Retreatment With Bortezomib(Drug information on bortezomib)-Based Therapy
Prospective data have become available on patients with relapsed and refractory MM who were heavily pretreated with bortezomib as part of initial or later therapy for their disease. An open-label phase IV trial, performed at 23 community-based centers, assessed retreatment in patients who responded to initial bortezomib therapy for ≥ 4 months and received no interim anti-myeloma therapy before bortezomib retreatment. The median number of prior lines of therapy was 4 (range, 1–8). Of the 32 subjects, 8 were retreated with bortezomib monotherapy and 24 received bortezomib/dexamethasone. The ORR with retreatment was 50%, and the median progression-free interval was 6.6 months. Thirteen patients (41%) had new or worsening PN during bortezomib retreatment, and 4 patients had toxicities that were considered at least possibly related to bortezomib: grade 2 neutropenia, grade 2/3 thrombocytopenia, and one case of reversible grade 3 congestive heart failure.
Encouraging responses to bortezomib retreatment, alone or with dexamethasone(Drug information on dexamethasone), have also been observed in an ongoing international phase II trial. Patients were eligible if they responded to a bortezomib-based regimen as most recent treatment and had a treatment-free interval of ≥ 6 months. Fifty-nine percent had received at least three lines of prior therapy. In 97 patients evaluable for efficacy, the ORR was 27%, with 3% CR. The ORR was similar for the 69% of patients treated with bortezomib/dexamethasone and those who received bortezomib alone. Of the 100 patients in the safety analysis, 6% discontinued treatment due to grade 3 PN and 4% due to other treatment-emergent adverse events thought to be bortezomib-related.
The combination of bortezomib and pegylated liposomal doxorubicin(Drug information on doxorubicin) (PLD; Doxil) was FDA-approved in 2007 for patients who have received at least one prior anti-myeloma therapy and have not received bortezomib. Approval was based on data from the phase III DOXIL-MMY-3001 trial, which demonstrated that the combination reduced the risk of disease progression by 45% over bortezomib alone and resulted in significantly better OS (Table 2). An updated analysis (median follow-up, 11 months) confirmed the improvement in TTP and OS. The safety profile of the combination was consistent with the known toxicities of the two agents, but there was an increase in grade 3/4 adverse events in the bortezomib/PLD group—mostly myelosuppression and gastrointestinal events. Despite prior anthracycline therapy in nearly 70% of patients, the addition of PLD to bortezomib did not significantly increase cardiac toxicity, although a greater frequency of cardiac events was noted.
Subgroup analyses showed that TTP was superior with bortezomib/PLD regardless of previous anthracycline exposure, the number of lines of prior therapy, disease stage, or time since initial diagnosis.[24,25] In the early-relapse group (relapse within 12 months after autologous stem cell transplantation [ASCT]), 1-year survival was significantly better with bortezomib/PLD than with bortezomib alone.
The phase III registration trials of lenalidomide (Revlimid) for relapsed and refractory MM compared lenalidomide/dexamethasone (len/dex) with high-dose dexamethasone alone.[9,10] Both studies (MM-009, conducted in North America, and MM-010, conducted in Europe, Israel, and Australia) showed that len/dex was superior with respect to response rates, TTP, and OS (Table 2). High ORR, long TTP, and manageable adverse events with len/dex were observed in patients ≥ 65 years old and in those with certain high-risk disease features (IgA subtype, advanced Durie-Salmon stage, or Eastern Cooperative Oncology Group performance status ≥ 1). Len/dex was FDA-approved for relapsed and refractory MM in 2006.
In the phase III trials, the grade 3/4 adverse events of importance with len/dex included venous thromboembolism (VTE), thrombocytopenia, and neutropenia.[9,10] Recent data from an expanded access program showed that among 1,438 patients who received len/dex for relapsed and refractory MM, the most common grade ≥ 3 toxicities were hematologic (45%). Grade ≥ 3 VTE occurred in 6% of patients. The most common nonhematologic serious adverse events included pneumonia (8%) and pyrexia (4%); toxicities proved generally manageable, and rates of PN and constipation were very low.
A pooled update of MM-009/010, with median follow-up of 48 months, showed a significant survival benefit of len/dex even with 48% of patients in the control arm crossing over to lenalidomide at the time of disease progression or study unblinding.
In certain instances, dexamethasone dose adjustments are warranted in patients with relapsed and refractory MM, particularly elderly individuals and those on combination therapy. In MM-009/010, after four cycles, dexamethasone 40 mg was administered only on days 1 to 4. If needed due to toxicities, dexamethasone dose reductions included the following: 40 mg on days 1 to 4 every 2 weeks, 40 mg on days 1 to 4 every 4 weeks, and 20 mg on days 1 to 4 every 4 weeks. Dose reduction resulted in better efficacy and improved tolerability, according to a post hoc analysis of 233 patients.
Lenalidomide can also be administered as a single agent for patients in whom a steroid-sparing approach is preferred. Lenalidomide monotherapy produced meaningful long-term benefit in patients with relapsed and refractory MM in a single-arm, open-label phase II trial. The primary endpoint of CR plus PR was achieved in 26% of 222 patients. Of note, the ORR was similar regardless of type of prior treatment (thalidomide [Thalomid], bortezomib, or ASCT) and number of prior treatment regimens (≤ 2 vs ≥ 3). The response rates, TTP, and OS were not as promising as in the registration trials of len/dex,[9,10] but those studies enrolled less heavily pretreated patients and excluded dexamethasone-resistant patients. The most common grade 3/4 adverse events in the trial of lenalidomide monotherapy were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which were manageable with dose reduction. Grade 3/4 febrile neutropenia occurred in 4% of patients and grade 3/4 thrombotic events in 5%. Grade 2 PN occurred in 3% of patients, and there were no cases of grade 3/4 PN, with excellent tolerability of single-agent lenalidomide overall.
Preclinical studies demonstrating synergy between lenalidomide and bortezomib provided the rationale for the development of lenalidomide/bortezomib/dexamethasone (RVD) in relapsed and refractory MM. In a phase II trial, RVD was highly active in patients with relapsed and refractory MM (Table 2), including ORRs of 73% in patients with adverse cytogenetics, 57% in patients with prior bortezomib therapy, and 57% in patients with prior thalidomide(Drug information on thalidomide) therapy. Toxicities were manageable and included grade 1/2 myelosuppression, grade 3 atrial fibrillation, and grade 3 PN. One patient died on-study from fungal pneumonia, possibly due to dexamethasone, but treatment was otherwise well tolerated. This triplet is now also being investigated in the front-line setting.