Purpose: Carfilzomib, a selective proteasome inhibitor, has shown 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 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly.

Results: Forty patients enrolled in six 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 after dose was more than 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 the 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. Clin Cancer Res; 19(8); 2248–56. ©2013 AACR.

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 the 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 multiple myeloma. 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 shows encouraging activity in patients with no grade 3/4 neuropathy. Combination therapy did not impact the extent of proteasome inhibition. On the basis of these results, the maximum planned dose of CRd is being further evaluated in a phase II dose-expansion study.

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, 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 multiple myeloma 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 multiple myeloma led to good antitumor activity, but with notable toxicities (5, 6). In a phase II 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 of 26 months (6). However, grade 1/2 peripheral neuropathy was reported in 64% of patients, with 40% of patients requiring a dose reduction for any reason (6).

Carfilzomib (Onyx Pharmaceuticals; ref. 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). On the basis of findings from the pivotal trial, PX-171-003-A1 (NCT00511238; ref. 9) single-agent carfilzomib was recently approved in the United States for the treatment of patients with multiple myeloma who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have shown 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 peripheral neuropathy (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 multiple myeloma. 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.

Patients

Patients with symptomatic multiple myeloma and relapsed or progressive disease after 1 to 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 to a prior therapy, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 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 nonsecretory or hyposecretory multiple myeloma or primary refractory multiple myeloma (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 before 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 Harmonisation 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. 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 to 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 to 21; and dexamethasone was administered once per week on days 1, 8, 15, and 22.

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 intravenously, and carfilzomib was administered intravenously over 2 to 10 minutes. 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.

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 intravenously, and carfilzomib was administered intravenously over 2 to 10 minutes. 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.

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Table 1.

Dose-limiting toxicity criteria

Nonhematologic:
  • ≥Grade 2 neuropathy with pain

  • ≥Grade 3 nonhematologic 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 to 4 thrombocytopenia associated with bleeding

  • Treatment delay > 21 days for toxicity

 
Nonhematologic:
  • ≥Grade 2 neuropathy with pain

  • ≥Grade 3 nonhematologic 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 to 4 thrombocytopenia associated with bleeding

  • Treatment delay > 21 days for toxicity

 

Abbreviation: ANC, absolute neutrophil count.

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 before subsequent carfilzomib doses. Prophylactic antibiotic (cycle 1 only), antiviral agents, proton pump inhibitor, and hydration were also required. Aspirin (81–325 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 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 stable disease or better was maintained through 12 cycles, patients could receive up to 6 additional treatment cycles as part of this study on the modified carfilzomib schedule until development of progressive disease 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 this study following a protocol amendment that removed the treatment cap.

Study assessments

Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0; ref. 16). Serious adverse events 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 Uniform Response Criteria: stringent complete response (sCR), complete response, very good partial response (VGPR), PR, stable disease, and progressive disease (17), with the addition of minimal response according to the European Bone Marrow Transplant criteria (18). Calculated efficacy variables included best overall response rate (ORR, PR or better), clinical benefit rate (CBR, minimal response or better), duration of response (DOR), duration of clinical benefit (DCB), and progression-free survival (PFS).

Whole blood samples for pharmacodynamic assays were collected predose and 60 minutes postdose 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).

Statistical analysis

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.

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 ECOG performance status of 0 to 1 (Table 2). The majority of patients had received 2 or more prior multiple myeloma 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 stable disease or progressive disease, or discontinued treatment due to progressive disease), 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, y, 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, y, 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) 
N = 40
Male, n (%) 22 (55) 
Age, y, 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, y, 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 as 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 before completing the protocol-specified number of cycles, 19 discontinued due to progressive disease, 4 discontinued due to an adverse event, 2 withdrew consent, and 3 discontinued for other reasons. The 4 patients who discontinued primarily due to an adverse event reported 7 adverse events leading to discontinuation of CRd: pyrexia, influenza, neutropenia and thrombocytopenia, and diarrhea, dehydration, and urinary tract infection. Among these 7 adverse events, 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 adverse event of any grade during CRd therapy (Table 3). Grade 3 or 4 adverse events were reported in 97.5% of patients, and 52.5% experienced a serious adverse event. Adverse event rates among cohorts were comparable, but the limited sample size precludes any statistical comparisons. The most common adverse events 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 adverse events 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 adverse events of heart failure, arrhythmia, cardiomyopathy, or ischemic heart disease during this study, whereas 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 adverse event 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 1/2Grade 3/4All 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) 
Nonhematologic 
 Fatigue 22 (55.0) 3 (7.5) 25 (62.5) 
 Diarrhea 19 (47.5) 2 (5.0) 21 (52.5) 
 Cough 17 (42.5) 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) 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) 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) 10 (25.0) 
 Pain in extremity 10 (25.0) 10 (25.0) 
 Paraesthesia 10 (25.0) 10 (25.0) 
 Arthralgia 9 (22.5) 9 (22.5) 
 Hyponatremia 3 (7.5) 6 (15.0) 9 (22.5) 
 Insomnia 9 (22.5) 9 (22.5) 
 Dizziness 8 (20.0) 8 (20.0) 
 Hypomagnesemia 8 (20.0) 8 (20.0) 
 Hypophosphatemia 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) 
Adverse event, n (%)Grade 1/2Grade 3/4All 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) 
Nonhematologic 
 Fatigue 22 (55.0) 3 (7.5) 25 (62.5) 
 Diarrhea 19 (47.5) 2 (5.0) 21 (52.5) 
 Cough 17 (42.5) 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) 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) 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) 10 (25.0) 
 Pain in extremity 10 (25.0) 10 (25.0) 
 Paraesthesia 10 (25.0) 10 (25.0) 
 Arthralgia 9 (22.5) 9 (22.5) 
 Hyponatremia 3 (7.5) 6 (15.0) 9 (22.5) 
 Insomnia 9 (22.5) 9 (22.5) 
 Dizziness 8 (20.0) 8 (20.0) 
 Hypomagnesemia 8 (20.0) 8 (20.0) 
 Hypophosphatemia 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% confidence interval (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])
123456
(15/10/40)(15/15/40)(15/20/40)(20/20/40)(20/25/40)(27/25/40)Overall
n = 6n = 6n = 8n = 6n = 6n = 8n = 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 
Dose cohort (CFZ [mg/m2] + LEN [mg] + DEX [mg])
123456
(15/10/40)(15/15/40)(15/20/40)(20/20/40)(20/25/40)(27/25/40)Overall
n = 6n = 6n = 8n = 6n = 6n = 8n = 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 

