Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis

The phase 3 A.R.R.O.W. study demonstrated that treatment with once-weekly carfilzomib (70 mg/m2) and dexamethasone (once-weekly Kd70 mg/m2) improved progression-free survival compared with twice-weekly carfilzomib (27 mg/m2) and dexamethasone (twice-weekly Kd27 mg/m2) in patients with relapsed and refractory multiple myeloma (RRMM; median, 11.2 versus 7.6 months; hazard ratio [HR] = 0.69; 95% confidence interval, 0.54–0.88; P = 0.0029). Once-weekly dosing also improved response rates and depth of response. We performed a subgroup analysis from A.R.R.O.W. according to age (<65, 65–74, or ≥75 years), renal function (creatinine clearance <50, ≥50–<80, or ≥80 mL/min), number of prior therapies (2 or 3), and bortezomib-refractory status (yes or no). Compared with twice-weekly Kd27 mg/m2, once-weekly Kd70 mg/m2 reduced the risk of progression or death (HR = 0.60–0.85) and increased overall response rates in nearly all the examined subgroups, consistent with reports in the overall A.R.R.O.W. population. The safety profiles of once-weekly Kd70 mg/m2 across subgroups were also generally consistent with those in the overall population. Findings from this subgroup analysis generally demonstrate a favorable benefit–risk profile of once-weekly Kd70 mg/m2, further supporting once-weekly carfilzomib dosing as an appropriate treatment option for patients with RRMM, regardless of baseline patient and disease characteristics.


Introduction
Multiple myeloma (MM) is the third most common hematologic malignancy worldwide, characterized by excessive proliferation of monoclonal plasma cells 1,2 . The development of novel anti-MM agents has expanded treatment options for MM patients and improved outcomes 3 . Despite recent treatment advances, MM remains incurable, with most patients relapsing and developing treatment-refractory disease 1 . Relapsed and refractory MM (RRMM) represents a challenging disease to treat, given the heterogeneity of the disease and patient population [3][4][5] .
Importantly, advanced age, Eastern Cooperative Oncology Group performance status (ECOG PS), International Staging System (ISS), renal impairment, exposure to multiple lines of therapy, refractoriness to treatment, and the presence of high-risk cytogenetics have been associated with poor prognosis and shorter survival in patients with MM (including RRMM) [6][7][8][9][10] . Therefore, there is a continued need to identify safe and efficacious and ultimately convenient treatments across the heterogeneous RRMM patient population. For treatments with demonstrated safety and efficacy, convenience represents an important factor for optimizing adherence and patient quality of life [11][12][13] . Carfilzomib (K) is a second-generation proteasome inhibitor (PI) with selective, irreversible, robust, and welltolerated activity in MM, both as single agent 14 and in combination with dexamethasone (Kd) or lenalidomide plus dexamethasone (KRd) when administered as a twiceweekly infusion in patients with RRMM 15 . Efficacy and safety of twice-weekly carfilzomib-based therapies were previously demonstrated in the phase 3 ASPIRE and ENDEAVOR trials [16][17][18][19] . Importantly, the treatment effect of carfilzomib was confirmed across several patient subgroups [20][21][22][23][24][25][26] . The favorable benefit-risk profile of twiceweekly carfilzomib-based therapies versus standards of care (SOCs) provided an opportunity to consider the value of more convenient once-weekly carfilzomib therapy for patients with RRMM.
The randomized phase 3 A.R.R.O.W. trial (NCT02412878) was designed to evaluate a once-weekly carfilzomib dosing schedule compared with twice-weekly administration in patients with RRMM 27 . Patients were randomly assigned to receive once-weekly carfilzomib (70 mg/m 2 ) with dexamethasone (once-weekly Kd70-mg/ m 2 arm) or twice-weekly carfilzomib (27 mg/m 2 ) with dexamethasone (twice-weekly Kd27-mg/m 2 arm). In the prespecified interim analysis, progression-free survival (PFS) and overall response rate (ORR) were improved in the once-weekly Kd70-mg/m 2 arm versus the twiceweekly Kd27-mg/m 2 arm (median PFS: 11.2 months versus 7.6 months; hazard ratio [HR] = 0.69; 95% confidence interval (CI), 0.54-0.88; P = 0.0029; ORR: 62.9% versus 40.8%). A greater proportion of once-weekly Kd70 mg/m 2 patients achieved a very good partial response or better (≥VGPR) and complete response or better (≥CR) compared with twice-weekly Kd27 mg/m 2 patients (≥VGPR, 34.2% versus 13.4%; ≥CR, 7.0% versus 1.7%). Safety was generally comparable between the treatment arms 27 . Results from A.R.R.O.W. led to the recent approval of once-weekly Kd70 mg/m 2 for the treatment of patients with RRMM 15,27 . Furthermore, compared with twice-weekly Kd27 mg/m 2 , once-weekly Kd70 mg/m 2 improved treatment adherence, patient satisfaction, and health-related quality of life in patients with RRMM 13 . Overall, these results support the value of once-weekly carfilzomib as an additional, more convenient treatment option for patients with RRMM. Here we report results from a pre-planned subgroup analysis of A.R.R.O.W. to evaluate treatment effects by age, renal function, number of prior therapies, bortezomib-refractory status, ISS, and ECOG PS.

