Patient Characteristics, Disposition, and Determination of MTD
A total of 38 patients were enrolled, including 12 patients (32%) with relapsed and 26 patients (68%) with relapsed/refractory MM. Baseline patient characteristics are listed in ; the median number of prior treatments was five (range, one to 14). Prior therapies, received at any time point, included dexamethasone (89%), thalidomide (87%), bortezomib (55%), stem-cell transplantation (61%), and lenalidomide (18%). Among 38 patients, 24 (63%) were refractory to thalidomide, 16 (42%) were refractory to bortezomib, and six (16%) were refractory to lenalidomide.
Patient Demographic and Baseline Clinical Characteristics
Patient disposition is detailed in . Two patients (one each from dose levels 3 and 5) experienced rapid disease progression within cycle 1 and were not evaluable for response, assessment for DLT, and determination of the MTD; an additional patient was enrolled at each of these dose levels. One patient experienced DLT (transient grade 3 asymptomatic hyponatremia) in dose level 4, and two experienced DLT in dose level 6 (one grade 3 herpes zoster virus reactivation in a patient who was noncompliant with antiviral prophylaxis, and one grade 4 neutropenia that was reversed with dose reduction and G-CSF support). The MTD, therefore, was determined to be lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2.
Patient Disposition per Dose Level
Drug Exposure and Safety
Patients received a median of 10.5 treatment cycles of lenalidomide (range, one to 74 cycles) and a median of 10 cycles of bortezomib (range, one to 74 cycles). Dexamethasone was added on occurrence of progression for 18 patients (47%); the median duration of dexamethasone therapy was six cycles (range, one to 29 cycles). Thirteen patients (34%) received lenalidomide and bortezomib for more than 1 year. At data cutoff in November 2008, one patient remained on treatment after having received 74 cycles of lenalidomide and bortezomib. Treatment was discontinued in the remaining patients because of PD (n = 22; 58% of all patients), completion of protocol treatment (n = 4; 11% of all patients), unacceptable toxicity (n = 4; 11% of all patients), withdrawal of consent (n = 4; 11% of all patients), physician decision (n = 1; 3% of all patients), death as a result of aspiration pneumonia not considered treatment-related (n = 1; 3% of all patients), and reason unspecified (n = 1; 3% of all 38 patients).
Treatment-related AEs that occurred with a frequency of 25% or greater are listed in . Sensory PNY was reported in 16 patients (42%; 90% CI, 29% to 57%), including seven patients (18%) with grade 1 PNY and nine patients (24%) with grade 2 PNY. No grades 3 or 4 sensory PNY occurrences were observed. The most common grade 3 or greater toxicities include neutropenia (63%; 90% CI, 49% to 76%), thrombocytopenia (45%; 90% CI: 31% to 59%), anemia (18%; 90% CI, 9% to 32%), and leukopenia (18%; 90% CI, 9% to 32%). Other treatment-related, grades 1 or 2 toxicities (in 25% or more of patients) included diarrhea (39%), pruritus (29%), musculoskeletal/soft tissue conditions (specifically, cramps; 26%), and nausea (26%). One patient experienced deep-vein thrombosis (DVT) while receiving lenalidomide alone plus low-molecular-weight heparin (LMWH).
Summary of Treatment-Related Adverse Events
Four patients discontinued treatment because of the following unacceptable toxicities: one dexamethasone-related toxicity, one occurrence of pneumonitis considered possibly related to lenalidomide therapy, and two persistent occurrences of cytopenias that also were possibly related to lenalidomide therapy. Four patients required dose reductions for lenalidomide, 14 for bortezomib, 11 for both agents, and six for dexamethasone. Ninety-five percent of the lenalidomide dose modifications and 82% of the bortezomib dose modifications occurred within the first eight cycles.
For those patients who experienced sensory PNY, supplements, including folate, B-complex vitamins, and amino-acids, were administered. Analgesics used included duloxetine, acetaminophen, gabapentin, and pregabalin. Eighteen patients (47%) received treatment (or prophylaxis) for sensory neuropathy that was present or that developed during the study. Fifteen patients (39%) received thromboprophylaxis; nine patients received aspirin (81 to 325 mg/d), one received warfarin alone, one received LMWH alone, and four patients received aspirin and warfarin, either simultaneously (n = 2) or warfarin followed by aspirin (n = 2).
Thirty-six patients were included in the response-evaluable population. MR or better to lenalidomide combined with bortezomib was observed in 61% of the patients (90% CI, 46% to 75%), which included an 8% CR/nCR rate (); 36% of patients achieved MR or greater at the MTD. Among the 22 responders, the median TTR was 1.4 months (range, 0.7 to 39 months), and the median DOR was 10.8 months (95% CI, 1.1 to 33.3 months). Among 18 patients who received dexamethasone because of PD, 83% (90% CI, 62% to 95%) had at least SD with PR in three patients (17%), MR in two patients (11%), and SD in 10 patients (56%); the median TTR was 0.9 months.
Best Response to Lenalidomide Plus Bortezomib Combination Therapy
Among the 24 patients who were refractory to prior bortezomib, lenalidomide, and/or thalidomide, six (25%; 90% CI, 12% to 44%) achieved at least PR, and 12 (50%; 90% CI, 32% to 68%) achieved at least MR on this trial. Among the seven patients refractory to thalidomide, two achieved CR/nCR, one achieved PR, one achieved MR, and three had SD. Among two patients refractory to bortezomib, one achieved an MR, and one had PD. Among nine patients refractory to bortezomib and thalidomide, one achieved PR, three achieved MR, four had SD, and one was unevaluable for response. Among three patients refractory to lenalidomide and thalidomide, one achieved a PR, one achieved MR, and one had PD. Among three patients refractory to all three agents, one achieved nCR, and two had SD.
TTE and OS Data
For the 36 response-evaluable patients who received lenalidomide plus bortezomib, the median TTP was 7.7 months (A); an estimated 42% (95% CI, 25% to 59%) and 18% (95% CI, 5% to 31%) of patients had not experienced progression at 1 and 2 years, respectively. Median PFS was 6.9 months (B), and the estimated 1-year and 2-year PFS rates were 44% (95% CI, 27% to 60%) and 20% (95% CI, 7% to 34%), respectively. During a median follow-up of 36 months, 19 patients have died and 17 remain alive, as of November 2008. The median OS was 37 months (C), and the estimated 1-year and 2-year OS rates were 77% (95% CI, 63% to 91%) and 50% (95% CI, 33% to 67%), respectively. All nine patients with follow-up of 24 to 37 months are currently alive and censored; therefore, median OS may change with additional follow-up.
Kaplan-Meier estimates (in months) and 95% CIs of (A) time to progression, (B) progression-free survival, and (C) overall survival in 36 patients.
To date, 13 of the 18 patients who received dexamethasone have subsequently experienced progression, and the median TTP was 6.1 months (95% CI, 2.7% to 14.6%) from the time of dexamethasone addition.