For patients with multiple myeloma (MM) who experience relapse, important advances in medical therapies in the past decade have doubled the duration of survival, mainly because of the effectiveness of novel agents such as thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid). Eventually, however, refractory disease develops in almost all patients. Clinicians, who had few treatment options available to them before the year 2000, now have many new agents and combination therapies at their disposal for the treatment of relapsed/refractory MM. Although this represents a clear benefit, at the same time it has its own difficulty—namely, knowing which approach to use in individual patients based on the available evidence.
Unfortunately, while survival has increased, the duration of response to postrelapse therapies becomes progressively shorter, so clinicians must try to maximize the efficacy of available treatments through use of the most appropriate combinations and sequences of agents. This requires careful assessment of the patient's previous treatments and response, the characteristics of their disease/relapse, and their clinical status and history of comorbidities.
The current goals in relapsed MM are: (1) to optimize the efficacy of thalidomide, bortezomib, and lenalidomide through their most appropriate combinations; (2) to determine the optimal sequences of treatment; and (3) to promote active clinical research into new experimental agents. Here we present an approach to the assessment of patients with relapsed/refractory MM and the current evidence for various treatment options, as well as the considerations to bear in mind when developing an individualized treatment plan.
Relapse After Previous Treatment
The International Myeloma Working Group has developed criteria for defining progressive disease based on indicators of increasing disease and/or end-organ damage, which in turn can be used to identify patients with refractory or relapsed disease (Table).[2,4,5]
Relapse after thalidomide
The synthetic glutamic acid derivative thalidomide is an immunomodulator and was the first of the novel agents to gain widespread acceptance for the treatment of MM. The addition of thalidomide to standard therapies significantly improves response rates and survival in previously untreated patients, and it also improves survival when used as maintenance therapy after stem-cell transplant (SCT). National Comprehensive Cancer Network (NCCN) guidelines now recommend thalidomide-based regimens as one of the possible primary induction regimens for transplant and nontransplant patients, as well as for maintenance or salvage therapy. Consequently, an increasing number of relapsed/refractory patients are presenting after prior thalidomide exposure.
There is some evidence that patients who have previously received thalidomide obtain less benefit from subsequent treatment with novel agents than those who are thalidomide naive.[8-10] In both the Assessment of Proteasome Inhibition for Extending Remission (APEX) study and a pooled analysis of two phase III clinical trials (MM-009 and MM-010), patients who had received thalidomide previously had a lower overall response rate than those who were thalidomide naive.[8,9] In the APEX study, the thalidomide-experienced group also had a shorter time to progression (TTP; P = .004) and lower overall survival (P < .01) compared with thalidomide-naive patients. This is probably not a specific effect of thalidomide but something inherent to the tumor cells at relapse, since they are usually more resistant to rescue therapies than the original naive (non–treatment exposed) cells. In fact, previous thalidomide treatment did not affect the difference between the treatment groups studied; bortezomib (APEX) or lenalidomide + dexamethasone (MM-009/MM-010) therapies were significantly more effective than dexamethasone alone in both thalidomide-experienced and thalidomide-naive subgroups.[8,9] In addition, Sonneveld et al found that prior exposure to an immunodulatory drug (IMiD)—which was thalidomide in 94% of cases—did not affect the response to bortezomib and pegylated liposomal doxorubicin (PLD). Objective response rate, TTP, and overall survival were similar in patients who had and had not received IMiDs previously. Other researchers have also found that lenalidomide ± dexamethasone was similarly effective in thalidomide-pretreated and thalidomide-naive patients.[12-14] An interesting analysis was recently done of the ability of an IMiD to rescue patients previously refractory to a different IMiD. In patients who relapsed after thalidomide, 46% and 80% of patients were rescued by lenalidomide or pomalidomide, respectively.
On the basis of these data, it would be reasonable to change drug class and to use a bortezomib-based therapy in patients who have relapsed after thalidomide treatment, but the use of lenalidomide + dexamethasone is also feasible, particularly in those patients who are intolerant of thalidomide.
