Phase Ib Dose-escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-dose Dexamethasone in Relapsed or Progressive Multiple Myeloma

Abstract

Purpose

Carfilzomib, a selective proteasome inhibitor, has demonstrated safety and efficacy in relapsed and/or refractory multiple myeloma. This Phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a Phase II expansion study.

Experimental Design

Patients with multiple myeloma who relapsed after 1–3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15–27 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10–25 mg on Days 1–21; and dexamethasone 40 mg weekly.

Results

Forty patients enrolled in 6 cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the Phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no Grade 3/4 neuropathy reported. Proteasome inhibition 1 hour post-dose was >80% in Cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and median duration of response and progression-free survival were 11.8 and 10.2 months, respectively.

Conclusion

The maximum planned CRd dose—carfilzomib 27 mg/m², lenalidomide 25 mg, and dexamethasone 40 mg—was recommended for further study, with promising safety and efficacy.

Introduction

In the past decade, the introduction of the immunomodulatory agents thalidomide and lenalidomide and the proteasome inhibitor bortezomib has significantly advanced the management of multiple myeloma (MM), offering patients effective disease control with improved tolerability compared with past treatment regimens (1, 2). Clinical studies have shown that combinations including an immunomodulatory agent and/or bortezomib can also improve response and disease control in patients with advanced MM compared with standard treatment, but combination therapies are commonly associated with increased toxicity (3, 4).

Adding bortezomib to the combination of lenalidomide and dexamethasone (RVD) in patients with relapsed and relapsed/refractory MM led to good antitumor activity, but with notable toxicities (5, 6). In a phase 2 study, 64% of patients achieved at least a partial response (PR), with a median time to progression (TTP) of 9.5 months and a median overall survival (OS) of 26 months (6). However, Grade 1/2 peripheral neuropathy (PN) was reported in 64% of patients, with 40% of patients requiring a dose reduction for any reason (6).

Carfilzomib (Onyx Pharmaceuticals, South San Francisco, CA) (7) is a structurally and mechanistically distinct proteasome inhibitor that selectively binds to both the constitutive proteasome and immunoproteasome, resulting in sustained inhibition of proteasome activity (8). Based on findings from the pivotal trial, PX-171-003-A1 (NCT00511238),(9) single-agent carfilzomib was recently approved in the United States for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy (7). Clinical experience with single-agent carfilzomib has yielded an acceptable tolerability profile with the most common toxicities generally being hematologic in nature (10). Importantly, there has been no significant association between carfilzomib and PN (11).

In view of the clinical experience with carfilzomib as well as the preclinical efficacy of combination therapy (12), a Phase Ib dose-escalation trial was initiated to assess the safety and potential activity of carfilzomib in combination with lenalidomide and dexamethasone (CRd) in patients with relapsed or progressive MM. Herein we report the Phase I dose-escalation portion of the study. Results from the ongoing Phase II dose-expansion portion will be reported separately.

Methods

Patients

Patients with symptomatic MM and relapsed or progressive disease after 1–3 prior lines of therapy were eligible provided their disease was measurable by serum and urine protein electrophoresis or, when appropriate, quantitative immunoglobulin levels (13). There were no restrictions on the type of prior treatment, but generally, systemic therapies should have been discontinued for at least 3 weeks and treatment with radiation or immunotherapy for at least 4 weeks. Patients previously treated with lenalidomide or bortezomib must not have progressed during the first 6 months of treatment (3 months in Amendment 2) with either drug and must not have discontinued lenalidomide treatment due to intolerance. Refractory status to drugs other than bortezomib and lenalidomide was not recorded. Additional eligibility criteria included having achieved at least a minimal response (MR) to a prior therapy, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, a life expectancy of longer than 3 months, and normal hepatic function. The minimum laboratory requirements included absolute neutrophil count of ≥1,000, hemoglobin ≥8 mg/dL, platelet count ≥50,000/mm³, and creatinine clearance ≥50 mL/min.

Patients with non-secretory or hyposecretory MM or primary refractory MM (defined as disease progression within 90 days of initiation of first-line treatment) were excluded. Other exclusion criteria included the presence of significant medical conditions such as substantial neuropathy at baseline (Grades 3 or 4, or Grade 2 with pain) or within 14 days prior to entering the study and substantial cardiovascular disease, including congestive heart failure (New York Heart Association [NYHA] class III–IV), symptomatic ischemia, myocardial infarction within 6 months, and uncontrolled hypertension.

