Relapse/Refractory Myeloma Patient: Potential Treatment Guidelines
Authors: Jesús F. San Miguel
Journal: Journal of Clinical Oncology (2009)

The survival of patients with multiple myeloma (MM) has significantly increased over the past decade, mainly due to the efficacy of novel agents such as thalidomide, bortezomib, and lenalidomide, used as rescue therapies. Thus, at the Mayo Clinic, it was observed that patients relapsing after the year 2000 had a 12-month improvement in survival from the time of relapse compared with those who relapsed before this date (23.9 v 11.8 months). Nevertheless, the duration of subsequent responses to rescue treatments is progressively shorter. Therefore, the current goals in relapsed MM are to optimize the efficacy of the three aforementioned drugs through their most appropriate combinations, to determine the optimal sequences of treatment, and to promote active clinical research into new experimental agents. In the context of relapse, we are probably moving from one extreme to the other, whereby no drugs were available for relapsed patients until 2000, but many options have since become available. These new treatment options are usually based on the results of small pilot studies with short follow-up, and consequently the field of rescue treatments has become a tower of Babel in which numerous physicians demand appropriate guidelines and more uniform treatment approaches. In this issue of Journal of Clinical Oncology, Richardson et al report on a phase I, dose escalation study, designed to evaluate the safety and maximum tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or relapsed and refractory MM. The addition of dexamethasone was permitted after two cycles in patients with progressive disease. Thirty-eight patients were enrolled (32% with relapsed and 68% with relapsed and refractory MM), 63% of whom were previously refractory to thalidomide, 42% to bortezomib and 16% to lenalidomide. The MTD was established at 15 mg and 1.0 mg for lenalidomide (for 14 days) and bortezomib (days 1, 4, 8, 11 every 3 weeks), respectively. Sixty-one percent of patients achieved at least minor responses (including 39% partial response [PR] and 8% complete response/ near complete response) with a median time to progression of 7.7 months. Among the 18 patients who received dexamethasone due to progressive disease, 83% achieved at least stable disease, with 17% PR. Responses were also observed in patients previously refractory to the novel agents (50% minor responses, including 25% PR). Treatment was well tolerated, with only four discontinuations due to unacceptable toxicity. Most importantly, none of the patients experienced grade 3 or 4 peripheral neuropathy and there was only one case of deep vein thrombosis. What lessons can be learned from this study? First, these types of combinations should be supported by preclinical studies, as is the case with the Dana-Farber Cancer Center investigators who previously showed that lenalidomide reinforces the activity of both bortezomib and dexamethasone, probably through a dual caspase 8 and 9–mediated apoptotic pathway. Second, the study showed activity in patients previously refractory to bortezomib and immunomodulatory drugs (IMIDs), which suggests that the combination may resensitize previously resistant tumor cells. Nevertheless, to confirm this latter statement, the ideal setting would be a patient in whom the two last lines of therapy were based on bortezomib and lenalidomide, who showed no response and progressive disease under each treatment separately, but who then responded to the combination, providing that the dose of dexamethasone was equivalent. The third lesson concerns the MTD. As has been acknowledged by Richardson et al this could have been higher if appropriate antiviral and granulocyte colony-stimulating factor prophylaxis had been used. In fact, although comparison with newly diagnosed patients is not always appropriate because relapsed patients have fewer bone marrow reserves and do not tolerate treatment so well, in the first-line context, higher doses of lenalidomide (25 mg/d) and bortezomib (1.3 mg/m) are currently being combined. The fourth lesson concerns the addition of dexamethasone. In line with the preclinical studies and the clinical synergistic effect observed for lenalidomide plus dexamethasone, the addition of dexamethasone in this trial contributed to rescue patients with progressive disease. Accordingly, we would favor the use of the triplet (bortezomib, lenalidomide, and dexamethasone) instead of the doublet (bortezomib and lenalidomide). This is also supported by an ongoing phase II trial, conducted by the same group, showing 67% PR when using bortezomib, lenalidomide, and dexamethasone in relapse/refractory patients with MM, a figure clearly superior to the 39% PR obtained here with bortezomib and lenalidomide. In patients with relapse/refractory MM, the most relevant question is whether to use all the active drugs at the same time or sequentially. Moreover, it needs to be proved that the combination of a proteasome inhibitor and one IMID is superior to the combination of either of the two drugs plus an alkylating agent or anthracyclines with corticosteroids. In fact, similar results have been obtained with combinations such as bortezomib, cyclophosphamide, and dexamethasone or lenalidomide, doxorubicin, and dexamethasone, and this could be considered as an additional argument in favor of the sequential rather than simultaneous use of bortezomib and lenalidomide. On this basis, can guidelines for the treatment of patients with relapsed and refractory myeloma be proposed? The most important recommendation is probably that a careful and comprehensive clinical judgment should be made about three key factors: drugs used in previous lines of therapy and their efficacy, type of relapse, and patient characteristics. A detailed list of the drug combinations used (alkylating agent, IMID, or bortezomib based), with the degree of response obtained and the duration of responses, is critical in order to make decisions about the possibility of retreatment with the same drug or with a combination based on previously sensitive agents, and of avoiding drugs that have shown little or no efficacy and which will only contribute to increased toxicity. The type of relapse is also important, since, in the case of an aggressive relapse, multidrug combinations Editorial