Study design and participants
Full A.R.R.O.W. study design details have been published previously 27 . Eligibility criteria included: two or three previous lines of therapy, prior exposure to a PI and an immunomodulatory drug (IMiD), refractory to most recent therapy, measurable disease (per International Myeloma Working Group [IMWG] consensus criteria 28,29 ), ECOG PS of 0 or 1, and calculated or measured creatinine clearance (CrCL) of ≥30 mL/min. The primary endpoint of A.R.R.O.W. was PFS. Secondary endpoints included ORR, OS, and safety. The study protocol was approved by the institutional review boards or ethics committees of all participating sites, and all patients provided written informed consent.

Subgroups
Patients in the intention-to-treat (ITT) population were grouped according to age (<65, 65-74, or ≥75 years), renal function (baseline CrCL <50, ≥50 to <80, or ≥80 mL/min), prior lines of therapy (2 or 3), bortezomib-refractory status (yes or no), ECOG PS (0 or 1), and ISS stage (stages 1 and 2 or stage 3). Within 21 days prior to randomization, adequate bone marrow and organ function assessments were performed at a central laboratory. Renal function was calculated using the Cockcroft and Gault formula as follows: [(140 − Age) × Mass (kg)/(72 × Creatinine (mg/dL)]; results were multiplied by 0.85 for female patients. Patients were considered refractory to bortezomib if (A) they were non-responsive to any regimen containing bortezomib (i.e., best overall response was stable or progressive disease) or (B) disease progression occurred within 60 days of bortezomib treatment discontinuation 27 . Here we report analyses of PFS, ORR, and safety in these prespecified subgroups. OS was not included because this data was not mature at the time of the interim analysis.
Assessments PFS, ORR, and best overall response were assessed in the ITT population. Response and disease progression were evaluated from the time of randomization in accordance with the IMWG Uniform Response Criteria 28,29 . Safety was assessed in all patients who received at least one dose of carfilzomib or dexamethasone.

Statistical analyses
Median PFS was estimated using the Kaplan-Meier method. HRs and corresponding 95% CIs were estimated using an unstratified Cox proportional hazards model. Comparisons between treatment arms were evaluated using an unstratified log-rank test. The Clopper-Pearson method was used to estimate 95% CIs for ORR. Mantel-Haenszel unadjusted estimates were used to estimate the odds ratio (OR) and corresponding 95% CI. Comparisons between treatment arms were evaluated using Fisher exact test. Reported P values are one sided and unadjusted for multiple comparisons.

Data sharing
Qualified researchers may request data from Amgen clinical studies. Complete details are available at the following: http://www.amgen.com/datasharing.

Patient enrollment
The cutoff date for the pre-planned interim analysis was June 15, 2017 27 . Within the ITT population (N = 478), 240 patients received once-weekly Kd70 mg/m 2 and 238 received twice-weekly Kd27 mg/m 2 . Baseline characteristics were generally balanced between treatment arms across subgroups. Select characteristics with ≥10% difference between treatment arms are shown in Supplementary Tables 1-4.
ORR was improved with once-weekly Kd70 mg/m 2 across all renal function subgroups (

