‘Primary therapy for patients with multiple myeloma (MM) has thankfully become an exciting area of novel choices,” noted Paul Richardson, MD, of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, in Boston. Although median survival has improved to nearly 5 years with standard treatments, he added, “we obviously need to do much better.”
Our growing understanding of cellular mechanisms, proteins, and key signal transduction factors “has led to a tremendous opportunity in the context of new drug development,” Dr. Richardson explained. A key feature of thalidomide and related immunomodulatory drugs, is that they attack multiple targets in the microenvironment of the myeloma cell. The effects of these agents include apoptosis; inhibition of angiogenesis, MM cell adhesion to bone marrow stem cells, and cytokine circuits; and an enhanced host immune response. Similarly, the first-in-its-class proteasome inhibitor bortezomib (Velcade) directly targets the myeloma cell, but also targets the interaction between the tumor cell and the bone marrow microenvironment.
A key goal of induction therapy is to improve complete response (CR) rates, and the myriad combinations of agents being studied in clinical trials may play a positive role. Reaching higher rates of CR and partial response (PR) may optimize stem cell transplantation (SCT) and possibly enhance therapeutic outcomes in non-transplant candidates, said Dr. Richardson.
The efficacy of thalidomide/dexamethasone in newly diagnosed, untreated MM, which has been confirmed in a series of phase II studies, has led to phase III studies, such as the Eastern Cooperative Oncology Group (ECOG) E1A00 trial (Rajkumar V et al. J Clin Oncol 2006;24:431). When this drug combination was compared with high-dose dexamethasone alone, superior response rates (63% vs 41%) but more adverse events, particularly thromboembolic disease, were associated with thalidomide/dexamethasone. For patients progressing to transplantation, adequate stem cell harvest was achieved with both thalidomide/dexamethasone and dexamethasone alone. The investigators recommended that the higher response rate of the combination be weighed against its increased toxicity and that prophylaxis for deep-vein thrombosis be used with this regimen.
To improve the side-effect profile of the previous regimen, Rajkumar and colleagues at the Mayo Clinic performed a phase II trial using lenalidomide (Revlimid) plus dexamethasone as initial therapy for newly diagnosed MM (Blood 2005;106:40504053). A total of 91% of patients achieved a partial response, with 32% achieving a very good partial response and 6% achieving a complete response. Dr. Richardson described these results as “very compelling evidence” of the activity of this combination. In addition, the nonhematologic side effects were manageable, according to the investigators, and “some of the neuropathy seen with thalidomide was not seen with this combination,” added Dr. Richardson. Thromboprophylaxis was used in this study, and only one significant thromboembolic event was reported. The time to response was rapid, and stem cells were collected successfully.
“Given the compelling results and the high rates of response seen with monotherapy with bortezomib in the relapsed/refractory setting,” said Dr. Richardson, the drug has been studied in the up-front setting as well. In a study of 63 evaluable patients with untreated MM, bortezomib monotherapy was associated with an overall response rate of 40% and a complete response rate of 10%. (Anderson K et al. J Clin Oncol 2006;24[18S]:7504). Regarding its safety profile, transient thrombocytopenia and neutropenia were manageable, according to Dr. Richardson, one of the co-investigators, and although peripheral neuropathy was a challenge in treated patients, symptoms seemed to improve with dose modification in most cases. Interestingly, there was not one case of deep-vein thrombosis, and Dr. Richardson referred to emerging data “suggesting that bortezomib may actually have protective effects in the context of this prothrombotic state.”
Bortezomib combinations for newly diagnosed MM have also undergone evaluation. Several trials with bortezomib and dexamethasone have confirmed the efficacy of this combination, with positive overall response rates in two American studies of more than 90%, reported Dr. Richardson. The addition of thalidomide to this combination (VTD regimen) produced a higher response rate than that seen in prior series with just thalidomide/dexamethasone (92% vs 68%). “No serious complications were associated with the VTD regimen,” he added.
Different combinations of agents that include oral melphalan (Alkeran) and prednisone (MP regimen) have demonstrated efficacy in elderly patients with newly diagnosed MM. In a multicenter, randomized trial of 255 patients between the ages of 60 and 85 years, higher response rates and longer event-free survival were achieved with first-line MP plus thalidomide (MPT regimen) compared with MP alone (Palumbo A et al. Lancet 2006;367:825831). Combined CR and PR rates were 76% for the MPT arm and 48% for the MP arm alone, and the 2-year event-free survival rates were 54% for patients receiving MPT and 27% for those who received MP. Although more grade 3/4 adverse events occurred with MPT, prophylaxis with enoxaparin (Lovenox) significantly reduced the rate of thromboembolism.
Another study of 447 elderly patients with newly diagnosed MM from 72 centers in France, Belgium, and Switzerland compared MP, MPT and a melphalan based regimen. MPT was far more effective than either standard front-line MP alone or intensive high-dose chemotherapy in improving both progression-free and overall survival rates, according to Facon and colleagues (J Clin Oncol 2006;24[18S]:1). “MPT trumped all three regimens in the context of survival advantage, and that was really a remarkable finding,” Dr. Richardson stated. The median survival was 54 months with MPT, compared with 32 months with MP and 39 months with high-dose chemotherapy. Safety concerns with MPT included the higher incidence of thrombosis and peripheral neuropathy associated with thalidomide; for future trials, the investigators suggested incorporating thromboprophylaxis as well as lowering the dose or shortening the duration of thalidomide therapy.
