteria (BMPC >20%, monoclonal spike >2 g/dL, serum FLC ratio >20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria), and the IMWG 2020 plus cytogenetic criteria (IMWG 2020 criteria + presence of ≥1 high-risk cytogenetic abnormalities [t(4;14), t(14;16), +1q and/or del13q]; ≥3 factors=high risk). Results : Dara tx showed a PFS benefit across all IMWG 2020 risk subgroups (low: hazard ratio [HR], 0.59; intermediate: HR, 0.70), with the largest benefit in the high-risk subgroup, where the PD/death rate in the ActMon arm was ~1.6-fold that in the Dara arm (62.8% vs 37.5%; HR, 0.36). This benefit of Dara vs ActMon was preserved over time, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. There was a positive trend favoring Dara for time to 1L MM treatment across all IMWG 2020 risk groups (low-risk HR, 0.63; 95% CI, 0.22–1.80; intermediate-risk HR, 0.57; 95% CI, 0.35–0.92; high-risk HR, 0.39; 95% CI, 0.25–0.62). IMWG 2020 plus cytogenetic risk classification results will be available at the time of presentation. When comparing the younger (<65y HR, 0.51; 95% CI, 0.32–0.79) vs the older (≥65y, HR, 0.50; 95% CI, 0.32–0.77) pt population, a PFS benefit was observed regardless of age. Similarity was also observed in TEAE incidence rate when looking into <65, 65 to <75, and ≥75 y subgroups (82.7%, 81.1%, and 87.5% with ActMon; 96.2%, 98.5%, and 95.2% with Dara); however, serious TEAEs were more frequently observed in older ActMon pts (12.2%, 18.9%, and 50.0% with ActMon; 24.8%, 35.8%, and 28.6% with Dara). Across all pts treated/monitored in AQUILA, 23 (11.9%) and 41 (20.9%) pts in the Dara and ActMon arms, respectively, received autologous stem cell transplant as part of their first tx after progressing to active MM, with very limited plerixafor use (Dara, 3 [1.6%] vs ActMon, 9 [4.6%]). Median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 pts in the Dara arm and 5.1 (2–21)×106 cells/kg body weight among 39 pts in the ActMon arm. Conclusions : In this analysis, pts with high-risk SMM from the phase 3 AQUILA study treated with Dara monotherapy experienced long-term PFS benefit across IMWG 2020 subgroups, with the most pronounced benefit in the high-risk subgroup. No notable differences in PFS or safety were observed across age subgroups. Early Dara tx for high-risk SMM did not have a detrimental impact on stem cell yield. Although mature OS analyses are forthcoming, overall, these results further support early intervention with Dara monotherapy vs ActMon among pts with high-risk SMM, regardless of risk stratification criteria used.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and <100, and/or clonal BMPCs >50% to <60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P <0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P <0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P <0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.