ECOG PS and ISS stage
Rates of grade ≥3 TEAEs of interest are shown in Supplementary Table 5. The incidence of grade ≥3 cardiac failure (once-weekly Kd70 mg/m 2 and twice-weekly Kd27 mg/m 2 ) by ECOG PS was 1.7% and 2.6% (ECOG PS of 0) and 4.2% and 5.9% (ECOG PS of 1). The rates of grade ≥3   TEAEs are defined as any adverse event with an onset date from the first dose through 30 days after the last dose of any study drug.
Adverse events were coded using MedDRA version 20.0 and graded using NCI-CTCAE (version 4.03). Subjects were counted only once for each search strategy and each preferred term. Adverse events (peripheral neuropathy, cardiac failure, ischemic heart disease, and pulmonary hypertension) are listed as SMQ, narrow scope or preferred terms (acute kidney injury, anemia, thrombocytopenia, and neutropenia).   TEAEs are defined as any adverse event with an onset date from the first dose through 30 days after the last dose of any study drug.
Adverse events were coded using MedDRA version 20.0 and graded using NCI-CTCAE (version 4.03). Subjects were counted only once for each search strategy and each preferred term. Adverse events (peripheral neuropathy, cardiac failure, ischemic heart disease, and pulmonary hypertension) are listed as SMQ, narrow scope or preferred terms (acute kidney injury, anemia, thrombocytopenia, and neutropenia). cardiac failure (once-weekly Kd70 mg/m 2 and twiceweekly Kd27 mg/m 2 ) by ISS stage were 2.3% and 4.0% (ISS stages 1 and 2) and 4.8% and 3.7% (ISS stage 3).