Relapse after lenalidomide
Lenalidomide is a second-generation immunomodulator (and the first IMiD); it is currently recommended in combination with dexamethasone for patients with relapsed/refractory MM. In addition, it is being used in newly diagnosed cases as primary induction therapy before SCT (bortezomib + lenalidomide + dexamethasone [VRD] or lenalidomide + low-dose dexamethasone [RD] regimen); in combination with low-dose dexamethasone for long-term treatment; with melphalan and prednisone as primary induction therapy in patients who are not SCT candidates; and as single-agent maintenance therapy.
Patients who relapse after lenalidomide are candidates for treatment with bortezomib + dexamethasone ± either an alkylating agent or an anthracycline. As previously mentioned, Sonneveld et al found no difference in the response to bortezomib ± PLD in patients who had previously received immunomodulators (principally thalidomide, but lenalidomide in 6% of cases) compared with those who were thalidomide- or lenalidomide-naive. In patients who relapse after lenalidomide and who are also refractory to or intolerant of bortezomib, it may be feasible to try a thalidomide-containing regimen as an alternative. Madan et al reported that 25% of patients who relapsed after or were refractory to lenalidomide responded to thalidomide, and 83% responded to pomalidomide.
Guglielmelli et al treated 20 patients who had relapsed after lenalidomide with thalidomide-containing regimens and achieved a clinical response rate of 40%, with an additional 40% of the patients having stable disease. Median progression-free survival (PFS) was 5.5 months and overall survival was 18 months. Similarly, the novel IMiD pomalidomide in combination with low-dose dexamethasone achieved a clinical response rate of 47% and a stable disease rate of 35% in a small series of patients refractory to lenalidomide (n = 34). In this study, median PFS was 4.8 months and overall survival was 13.9 months. Taken together, the results of these studies suggest that there is only partial cross-resistance between different IMiDs.
It may also be feasible to re-administer lenalidomide in combination with other cytotoxic agents in order to reestablish response. In a small retrospective study in 14 patients who were refractory to lenalidomide + dexamethasone, a clinical response rate of 64.3% was achieved using lenalidomide + cyclophosphamide + prednisone. However, these results should be interpreted with caution because of the sample size and retrospective character of the analysis. The combination of lenalidomide + bortezomib may also be a viable option in patients who have previously received combinations containing either of these agents. In a phase I study of 38 patients who had MM that was relapsed or refractory following treatment with thalidomide, lenalidomide, and/or bortezomib, the combination of lenalidomide + bortezomib showed promising activity, with 61% of patients achieving a minimal response or better. Nevertheless, it is difficult to determine whether the benefit was due to the activity of one of the agents to which the cells were not resistant or whether there is a real synergism among these drug combinations.
Relapse after bortezomib
Bortezomib is a first-generation proteasome inhibitor (PI). Multiple bortezomib-based regimens are recommended as primary induction therapy for SCT candidates and for patients not eligible for SCT. Therefore, a growing proportion of patients with relapsed/refractory MM have previously received bortezomib-based therapy.
Patients who relapse after bortezomib may receive another course of bortezomib-based therapy if they had an initial response to bortezomib lasting at least 6 months and had no intervening therapies. In a small study of bortezomib retreatment (n = 32), the overall response rate (better than minimal response) was 50%, but was greater in patients with a treatment-free interval of at least 6 months (56%) compared with patients treated within 6 months (33%). In this study, 75% of patients received bortezomib retreatment in combination with dexamethasone. A prospective, international phase II study (the RETRIEVE study) was conducted in 128 patients to evaluate the efficacy and safety of retreatment with bortezomib. Interim results confirmed that retreatment is an active therapeutic option, and 63% and 52% of patients who achieved a complete response (CR) or a partial response (PR), respectively, to initial bortezomib treatment responded to retreatment. In addition, bortezomib retreatment was well tolerated without evidence of cumulative toxicity.