Study design and study drug administration

This was a multicenter, single-arm, open-label, Phase Ib dose-escalation study. The study was approved by review boards at all participating centers and conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice; all patients provided written informed consent. The study is registered at ClinicalTrials.gov (NCT00603447).

The primary objective of the study was to determine the safety and maximum tolerated dose (MTD) of carfilzomib and lenalidomide as part of a combination regimen with a fixed dose of dexamethasone. Secondary endpoints included efficacy and pharmacodynamics (PDn). The MTD and a qualitative assessment of safety and tolerability, disease response, and biologic activity were used to determine the recommended dose schedule for the Phase II dose-expansion portion of the study.

A standard 3+3 dose-escalation design was used to determine the MTD (14). Dose escalation continued until the maximum planned dose (MPD) was reached as long as no more than 1 of 3 (or 6) patients experienced a dose-limiting toxicity (DLT; Table 1). If no MTD was identified, the MPD would be used in the Phase II expansion cohort. Figure 1 details the schedule and dose levels for each drug by cohort. At the time the study was initiated, single-agent carfilzomib had been tested at doses up to 20/27 mg/m² as a 2- to 10-minute infusion (20 mg/m² for the first 2 doses of the first cycle, 27 mg/m² thereafter), and this dose was chosen as the highest carfilzomib dose to be tested in combination (15). In the lowest dose cohort, carfilzomib was initiated at 15 mg/m² and lenalidomide at 10 mg. Dexamethasone was maintained at a fixed dose of 40 mg across all dose cohorts. The regimen was administered in a 28-day cycle with 3 weeks on treatment followed by 1 week of rest. Carfilzomib was administered by intravenous infusion over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 (Days 1, 2, 15, and 16 after Cycle 12); lenalidomide was administered orally on Days 1–21; and dexamethasone was administered once per week on Days 1, 8, 15, and 22.

Table 1.

Dose-limiting Toxicity Criteria

Non-hematologic: ≥Grade 2 neuropathy with pain ≥Grade 3 non-hematologic toxicity (excluding nausea, vomiting, diarrhea, hyperglycemia due to dexamethasone treatment, or rash due to lenalidomide) ≥Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy ≥Grade 4 fatigue persisting for >7 days Treatment delay >21 days for toxicity

Hematologic: • Grade 4 neutropenia (ANC <500/mm3) lasting for >7 days • Febrile neutropenia (ANC <1,000/mm3 with a fever ≥38.3°C) • Grade 4 thrombocytopenia (<25,000/mm3) that persists for ≥7 days, despite holding treatment • Grade 3–4 thrombocytopenia associated with bleeding • Treatment delay >21 days for toxicity

Abbreviation: ANC, absolute neutrophil count

Figure 1. Carfilzomib-lenalidomide-dexamethasone (CRd) dosing cycle.

Dosing cycle and dose levels of CRd in 6 dose-escalation cohorts are depicted. Lenalidomide was administered orally, dexamethasone was administered orally or IV, and carfilzomib was administered IV over 2–10 minutes. Abbreviation: D, day.

^aMaintenance therapy (Cycle 13+) does not include carfilzomib dosing on Days 8 and 9.

^bCarfilzomib 20 mg/m² on Days 1 and 2 in Cycle 1; 27 mg/m² thereafter.

Dose modifications were permitted to manage toxicity and could include dose delay until resolution or improvement of toxicity, or dose reduction by 1 dose level. During Cycle 1, dosing was held for any DLT. If symptoms of infusion-related reactions occurred after carfilzomib administration, an additional 4 mg dexamethasone could be given prior to subsequent carfilzomib doses. Prophylactic antibiotic (Cycle 1 only), antiviral agents, proton pump inhibitor, and hydration were also required. Aspirin (810325 mg daily, unless active bleeding with platelets <50,000/mm³) and anticoagulant were required to prevent potential thromboembolic complications of lenalidomide. Allopurinol prophylaxis was permitted at the treating physician’s discretion for patients at potential risk of tumor lysis syndrome due to high tumor burden.