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

aPartial response or better.

bMinimal response or better.

Pharmacodynamics

Pharmacodynamics analysis revealed significant proteasome inhibition after carfilzomib dosing (Fig. 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 before 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 predose 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; PBMC, peripheral blood mononuclear cells; SEM, standard error of the mean.

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 predose 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; PBMC, peripheral blood mononuclear cells; SEM, standard error of the mean.

Close modal

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 multiple myeloma after 1 to 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, showed encouraging response rates.

Although the majority of patients experienced grade 3/4 adverse events, few patients required dose reduction or treatment discontinuation due to toxicity. Grade 3/4 adverse events in the current phase I study, primarily hematologic toxicities, are consistent with earlier studies in patients with advanced multiple myeloma that used similar doses of single-agent carfilzomib, (9, 20–22) or the combination of lenalidomide and dexamethasone (RD) or RVD (5, 6, 23–25). Among nonhematologic adverse events of any grade, cough and dyspnea were reported in more than one-third of patients, a finding consistent with previous studies with single-agent carfilzomib (26). These adverse events 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 multiple myeloma receiving 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 with those from a phase II study of RVD in patients with relapsed and relapsed/refractory multiple myeloma (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 multiple myeloma 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 peripheral neuropathy or worsening of existing neuropathy.

Several adverse events 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; ref. 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 more than 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 pharmacodynamics 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 multiple myeloma, 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 multiple myeloma, 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 multiple myeloma that had relapsed after treatment with 1 to 3 prior regimens (34). Two phase II studies in patients with newly diagnosed multiple myeloma (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.

R. Niesvizky has a commercial research grant, honoraria from speakers' bureau, and is a consultant/advisory board member of Onyx Pharmaceuticals, Inc., Celgene, and Millenium. T.G. Martin has honoraria from speakers' bureau of Celgene. W.I. Bensinger has a commercial research grant from Onyx Pharmaceuticals and Celgene, has honoraria from speakers' bureau from Celgene, and is a consultant/advisory board member of Onyx Pharmaceuticals, Inc. and Celgene. M. Alsina has honoraria from speakers' bureau from Onyx Pharmaceuticals, Inc. D.S. Siegel has honoraria from speakers' bureau from Celgene and Onyx Pharmaceuticals, Inc. R.Z. Orlowski has commercial research grant and is a consultant/advisory board member of Onyx Pharmaceuticals, Inc. M. Wang has a commercial research grant and has honoraria from speakers' bureau from Onyx Pharmaceuticals, Inc. No potential conflicts of interest were disclosed by the other authors.

Conception and design: R. Niesvizky, W.I. Bensinger, M. Alsina, L.A. Kunkel, A.F. Wong, R.Z. Orlowski

Development of methodology: M. Alsina, L.A. Kunkel, A.F. Wong

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): T.G. Martin III, W.I. Bensinger, M. Alsina, D.S. Siegel, A.F. Wong, S. Lee, R.Z. Orlowski, M. Wang

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R. Niesvizky, W.I. Bensinger, D.S. Siegel, A.F. Wong, S. Lee, M. Wang

Writing, review, and/or revision of the manuscript: R. Niesvizky, T.G. Martin III, W.I. Bensinger, M. Alsina, D.S. Siegel, L.A. Kunkel, A.F. Wong, S. Lee, M. Wang

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Lee

Study supervision: R. Niesvizky, L.A. Kunkel, A. M. Wang

The authors thank all of the patients who contributed to this study and their families. The authors also thank the staff from the additional participating study sites and all of the participating research nurses and data coordinators. Critical review was provided by Thomas Renau (Onyx Pharmaceuticals, Inc.).

The study was supported by Onyx Pharmaceuticals, Inc. Study drugs were provided free of charge by Celgene (lenalidomide) and Onyx (carfilzomib and dexamethasone). Melanie Watson (Fishawack Communications) provided medical writing assistance, which was funded by Onyx Pharmaceuticals, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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