The obvious alternative approach for bortezomib-treated patients is the use of an IMiD-based therapy. Both thalidomide and lenalidomide have been shown to be effective in bortezomib-treated patients, [13,22] with no difference in response between bortezomib-experienced and bortezomib-naive patients. The most relevant data come from the MM 09/10 trials in more than 700 patients with relapsed/refractory disease who were randomly assigned to receive either lenalidomide + dexamethasone or dexamethasone alone. Twenty-seven of these patients were previously exposed to bortezomib, and the response rate to lenalidomide + dexamethasone in this subset was 68%.
When options are limited in patients with bortezomib-refractory disease, treatment with an experimental agent may be considered. The next-generation PI carfilzomib has been tested as monotherapy in heavily pretreated patients with relapsed/refractory disease. This regimen avoids the use of corticosteroids and anthracyclines in a vulnerable population, and is well tolerated.[23-25] A better than minimal response was achieved in 26% of patients who had been previously exposed to bortezomib and in 60% of bortezomib-naive patients.
Relapse after thalidomide, lenalidomide, and bortezomib
The prognosis for patients who relapse after treatment with bortezomib + either lenalidomide or thalidomide is poor, with a median event-free survival of only a few months and overall survival of 6 months. Treatment options for these patients are limited, but may include the addition of other cytotoxic agents such as cyclophosphamide or doxorubicin to lenalidomide-, thalidomide-, or bortezomib-based therapy. Another option is the use of cytotoxic regimens that have not been tried previously, such as a combination of etoposide, dexamethasone, and cisplatin with either cytarabine or cyclophosphamide.
The optimal approach for patients who relapse after exposure to a combination of novel agents is to include them in a clinical trial with an investigational agent. Carfilzomib and pomalidomide have both shown efficacy in patients whose disease is refractory to bortezomib and lenalidomide/thalidomide.[27,28] Other agents under investigation include tanespimycin, vorinostat (Zolinza), panobinostat, and perifosine.
Aggressive relapse or extramedullary disease
Patients with an aggressive relapse often benefit from the use of drug combinations that include high-dose corticosteroids (dexamethasone) to achieve rapid disease control. Good response rates have been reported in 58% of patients with fulminant progression of MM who were treated with melphalan at 100 mg/m2 and peripheral blood stem-cell support followed by consolidation with thalidomide- or bortezomib-based regimens. However, these results need to be confirmed.
Extramedullary (EM) disease carries a poor prognosis and is becoming increasingly common as MM patients survive longer. Patients who present with or develop EM involvement have a significantly shorter overall survival and PFS compared with patients without EM disease. Although it has been suggested that thalidomide may contribute to the later development of EM relapse, a more recent analysis indicates that the occurrence of EM spread is not influenced by previous treatment with high-dose therapy, thalidomide, or bortezomib. Patients who develop EM disease usually receive systemic therapy and/or radiotherapy. Currently, there are limited clinical trial data on the efficacy of treatments for EM disease, and most of these are retrospective or from case series. Some studies suggest that the response to thalidomide is poor in patients with EM tumors,[32-34] although there are case reports of good responses to thalidomide.[35,36] Bortezomib may be more effective,[31,32] but as with thalidomide, reports of efficacy are inconsistent. Bortezomib may need to be used in combination with other cytotoxic agents and corticosteroids to achieve control of EM disease.[38,39] There are currently limited data on the use of lenalidomide in patients with EM disease, but it has been reported that lenalidomide in combination with dexamethasone was effective in 25% of patients with EM tumors and in 63% of patients without EM tumors. The presence of EM disease was an independent predictor of a poor response. Melphalan, 100 mg/m2, and peripheral blood stem-cell support followed by consolidation with thalidomide- or bortezomib-based regimens may be another treatment option; this approach achieved complete or partial regression of EM tumors in 7 of 10 treated patients in a recent retrospective analysis.
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