After Cycle 1, patients continued treatment at the assigned dose level. If stable disease (SD) or better response was achieved after 4 cycles, patients could receive up to 8 additional cycles of CRd therapy. Once the MTD was defined or the MPD was reached, patients without disease progression who completed at least 4 cycles could escalate to the MTD or MPD to possibly improve response. If SD or better was maintained through 12 cycles, patients could receive up to 6 additional treatment cycles as part of the current study on the modified carfilzomib schedule until development of progressive disease (PD) or unacceptable toxicity. Patients who completed 18 cycles had the option of enrolling in an open-label extension study, PX-171-010 (NCT00884312), or could continue on the current study following a protocol amendment that removed the treatment cap.

Study assessments

Adverse events (AEs) were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 3.0) (16). Serious AEs (SAEs) included events that resulted in death or immediate risk of death, inpatient or prolonged hospitalization, or disability.

Treatment response was measured on Day 15 of Cycle 1 and Day 1 in subsequent cycles. Responses and progression were assessed by investigators and confirmed by the study sponsor according to the International Myeloma Working Group (IMWG) Uniform Response Criteria: stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, SD, and PD (17), with the addition of MR according to the European Bone Marrow Transplant (EBMT) criteria (18). Calculated efficacy variables included best overall response rate (ORR, PR or better), clinical benefit rate (CBR, MR or better), duration of response (DOR), duration of clinical benefit (DCB), and progression-free survival (PFS).

Whole blood samples for PDn assays were collected pre-dose and 60 minutes post dose on Days 1, 2, and 8 of Cycle 1 and on Day 1 of Cycle 2 at selected study centers. A fluorogenic assay with succinyl-Leu-Leu-Val-Tyr-AMC (LLVY) substrate was used to assess chymotrypsin-like proteasome activity in whole blood and peripheral blood mononuclear cells (PBMC) as previously described (15, 19).

Statistics

Approximately 25 patients were planned for enrollment, although additional patients could be enrolled in a cohort if earlier enrollees had not completed the first cycle. Descriptive statistics were used to summarize categorical and continuous data variables. Analysis of safety and efficacy data was conducted with all enrolled patients who received at least 1 dose of carfilzomib, lenalidomide, and dexamethasone (safety population). Time-to-event endpoints (DOR and PFS) were assessed by the Kaplan-Meier method.

Results

Patient enrollment began in June 2008. This analysis includes data collected through November 2012; median time on treatment was 7.2 months (range 0.2–42.4 months). Forty patients were enrolled at 5 centers in the United States. The median age was 61.5 years, median time since diagnosis was 3.3 years, and all but 1 patient (2.5%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (Table 2). The majority of patients had received 2 or more prior MM treatments (median 2, range 1–3), with the most common being corticosteroids (100.0%), bortezomib (75.0%), and lenalidomide (70.0%). Among the 28 patients who had previously received lenalidomide, 10 (35.7%; 25.0% overall) had refractory disease (defined as best response of SD or PD, or discontinued treatment due to PD), and 6 of 30 patients (20.0%; 15.0% overall) were refractory to prior bortezomib. A history of neuropathy (all Grade 1 or Grade 2 without pain) was reported in 82.5% of patients. At study entry, hematologic abnormalities were detected in a significant proportion of patients: 87.5% had anemia (17 patients [42.5%] Grade 2/3), 70% had neutropenia (5 patients [12.5%] Grade 2/3), and 35% had thrombocytopenia (5 patients [12.5%] Grade 2/3).

Table 2.