Another exciting combination for older patients with newly diagnosed MM, according to Dr. Richardson, is lenalidomide plus MP (R-MP). Palumbo et al (J Clin Oncol 2006;24[18S]:7518) reported that R-MP produced a significant response rate with a manageable toxicity profile. After 3 cycles of treatment, CR was observed in 10% of patients and PR was noted in 60%, they said. Furthermore, only one case of thromboembolism was recorded, and neuropathy was not detected. An update on these promising data is forthcoming.
If the new drugs described above continue to improve response rates in patients with MM, the role of high-dose therapy and autologous SCT may change. Currently, autologous SCT is the standard of care in myeloma because of its high response rate and relatively low morbidity and mortality, asserted William Bensinger, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. However, it is neither curative nor applicable to all patients. How to integrate these novel agents and combination regimens into the overall treatment strategy of patients with MM is a challenge, he added.
The most recent National Comprehensive Cancer Network (NCCN) treatment guidelines recognize the stratification of patients based on transplantation status. Patients who are transplant candidates should not receive stem cell toxins such alkylating agents as initial therapy. Therefore, initial options include thalidomide/dexamethasone (a category 1 option), Dr. Bensinger said, followed by lenalidomide/dexamethasone, bortezomib/dexamethasone, and then the more traditional regimens. For non-transplantation candidates MPT is considered a category 1 option, Dr. Bensinger explained, followed by MP and bortezomib. However, along with the impressive results linked with thalidomide and bortezomib comes excess toxicity, he added.
Achieving a CR appears to be important as a survival benefit, said Dr. Bensinger, but “the problem with many of the trials is that only a minority of patients achieve a CR. If less than half of your patients get a CR, you’re not likely to see big differences in median survival,” he reasoned. Dr. Bensinger also raised relevant unresolved questions: If patients experience a CR with conventional therapy, does that make them a better candidate for high-dose therapy? Does a CR with conventional therapy prior to high-dose therapy lead to a better outcome? Lastly, if there were better tools to define remission, could candidates for more aggressive therapy be identified?
Dr. Bensinger presented several strategies for achieving a CR with autologous SCT that have been explored, including tandem transplants, targeted radiotherapy, post-transplantation maintenance therapy, remission induction therapy before transplantation (such as bortezomib or immunomodulation with thalidomide derivatives), amifostine (Ethyol) with high-dose melphalan, and allogeneic SCT.
Most of the major tandem autologous transplant studies performed have not shown a significant difference in overall survival compared with single autografts, said Dr. Bensinger. Based on a subgroup analysis of some of these trials, it appears that patients in CR or near CR after the first autograft did not benefit from a second transplant, whereas patients with PR or stable disease did.
Early results with targeted radiotherapy indicate that it may be a viable way to improve the CR rate with SCT. In a small study out of the Mayo Clinic, the addition of targeted radiation with samarium-153-EDTMP to melphalan prior to autologous SCT was well tolerated with no major dose-limiting toxicities, reported Dr. Bensinger, and yielded an “impressive” 94% overall response rate.
Maintenance therapy after autologous SCT is the focus of an ongoing phase III Cancer and Leukemia Group B study (CALGB 100104). With a planned accrual of 462 patients, this trial is comparing lenalidomide with placebo. In addition, approaches to maintenance therapy including thalidomide have also been evaluated. In the IFM 99-02 trial, the use of thalidomide and pamidronate as maintenance therapy after tandem transplants offered highly significant event-free and overall survival advantages over observation or pamidronate alone, stated Dr. Richardson. Finally, data from the HOVON trial, a major study comparing thalidomide with bortezomib maintenance therapy for 2 years after autologous SCT, are forthcoming. Dr. Bensinger concluded that post-transplant maintenance therapy may be of benefit to some patients, although he prefers short courses of these agents rather than continuous use of them throughout treatment.
Remission induction therapy containing novel agents is being given before transplantation in an attempt to improve outcomes. According to Dr. Bensinger, bortezomib/dexamethasone given before SCT produced a 90% response rate, with 54% of patients in one study achieving either a CR or a solid PR. In an upcoming trial, traditional therapy will be compared with bortezomib/dexamethasone as induction therapy.
The use of amifostine in patients receiving high doses of melphalan in transplantation has also received some attention. In a randomized study, amifostine served as a radioprotectant in this population, reducing the incidence of mucositis, Dr. Bensinger said. In another multicenter trial using amifostine as cytoprotection in patients receiving escalating doses of melphalan (up to nearly 40% higher doses), 21 of 35 evaluable patients achieved a CR, “an extremely impressive CR rate with dose escalation of melphalan,” he added. Furthermore, Dr. Bensinger and colleagues at Fred Hutchinson Cancer Research Center are conducting a similar trial of amifostine in combination with standard versus high-dose melphalan therapy.
Finally, allogeneic SCT might represent an alternative strategy. Although still considered investigational, allogeneic reduced-intensity consolidation therapy appears to be a safe regimen that may reduce transplant-related mortality but increase relapse rates, concluded Dr. Bensinger.