Kenshi Suzuki

Background: In the global phase 3 AQUILA trial, daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death than active monitoring in patients with high-risk smoldering multiple myeloma without unexpected safety concerns (NCT03301220). Methods: Here, we report a subgroup analysis of Japanese patients from the trial. Among the 28 Japanese patients, 15 and 13 patients received daratumumab and active monitoring, respectively. Results: At the median follow-up of 60.9 months, the median progression-free survival was 59.1 and 24.8 months, respectively, with a hazard ratio of 0.25 [95% confidence interval (CI): 0.10–0.65] favoring daratumumab treatment. The overall response rate was 86.7% and 7.7%, with an odds ratio of 78.0 (95% CI: 6.24–974.71). Overall survival data were immature. Grade ≥3 adverse events were observed in five patients (33.3%) treated with daratumumab, which did not lead to treatment discontinuation, and no new safety concerns were noted. Conclusions: In this small-scale exploratory post hoc Japanese subgroup analysis, the efficacy of daratumumab monotherapy was generally comparable to that demonstrated in the global trial population, and no data suggesting new safety concerns were identified. These findings may provide useful information for determining treatment options in Japanese patients with high-risk smoldering multiple myeloma. Trial registration number: ClinicalTrials.gov number, NCT03301220.

In the phase 3 CEPHEUS study, daratumumab plus bortezomib/lenalidomide/dexamethasone (D‑VRd) increased overall MRD-negativity rates versus VRd in transplant-ineligible/transplant-deferred patients with NDMM. We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible, or deferred transplant as initial therapy, were randomized 1:1 to receive D-VRd or VRd. Overall MRD negativity (NGS) was defined as the proportion of patients achieving ≥CR and MRD-negative status assessed at 10-5 (primary endpoint) and 10-6 thresholds. A total of 395 patients were randomized (D-VRd, n=197; VRd, n=198). With 58.7-months median follow-up, overall MRD-negativity rates were significantly higher with D-VRd versus VRd (10-5, 60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; 10-6, 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P<0.0001 and P=0.0001, respectively). Sustained MRD negativity (≥12 months) was also significantly higher with D-VRd versus VRd (10-5: 49.2% vs 27.3%; 10-6: 34.0% vs 16.2%; each P<0.0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all pre-specified timepoints, and cumulatively, with D-VRd versus VRd (10-5 and 10-6). Among patients who achieved MRD negativity, PFS trended in favor of D-VRd versus VRd (10-5, HR, 0.61; 95% CI, 0.35-1.06; P=0.0755; 10-6, 0.66; 95% CI, 0.31-1.41; P=0.2811). Responses with D-VRd are deeper and more durable versus VRd, increasing overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS for patients treated with D-VRd versus VRd (intent-to-treat), with the potential to improve PFS even among patients who achieve MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. Registered at www.clinicaltrials.gov: NCT03652064.

In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.

The phase 3 CEPHEUS trial was conducted in 13 countries starting December 11, 2018 in patients with newly diagnosed multiple myeloma (NDMM) who were transplant-ineligible or for whom transplantation was not planned as initial therapy. Bortezomib, lenalidomide, and dexamethasone (VRd) with daratumumab (D-VRd) provided deeper, more durable responses and lowered the risk of disease progression or death compared with VRd. This analysis evaluated the efficacy and safety of D-VRd specifically in the Japanese subpopulation of the CEPHEUS trial (D-VRd: n = 9; VRd: n = 13). At a median follow-up of 59.0 months, the overall minimal residual disease (MRD) negativity rate was 77.8% with D-VRd and 46.2% with VRd (odds ratio: 4.08 [95% confidence interval: 0.60, 27.65]). The complete response or better rate was 88.9% with D-VRd and 76.9% with VRd. Median progression-free survival was not reached in either group, with a hazard ratio of 0.34 favoring D-VRd. The sustained (≥ 12 months) MRD negativity rate was 55.6% with D-VRd and 38.5% with VRd. Efficacy and safety results were similar to those observed in the global CEPHEUS population, supporting the use of D-VRd in Japanese patients with NDMM.

**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was | POSTER

Introduction: Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy. Methods: The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity. Results: Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA 6 months after elotuzumab initiation was 18.4%. The history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at 6 months was 15.1%. During CMVRA, the symptoms included fever in 8 cases, while retinitis was observed in 1 case. Five patients required antiviral therapy and CMV antigenemia resolved in all but 1 case. Conclusion: Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.

High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P < .0001) in the early-relapse (<24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P < .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10−5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM. These trials were registered at www.clinicaltrials.gov as #NCT02136134 (CASTOR) and #NCT02076009 (POLLUX).