Baseline Characteristics

	N=40
Male, n (%)	22 (55)
Age, years, median (range)	61.5 (43–81)
Race/ethnicity, n (%)
Caucasian	30 (75.0)
African American	6 (15.0)
Hispanic	3 (7.5)
Asian	1 (2.5)
Time since diagnosis, years, median (range)	3.3 (0.3–42.7)
ECOG performance score, n (%)
0	10 (25.0)
1	29 (72.5)
2	1 (2.5)
Immunoglobulin subclass, n (%)
IgG	28 (70.0)
IgA	8 (20.0)
Missing	4 (10.0)
FISH or Cytogenetics, n (%)a
Normal/favorable	25 (62.5)
Unfavorable	11 (27.5)
Missing/unknown	4 (10.0)
History of neuropathy, n (%)	33 (82.5)
Prior therapy regimens, median (range)	2 (1–3)
Prior therapy, n (%)b
Corticosteroids	40 (100.0)
Lenalidomide	28 (70.0)
Thalidomide	20 (50.0)
Bortezomib	30 (75.0)
Bortezomib + lenalidomide	25 (62.5)
Bortezomib + lenalidomide or thalidomide	28 (70.0)
Transplant	30 (75.0)
Alkylating agent	29 (72.5)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization.

^aUnfavorable by FISH: t(4;14), t(14;16), del(17p;13); unfavorable by cytogenetics: del(13q), t(4;14), t(14;16), del(17p;13).

^bExposure to multiple drugs was not necessarily concurrent.

Maximum tolerated dose

No DLTs were observed in the 5 lowest dose cohorts. Because of rapid enrollment into each cohort, the minimum of 3 patients was quickly reached and additional eligible patients were consented and enrolled before the decision for dose advancement to the next level could be made. Hence, each cohort, with the exception of Cohort 6, was overenrolled in the absence of DLTs. In Cohort 6, 1 patient experienced a DLT (Grade 4 neutropenia on Day 8 of Cycle 1) that was considered to be related to lenalidomide. The MTD was not reached since no other patient in Cohort 6 experienced a DLT, and the MPD—27 mg/m² carfilzomib with 25 mg lenalidomide and 40 mg dexamethasone—was considered the recommended dose for subsequent studies.

Safety and tolerability

All 40 patients were included in the safety analysis. The median dose of carfilzomib delivered was 20.0 mg/m². Overall, patients initiated a median of 8.5 cycles (range, 1–46) of CRd, with 29 patients starting at least 4 cycles of treatment and 16 patients starting at least 12. Two patients continued CRd treatment in the extension study (PX-171-010). At data cutoff, 2 patients remained on treatment in the current Phase I protocol.

Among the 28 patients who discontinued treatment prior to completing the protocol-specified number of cycles, 19 discontinued due to PD, 4 discontinued due to an AE, 2 withdrew consent, and 3 discontinued for other reasons. The 4 patients who discontinued primarily due to an AE reported 7 AEs leading to discontinuation of CRd: pyrexia; influenza; neutropenia and thrombocytopenia; and diarrhea, dehydration, and urinary tract infection. Among these 7 AEs, only influenza was considered unrelated to carfilzomib. Other reasons for discontinuation included the decision to undergo stem cell transplant (2 patients), and soft-tissue mass unrelated to treatment (1 patient). Two patients (5.0%), both in Cohort 6, required carfilzomib dose reductions, and 23 patients (57.5%) required carfilzomib dose delays. No deaths occurred during treatment or within 30 days of treatment discontinuation.

All patients experienced at least 1 AE of any grade during CRd therapy (Table 3). Grade 3 or 4 AEs were reported in 97.5% of patients, and 52.5% experienced a SAE. AE rates among cohorts were comparable, but the limited sample size precludes any statistical comparisons. The most common AEs of any grade were fatigue (62.5%), neutropenia (55.0%), diarrhea (52.5%), anemia (47.5%), cough (42.5%), and thrombocytopenia (40.0%), and the most common Grade 3/4 AEs were neutropenia (42.5%), thrombocytopenia (32.5%), lymphopenia (27.5%), and hyperglycemia (22.5%). One patient had febrile neutropenia. Neuropathic events (among events reported as peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, or neuropathy), all Grade 1 or 2 and considered related to treatment, were reported in 4 patients (10.0%), all of whom had a history of neuropathy. One patient (2.5%) in Cohort 5 experienced Grade 3 deep vein thrombosis that was considered to be unrelated to CRd treatment. No patients experienced cardiac AEs of heart failure, arrhythmia, cardiomyopathy, or ischemic heart disease during this study, while hypertension was reported for 3 patients (7.5%; 2 Grade 1, 1 Grade 3). Blood creatinine increased in 3 patients (7.5%; 1 Grade 1, 2 Grade 2); the AE resolved in 1 patient after treatment with a diuretic, and did not resolve in 2 patients. Renal failure was reported for 3 patients (7.5%; 1 each Grades 1, 2, and 3) who had history of renal impairment and/or hypertension; renal failure subsequently resolved in 2 of the patients.

