IMiD-based Combination Strategies
As advocated by the preclinical trials demonstrating synergy between IMiDs and melphalan, six Phase III trials demonstrated improved response rates with the addition of thalidomide to MP (MPT) versus MP but significant differences in PFS and OS were demonstrated in only two studies favoring MPT arm.[64,65] The HOVON study and GIMEMA study had improved PFS but no OS improvement in the MPT arm (both studies had thalidomide maintenance until progression of the disease). The Turkish study demonstrated significant response rates but nonsignificant survival advantage after 6 months of MPT treatment. Increased incidence of drug-resistant clones to thalidomide at relapse or effective salvage regimens in the control group may have been the reason for the absence of survival advantage. A meta-analysis of these six Phase III trials demonstrated the MPT regimen has superior RR, superior PFS and marginally improved OS with minimal additional toxicity compared with the use of MP alone.
Finally, the combination of the IMiD lenalidomide with bortezomib was also predicted to exhibit synergism in preclinical models and has been tested in clinical trials, in both patient groups with relapsed and newly diagnosed myeloma. Among relapsed myeloma patients, the ORR was 64% for the lenalidomide, bortezomib and dexamethasone (RVD) combination; and in the newly diagnosed myeloma patients, ORR was 98%. A total of 36% of the newly diagnosed patients achieved a CR/nCR. However, addition of more drugs is not always beneficial. From the Phase II EVOLUTION study that compared three arms (RVD; lenalidomide, bortezomib cytoxan and dexamethasone [RVCD]; bortezomib cytoxan and dexamethasone [VCD]), the efficacy of RVCD was similar to RVD with CR rate of 24% in both arms. Patients who achieved increased CR had MRD negativity in 48% versus 75% in RVCD versus RVD arms, respectively. The four-drug combination did not result in an increase in response rates but was associated with increased incidence of hematologic toxicities. As seen previously with VMPT, this study also suggests that with quadruplet combinations in conjunction with cytotoxic agents, the toxicities could outweigh the benefits of the potential anti-tumoral effects.
In addition to the effects of lenalidomide on directly inducing myeloma cell apoptosis via caspase-8, lenalidomide, which was originally developed as a TNF-a inhibitor, also exhibited immunomodulatory activity, perhaps more than thalidomide. Lenalidomide enhances host anti-tumor responses, natural killer T cell (NKT) function, increases T-cell secretion of IL2 and increases overall immune activation. Given these immune-based properties of lenalidomide, a strong argument can be made based on the preclinical and clinical rationale for combining lenalidomide with other similar 'immune based' treatment approaches, such as monoclonal antibodies, vaccines and so on. Clinical data show that responses with thalidomide are associated with increased IL2 and IFN-g secretion, a resultant effect of an increase in NKT cell number and/or function. For lenalidomide, data support ligand-dependent activation of NKT cell expansion following exposure to lenalidomide, both among normal healthy volunteers and myeloma patients. NKT cells expanded in the presence of lenalidomide had greater ability to secrete IFN-g in vitro too. As an extension of these observations, Tai et al. demonstrated in vitro that addition of lenalidomide to SGN-40, a monoclonal antibody targeting CD40, significantly enhances the antimyeloma efficacy in primary human myeloma cells.
From a clinical perspective, this preclinical concept has been validated by clinical trials combining the CS1 antibody elotuzomab with lenalidomide and low-dose dexamethasone. In a Phase I/II trial combining escalating doses of elotuzumab with lenalidomide plus low-dose dexamethasone, we demonstrated an ORR of 82%, with 96% of patients who had not previously received lenalidomide responding to the combination. Median TTP for this Phase II study has not been reached with a median follow-up of 16.4 months. Further Phase III trials are ongoing with this combination. This impressive activity occurred in the setting of no single agent activity for the antibody alone. Owing to this rationale, lenalidomide in combination with monoclonal antibody may be a promising therapeutic strategy that enhances the efficacy of lenalidomide; it is currently being tested in Phase III clinical trials.
With the newer third-generation IMiDs, early studies show enhanced activity in combination with other agents. In the relapsed setting, combination exerts increased antimyeloma effects and improved OS compared with the sequential regimens. This was demonstrated in the Phase I/II study comparing pomalidomide alone or in combination with low-dose dexamethasone (Pd) in patients with R/R MM who have been previously exposed to bortezomib and lenalidomide (60% patients refractory to bortezomib and lenalidomide). MTD was determined to be 4 mg on days 1–21 of the 28-day cycle. In the Phase II portion, ORR was 13% for pomolidomide-alone arm versus 34% in the Pd arm. Median OS was 14 months versus 17 months, respectively. In a similar patient population, IFM 2009-02 tested Pd in patients refractory to bortezomib and lenalidomide. The median duration of response with Pd is 8.1 months; median OS is 13.4 months. Adding a third agent improved these responses. Cyclophosphamide was combined with pomalidomide and prednisone in a Phase I/II study for R/R MM. Among this patient group where 56% of the patients were lenalidomide refractory, 66% PR and 28% VGPR were seen after a median of four cycles. Median PFS and OS were not reached after four cycles. Another regimen for R/R MM presented by Mark et al. substituted cyclophosphamide from the above study to clarithromycin (Biaxin® [Abbott Laboratories, IL, USA], pomalidomide, dexamethasone), and demonstrated 20% CR and 60% and median PFS of 8.1 months. At 9.4 months, 85% of patients were alive, suggesting that combining the drugs in the setting of R/R MM disease improved responses and increased PFS and OS, and that saving the treatment options for the future is not beneficial.
Expert Rev Hematol. 2012;5(5):533-545. © 2012 Expert Reviews Ltd.