Discussion
In this pre-planned subgroup analysis of the A.R.R.O.W. study, patients were evaluated by age, renal function, prior lines of therapy, bortezomib-refractory status, ECOG PS, and ISS stage. These factors have demonstrated prognostic significance in RRMM 6-10 and are important considerations when selecting therapy. Across nearly all examined subgroups in A.R.R.O.W., once-weekly administration of carfilzomib at the higher 70-mg/m 2 dose in combination with dexamethasone was associated with longer median PFS and higher ORR compared with twiceweekly administration of carfilzomib at the 27-mg/m 2 dose in combination with dexamethasone. These findings are consistent with those in the overall population 27 . Part of the observed benefit in patients receiving once-weekly Kd70 mg/m 2 in A.R.R.O.W. is likely due to the higher dose of carfilzomib administered in this treatment arm. Furthermore, patient-reported outcomes analysis reinforced that the higher 70-mg/m 2 carfilzomib dose is convenient and provided more favorable health-related quality of life than the 27-mg/m 2 carfilzomib dose 13 . Adherence to therapy might have improved for patients treated with once-weekly Kd70 mg/m 2 due to the more convenient weekly carfilzomib dosing schedule, which could have translated to improved clinical outcomes.
Elderly patients with MM are a challenging population to treat, in part due to higher chemotherapy toxicities 30 and comorbidity burden 31,32 . In ENDEAVOR and ASPIRE, analyses of twice-weekly carfilzomib-based therapies by age demonstrated consistent improvements in PFS and OS compared with the control treatment arms across all subgroups 20,21 . In A.R.R.O.W., once-weekly Kd70 mg/m 2 improved PFS and ORR for all age subgroups versus twice-weekly Kd27 mg/m 2 . Compared with the two older-age subgroups, patients in the younger subgroup (aged <65 years) received a greater median number of cycles of treatment in the once-weekly Kd70 mg/m 2 arm than in the twice-weekly Kd27 mg/m 2 arm. Since patients aged <65 years stayed on treatment longer with once-weekly Kd70 mg/m 2 compared with twiceweekly Kd27 mg/m 2 relative to the older-age subgroups, the younger-age patients receiving once-weekly Kd70 mg/ m 2 were able to derive a greater PFS benefit.
The safety profile for once-weekly Kd70 mg/m 2 was generally comparable to twice-weekly Kd27 mg/m 2 across all assessed age subgroups. In patients aged <65 years, the shorter median duration of carfilzomib administration in the twice-weekly Kd27 mg/m 2 arm (21.3 weeks) compared to once-weekly Kd70 mg/m 2 (41.1 weeks) may be partially explained by the higher incidence of disease progression or death in the twice-weekly Kd27-mg/m 2 arm (64.4%) compared to the once-weekly Kd70-mg/m 2 arm (51.0%) (Fig. 1a). In patients aged ≥75 years, the higher incidence of grade ≥3 TEAEs in the once-weekly Kd70-mg/m 2 group (84.4%) compared to those in the twice-weekly Kd27-mg/m 2 group (74.2%) may be due to the higher proportion of patients with baseline CrCL 30-<50 mL/min (56.5% versus 40.6%). Overall, once-weekly Kd70 mg/m 2 was effective and well tolerated in patients with RRMM regardless of age. The improved convenience of the once-weekly dosing schedule could be important for elderly patients with restricted mobility or for those who are working.
Impaired renal function is a common clinicopathological feature of MM that has been associated with worse prognosis and survival in patients 8 . Furthermore, drug dosing can be complicated by renal impairment, which can increase or worsen AEs 33 . In a subgroup analysis of ENDEAVOR, twice-weekly Kd56 therapy demonstrated clinically meaningful improvements in PFS and OS across renal subgroups, including severe renal impairment, compared with bortezomib-based therapy 26 . Our results show that patients administered once-weekly Kd70 mg/m 2 had longer median PFS and higher response rates compared with twice-weekly Kd27 mg/m 2 across all renal function subgroups, including patients with baseline CrCL <50 mL/min.
In patients with baseline CrCL <80 mL/min, rates of grade ≥3 TEAEs and TEAEs leading to treatment discontinuation were greater in the once-weekly Kd70-mg/m 2 group compared to the twice-weekly Kd27-mg/m 2 group. Specifically in patients with CrCL <50 mL/min, the incidence of TEAEs leading to carfilzomib treatment discontinuation was 28.6% for once-weekly Kd70 mg/m 2 compared with 14.7% for twice-weekly Kd27 mg/m 2 . Similar rates of grade ≥3 heart failure, hypertension, and acute kidney injury were reported for once-weekly Kd70 mg/m 2 and twice-weekly Kd27 mg/m 2 within each renal subgroup. Overall, once-weekly Kd70 mg/m 2 had a favorable benefit-risk profile relative to twice-weekly Kd27 mg/m 2 in patients with baseline CrCL ≥50 mL/min. In patients with decreased renal function (CrCL < 50 mL/ min), the once-weekly Kd70-mg/m 2 regimen improved PFS and response rates compared with the twice-weekly Kd27mg/m 2 regimen; however, a higher rate of AEs leading to carfilzomib treatment discontinuation was observed with once-weekly Kd70 mg/m 2 . Taken together, once-weekly Kd70 mg/m 2 demonstrates benefit over twice-weekly Kd27 mg/m 2 , although to a lesser extent in patients with CrCL <50 mL/min.
Previously treated patients with RRMM are a challenging population to treat, as the disease has been reported to become less sensitive or refractory to certain therapies with each successive line of treatment 6,34 . Previous subgroup reports from ASPIRE 22 and ENDEAVOR 23 demonstrated improved PFS and ORR of twice-weekly carfilzomib-based regimens compared to recent SOCs, regardless of the number of prior therapies patients had received before enrollment. Consistent with previous reports 22,23 , a greater benefit was observed in patients with fewer previous therapies, suggesting that carfilzomib efficacy (administered once-or twice-weekly) can be optimized by earlier administration in the disease course for patients with RRMM.