Table 3.

Adverse Events (n=40)^a,^b

Adverse event, n (%)	Grade 1/2	Grade 3/4	All grades
Hematologic
Neutropenia	5 (12.5)	17 (42.5)	22 (55.0)
Anemia	11 (27.5)	8 (20.0)	19 (47.5)
Thrombocytopenia	3 (7.5)	13 (32.5)	16 (40.0)
Lymphopenia	1 (2.5)	11 (27.5)	12 (30.0)
Leukopenia	2 (5.0)	7 (17.5)	9 (22.5)
Non hematologic
Fatigue	22 (55.0)	3 (7.5)	25 (62.5)
Diarrhea	19 (47.5)	2 (5.0)	21 (52.5)
Cough	17 (42.5)	0	17 (42.5)
Upper respiratory tract infection	14 (35.0)	1 (2.5)	15 (37.5)
Dyspnea	13 (32.5)	1 (2.5)	14 (35.0)
Pyrexia	14 (35.0)	0	14 (35.0)
Muscle spasms	12 (30.0)	1 (2.5)	13 (32.5)
Back pain	11 (27.5)	1 (2.5)	12 (30.0)
Hyperglycemia	3 (7.5)	9 (22.5)	12 (30.0)
Constipation	11 (27.5)	0	11 (27.5)
Peripheral edema	10 (25.0)	1 (2.5)	11 (27.5)
Rash	10 (25.0)	1 (2.5)	11 (27.5)
Hypokalemia	6 (15.0)	4 (10.0)	10 (25.0)
Nausea	10 (25.0)	0	10 (25.0)
Pain in extremity	10 (25.0)	0	10 (25.0)
Paraesthesia	10 (25.0)	0	10 (25.0)
Arthralgia	9 (22.5)	0	9 (22.5)
Hyponatremia	3 (7.5)	6 (15.0)	9 (22.5)
Insomnia	9 (22.5)	0	9 (22.5)
Dizziness	8 (20.0)	0	8 (20.0)
Hypomagnesemia	8 (20.0)	0	8 (20.0)
Hypophosphatemia	0	8 (20.0)	8 (20.0)
Shoulder pain	7 (17.5)	1 (2.5)	8 (20.0)
Vision blurred	7 (17.5)	1 (2.5)	8 (20.0)

^aAdverse events that develop on or after the first day of study treatment and within 30 days of the last dose

^bOccurring in ≥20% of patients at any grade

Efficacy

All 40 patients were evaluated for response. The ORR was 62.5%, and the CBR was 75.0%, with 1 patient achieving sCR (2.5%), 13 patients (32.5%) achieving VGPR, and 11 patients (27.5%) achieving PR (Table 4). The median DOR for patients achieving PR or better was 11.8 months (95% CI 5.8–21.1), median DCB was 14.1 months (95% CI 5.8–21.1), and the median PFS was 10.2 months (95% CI 6.5–15. 4).

Table 4.

Efficacy Endpoints Among Treated Patients (n=40)

	Dose Cohort (CFZ [mg/m2] + LEN [mg] + DEX [mg])
	1 (15/10/40) n=6	2 (15/15/40) n=6	3 (15/20/40) n=8	4 (20/20/40) n=6	5 (20/25/40) n=6	6 (27/25/40) n=8	Overall n=40
Best response, n (%)
Stringent complete response	0 (0.0)	0 (0.0)	1 (12.5)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.5)
Very good partial response	2 (33.3)	1 (16.7)	3 (37.5)	3 (50.0)	2 (33.3)	2 (25.0)	13 (32.5)
Partial response	1 (16.7)	0 (0.0)	2 (25.0)	1 (16.7)	2 (33.3)	5 (62.5)	11 (27.5)
Minimal response	0 (0.0)	2 (33.3)	1 (12.5)	1 (16.7)	1 (16.7)	0 (0.0)	5 (12.5)
Stable disease	2 (33.3)	2 (33.3)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	4 (10.0)
Progressive disease	1 (16.7)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (12.5)	2 (5.0)
Not evaluable	0 (0.0)	1 (16.7)	1 (12.5)	1 (16.7)	1 (16.7)	0 (0.0)	4 (10.0)
Overall response, n (%)a	3 (50.0)	1 (16.7)	6 (75.0)	4 (66.7)	4 (66.7)	7 (87.5)	25 (62.5)
95% CI	11.8–88.2	0.4–64.1	34.9–96.8	22.3–95.7	22.3–95.7	47.3–99.7	45.8–77.3
Median duration of response, mo	5.8	13.8	21.1	NE	18.8	11.3	11.8
95% CI	3.0–NE	NE–NE	5.6–41.5	2.6–NE	4.8–18.8	5.8–NE	5.8–21.1
Clinical benefit response, n (%)b	3 (50.0)	3 (50.0)	7 (87.5)	5 (83.3)	5 (83.3)	7 (87.5)	30 (75.0)
95% CI	11.8–88.2	11.8–88.2	47.3–99.7	35.9–99.6	35.9–99.6	47.3–99.7	58.8–87.3
Median duration of clinical benefit, mo	5.8	5.9	21.1	NE	18.8	14.1	14.1
95% CI	3.5–NE	5.1–14.3	2.8–42.5	2.6–NE	1.9–18.8	6.7–NE	5.8–21.1
Median progression-free survival, mo	3.9	9.9	23.7	NE	6.6	14.6	10.2
95% CI	0.5–NE	4.3–14.8	5.6–43.4	4.6–NE	2.8–20.7	1.0–NE	6.5–15.4

^aPartial response or better;

^bMinimal response or better

CFZ, carfilzomib; CI, confidence interval; DEX, dexamethasone; LEN, lenalidomide; NE, not evaluable.

Pharmacodynamics

PDn analysis revealed significant proteasome inhibition after carfilzomib dosing (Figure 2). In patients receiving 15 or 20 mg/m² of carfilzomib, mean inhibition of chymotrypsin-like activity in whole blood and PBMC 1 hour after the first dose in Cycles 1 and 2 ranged from 81.3% to 88.0% and from 82.7% to 88.5%, respectively. In whole blood, significant recovery of proteasome activity was not detected during Cycle 1, which is consistent with studies in animals (8). In PBMC, proteasome activity remained partially inhibited prior to Day 8 dosing, with mean inhibition ranging from 43.7% to 69.0%, and in most patients, had returned close to baseline levels by the start of Cycle 2. Overall, the extent of proteasome inhibition was similar between different dosing cohorts.

Figure 2. Proteasome inhibition in patients receiving CRd at 3 different dose levels.

Proteasome chymotrypsin-like activity was calculated as a percentage of Cycle 1 Day 1 pre-dose activity. Data from Cohorts 1 and 6 are presented to show inhibitory effects at the highest and lowest carfilzomib doses. Points represent means, error bars depict SEMs. Abbreviations: C, cycle; D, day; PBMC, peripheral blood mononuclear cells.

Discussion

The MTD of escalating carfilzomib and lenalidomide doses in combination with a fixed dose of dexamethasone was not established in patients with relapsed or progressive MM after 1–3 prior regimens, a quarter of whom were refractory to prior lenalidomide. The maximum planned CRd dose, combining 27 mg/m² carfilzomib with 25 mg lenalidomide and 40 mg dexamethasone, was generally well tolerated. Efficacy analysis, a secondary outcome, demonstrated encouraging response rates.

While the majority of patients experienced Grade 3/4 AEs, few patients required dose reduction or treatment discontinuation due to toxicity. Grade 3/4 AEs in the current Phase I study, primarily hematologic toxicities, are consistent with earlier studies in patients with advanced MM that used similar doses of single-agent carfilzomib,(9, 20–22) or the combination of RD or RVD (5, 6, 23–25). Among nonhematologic AEs of any grade, cough and dyspnea were reported in more than a third of patients, a finding consistent with previous studies with single-agent carfilzomib(26). These AEs may be related to the hydration requirements that were instituted during early clinical development to minimize the risk of tumor lysis and infusion effects. Although patient populations and treatment schedules/regimens differ between this Phase I study and previous studies, some observations are noteworthy. In contrast to patients with relapsed or refractory MM receiving lenalidomide and dexamethasone (RD) in 2 Phase III studies (23, 24), 1 patient receiving CRd in the current study experienced a Grade 3 thromboembolic event. When comparing the safety and tolerability results from the current study to those from a Phase II study of RVD in patients with relapsed and relapsed/refractory MM (n=64), the most notable differences in patients receiving RVD are Grade 3 peripheral motor neuropathy reported in 2 patients (3%) and dose reductions in 62% of patients (6).