The safety profiles for the prior lines subgroups were generally consistent with those reported for the overall population. In patients previously treated with three lines of therapy, the incidence of grade ≥3 TEAEs was greater in the once-weekly Kd70-mg/m 2 treatment arm (75.6%) compared with the twice-weekly Kd27-mg/m 2 arm (58.0%). This may be partially due to the higher proportion of patients aged 75-84 years (22.6% versus 11.5%) in the once-weekly Kd70-mg/m 2 treatment arm. Importantly, the incidence of grade ≥3 cardiac failure was <7% across treatment arms and was lower for once-weekly Kd70 mg/m 2 (2.6%-3.3%), and no additional toxicities were found. This subgroup analysis confirmed that onceweekly treatment with carfilzomib (70 mg/m 2 ) plus dexamethasone is safe, feasible, and superior to twice-weekly carfilzomib (27 mg/m 2 ) plus dexamethasone, regardless of the number of prior therapies.
Bortezomib is a common component of frontline therapies, and there is a need for effective salvage options in patients whose disease becomes refractory to this agent. The ASPIRE trial previously reported improved PFS and OS in bortezomib-refractory patients treated with twiceweekly KRd versus Rd 18,22 . In A.R.R.O.W., patients treated with once-weekly Kd70 mg/m 2 demonstrated longer median PFS and higher ORRs versus those treated with twice-weekly Kd27 mg/m 2 , regardless of disease sensitivity to bortezomib. In both treatment arms, absolute PFS durations and response rates were lower in patients with bortezomib-refractory disease compared with bortezomib-sensitive disease. This is consistent with the existence of some cross-resistance between the two PIs 35,36 . Taken together with ASPIRE, these results support the benefit of carfilzomib-based therapy for patients with disease refractory to bortezomib.
Safety profiles by bortezomib-refractory status were comparable to the overall population 27 . Once-weekly Kd70 mg/m 2 demonstrated improved efficacy with a similar safety profile compared to twice-weekly Kd27 mg/ m 2 , regardless of bortezomib-refractory status. As continuous treatment with lenalidomide has become a new SOC in frontline MM 37,38 , there is a need for active regimens to treat patients who have relapsed or become refractory to lenalidomide. In the A.R.R.O.W. trial, 401 (83.9%) patients had prior lenalidomide exposure and 356 (74.5%) were refractory to any prior lenalidomide 27 . Although lenalidomide-exposed and lenalidomiderefractory patient subgroups were not evaluated in this study, analyses from these subgroups are underway and will be presented in a separate paper.
ECOG PS (0-5) and ISS stages (1-3) are prognostic factors used to assess patients with MM 39,40 , with higher values associated with worse prognosis and greater susceptibility to AEs. In our study, grade ≥3 TEAEs, including cardiac TEAEs, were comparable across treatment arms, regardless of ECOG PS (0 or 1) or ISS stage (stage 1 and 2 or stage 3). Once-weekly Kd70 mg/m 2 , therefore, represents a tolerable therapeutic option in RRMM patients with advanced disease and functional impairment.
Limitations of this subgroup analysis of A.R.R.O.W. include the open-label trial design and the small numbers of patients in subgroups. In addition, the control group in our study was administered twice-weekly carfilzomib at a dose of 27 mg/m 2 in combination with dexamethasone; the currently approved dose of carfilzomib in combination with dexamethasone is 56 mg/m 2 (based on ENDEA-VOR 15,16 ), which was not yet approved during the enrollment period of the A.R.R.O.W. study. Nevertheless, findings from this study warrant further investigation.
Clinical practice guidelines from the National Comprehensive Cancer Network, American Society of Oncology, and Cancer Care Ontario recommend doublet and triplet regimens as treatment options for patients with previously treated MM 41,42 . In randomized trials, carfilzomib-and daratumumab-based triplets have improved PFS, ORR, and/or OS in relapsed and/or refractory MM patients relative to doublet therapies; however, triplet therapies were also associated with higher rates of toxicity in these studies 17,18,[43][44][45][46] . Therefore, patients with lower tolerance for increased toxicity, higher comorbidity burden, and/or frail status may not be suited for triplet therapies 42 . Comparisons of once-weekly Kd70 mg/m 2 with currently available data from triplet combination studies are challenging, given differences in patient population (e.g., prior therapy, sensitivity to IMiDs and/or PIs, baseline creatinine clearance) and stratification of subgroups 17,20,22,[43][44][45][46][47] . Future studies evaluating the efficacy and safety of once-weekly Kd70 mg/m 2 dosing relative to recommended triplet salvage regimens may further highlight the potential utility of once-weekly Kd70 mg/m 2 in the RRMM treatment armamentarium.

Conclusions
In this pre-planned subgroup analysis of the A.R.R.O.W. study, PFS and ORR were consistently improved in the once-weekly carfilzomib treatment arm at the higher 70mg/m 2 dose compared with the twice-weekly carfilzomib treatment arm at the 27-mg/m 2 dose across several important baseline patient and disease characteristics. The safety profiles of once-weekly Kd70 mg/m 2 in each patient subgroup were generally consistent with that in the overall population 27 . Overall, this subgroup analysis of A.R.R.O.W. supports the favorable benefit-risk profile of once-weekly Kd70 mg/m 2 and the use of this regimen as a safe, effective, and convenient treatment option for patients with RRMM, regardless of age, prior lines of therapy, and bortezomib-refractory status.