Neuropathy frequently occurs in patients with MM and is often associated with bortezomib or thalidomide treatment (27, 28). Only 4 patients (10.0%) in the present study experienced neuropathic events (all Grade 1/2), all of whom had a history of neuropathy. This low rate of neuropathic events is notable, considering that most patients (82.5%) in this study had a history of neuropathy and had previously received bortezomib. These early results suggest that the CRd combination, like single-agent carfilzomib (11), is not associated with substantial treatment-emergent PN or worsening of existing neuropathy.

Several AEs observed in this study have not typically been reported for single-agent carfilzomib, and may be related to the other drugs in the combination or the combination itself. Hyperglycemia, for instance, is a well-known side-effect of glucocorticoids, and has been reported with the use of dexamethasone alone or in combination with lenalidomide, thalidomide, or bortezomib (6, 24, 29). In a separate study, hyperglycemia was observed in 22.7% of patients when carfilzomib was given in combination with dexamethasone (40 mg weekly) (30), consistent with the incidence reported here. Hyperglycemia in the present study was managed with oral hypoglycemic agents or insulin, and did not lead to dose reduction. Likewise, rash has not been commonly reported with single-agent carfilzomib, but has been seen in earlier studies with lenalidomide, dexamethasone, and the RD regimen (31–33) and is commonly observed in clinical practice.

At all doses tested, carfilzomib administration resulted in >80% proteasome inhibition in whole blood and PBMC samples. This level of inhibition was consistent with the inhibition observed with single-agent carfilzomib (15), suggesting that the addition of lenalidomide and dexamethasone does not adversely affect the PDn of carfilzomib. Robust and sustained proteasome inhibition, as well as the notable ORR, DOR, and PFS, suggest promising antimyeloma activity with CRd in patients with relapsed or progressive MM, that will need to be confirmed in larger, controlled studies.

The safety and efficacy of the highest dose of CRd is being further evaluated in an expansion cohort with an additional 44 patients with relapsed or progressive MM, results of which will be reported separately. CRd is also being investigated in other Phase II and III clinical trials. A large Phase III randomized, controlled trial (CArfilzomib, lenalidomide, and dexamethaSone versus lenalidomide and dexamethasone for the treatment of PatIents with RelapsEd multiple myeloma [ASPIRE]; NCT01080391) is evaluating CRd head-to-head with Rd in patients with MM that has relapsed after treatment with 1–3 prior regimens (34). Two phase 2 studies in patients with newly diagnosed MM (NCT010129054 and NCT01402284) are also ongoing. Initial findings from the latter 2 trials are encouraging, with the depth of response improving with prolonged treatment (35, 36). Taken together, these data further support the safety and efficacy of the CRd combination.

Statement of Translational Relevance.

Carfilzomib is a proteasome inhibitor recently approved in the United States for the treatment of patients with relapsed and refractory multiple myeloma. Combining the proteasome inhibitor bortezomib with other antimyeloma agents can improve antitumor activity, although doses tolerated in combination—particularly for bortezomib with lenalidomide—are lower than those tolerated for either agent alone. Here we present results from the first Phase I dose-escalation study of carfilzomib in combination with lenalidomide and dexamethasone (CRd) in patients with relapsed or progressive MM. These data show that CRd is well tolerated at the maximum planned dose—carfilzomib 20/27 mg/m², lenalidomide 25 mg, and dexamethasone 40 mg—and demonstrates encouraging activity in patients with no Grade 3/4 neuropathy. Combination therapy did not impact the extent of proteasome inhibition. Based on these results, the maximum planned dose of CRd is being further evaluated in a Phase II dose-expansion study.