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).
When treating patients with relapsed/refractory multiple myeloma, clinicians should maximize the efficacy of treatment through use of the most appropriate combinations and sequences of agents. Treatment options depend on the duration and magnitude of response to previous therapies; the type and aggressiveness of the relapse; and patient factors such as comorbidities, performance status/quality of life, bone marrow reserve, renal function, previous toxicities (eg, peripheral neuropathy, venous thromboembolism), age, insurance coverage, distance from the hospital, and life expectancy. Patients who relapse within 1 year of a stem-cell transplant (SCT) may require multidrug rescue therapy, followed by allogeneic SCT with reduced-intensity conditioning or consolidation/maintenance therapy. Those with a long duration of remission (3 to 4 years) may undergo a second autologous SCT, using the original effective treatment protocol or a different combination as reinduction. Patients with intermediate remission duration (2 to 3 years) may benefit from the sequential use of novel agents as salvage therapy. In elderly patients, considerations of quality of life and cost constraints should be carefully weighed. At first relapse, the initial option would be to use a new scheme that is different from the one used for induction, unless the first remission was long enough to merit considering retreatment with the same scheme. At second or subsequent relapse, usually after having been treated with bortezomib (Velcade) and at least one immunomodulatory drug, enrollment in a clinical trial with experimental agents should be encouraged. This article describes the current evidence available for various treatment options as well as a personal approach to individualized therapy for relapsing patients.
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.
Definitions of Relapsed/Refractory and Progressive Myeloma, Based on International Myeloma Working Group Definitions
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.
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]
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.
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.
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.
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.
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.
Renal dysfunction is common in patients with MM, resulting primarily from the toxic effects of monoclonal light chains on the kidney, and secondarily from hypercalcemia. Dehydration, the use of nephrotoxic drugs (eg, aminoglycosides, nonsteroidal anti-inflammatory drugs [NSAIDs], contrast agents), and rarely, myeloma cell infiltration may also play a role.[41-43]
The efficacy and tolerability of bortezomib-based therapy appears to be good in patients with renal impairment and can reverse renal failure in a substantial number of patients.[45,46] This suggests that bortezomib is an appropriate option for patients with relapsed/refractory MM who have renal failure. Patients whose disease is refractory to, or who cannot tolerate, bortezomib may be candidates for thalidomide- or lenalidomide-based treatment.
Renal excretion of thalidomide is limited, so dose adjustment is not necessary in patients with renal dysfunction.[41,47] However, there are few data on the efficacy of thalidomide in patients with relapsed/refractory MM and renal impairment. In a small series of patients with relapsed/refractory MM and renal failure who were receiving thalidomide alone or in combination with dexamethasone, 15 of 20 patients achieved a major (> 50% decrease in serum or urine M-protein) or minor (> 25% decrease) response. Among these 15 patients, renal function normalized in 12 patients and improved in 2 patients. Although lenalidomide was shown to be excreted renally in a pooled analysis of data from two phase III trials (MM-009 and MM-010), the degree of renal impairment had only a modest effect on the response to lenalidomide + dexamethasone. Creatinine clearance improved in 72% of patients receiving lenalidomide and deteriorated in 1%. However, significantly more patients with moderate or severe renal impairment developed thrombocytopenia or required dose adjustment because of adverse events, compared with patients without renal impairment (P < .05). This suggests the need for dose adjustment of lenalidomide according to the degree of renal impairment, calculated using the Cockcroft-Gault formula. Renal impairment may also limit the use of further cycles of autologous SCT in patients with relapsed/refractory MM because of the increased toxicity of high-dose induction therapy. However, it may be attempted in patients younger than 60 years with chemosensitive disease and good performance status, using a high-dose regimen containing melphalan, 140 mg/m2.
If a thalidomide-based or lenalidomide-based combination is indicated, patients at high risk for venous thromboembolism (VTE) should receive thromboprophylaxis with oral anticoagulants or low molecular weight heparin, and those at low risk (≤ 1 VTE risk factor) may receive aspirin prophylaxis. The incidence of VTE with bortezomib is low (0.6% to 1.6%) and is unaffected by concomitant dexamethasone or erythropoietin use.
Preliminary data with the next-generation PI carfilzomib suggest that it is associated with a low incidence of VTE, similar to bortezomib. In a phase I study with the novel IMiD pomalidomide, VTE developed in 4 of 24 patients(16.7%), but no VTE events were reported when pomalidomide was administered on alternate days in a second phase I study (n = 20). Further data are needed to clarify the efficacy of daily or alternate-day dosing of pomalidomide in relation to the VTE risk.
Peripheral neuropathy is commonly associated with thalidomide and bortezomib therapies, so careful assessment of neurological function and potential subsequent dose modifications are important components of patient management when using both these agents. Once patients have experienced peripheral neuropathy, they may be more susceptible to the condition as an adverse effect during subsequent therapy. However, the incidence of peripheral neuropathy with lenalidomide was low in the major phase III studies in patients with relapsed/refractory MM.[56,57] Therefore, lenalidomide-based therapy is an appropriate choice for patients with treatment- or disease-related peripheral neuropathy. Of the emerging treatments for MM, carfilzomib appears to have a low potential for causing peripheral neuropathy (even in those with a history of neuropathy) and may be an alternative treatment option for susceptible patients.[53,58,59]
Patients with preexisting type 2 diabetes mellitus may be at risk for hyperglycemia if treatment includes corticosteroids. Also, those who have developed corticosteroid-related toxicity during previous lines of therapy may benefit from regimens using only a low dose of prednisone; from a corticosteroid-sparing regimen such as bortezomib; or from IMiDs in combination with PLD, an anthracycline, or an alkylating agent.
In patients who relapse after autologous SCT, treatment decisions will differ depending on the duration of remission following autologous SCT. In patients who relapse within 1 year of an autologous SCT, overcoming drug resistance should be a treatment goal, which may require multidrug therapy utilizing a combination of all potentially effective drugs. Those who achieve a very good PR or CR to the drug cocktail may proceed to allogeneic SCT with reduced-intensity conditioning if a related or unrelated donor is available, or they may receive consolidation/maintenance therapy. Patients who relapse after prolonged remission (eg, 3 or 4 years) may undergo a second autologous SCT; suitable reinduction regimens in these patients may include the original effective treatment protocol or a different combination, usually including one of the novel agents. Many patients fall into an intermediate category, in which their response to the initial SCT was neither brief nor prolonged (eg, 2 to 3 years). In these patients, we favor the sequential (rather than combined) use of novel agents as salvage therapy, switching to an alternative agent when the disease progresses. The possibility of a second transplant or even an allogeneic SCT can be discussed with these patients.
Treatment Options for Patients With Relapsed/Refractory Multiple Myeloma
In patients relapsing after allogeneic transplantation, the first option is to consider whether graft vs host disease (GVHD) has developed. If it has not, the first choice would be to give donor lymphocyte infusions. If the patient has already experienced GVHD, the rescue therapy would be similar to that proposed in the general recommendation/treatment algorithm (Figure). Unfortunately, in many of these patients the allogeneic SCT was performed as a late salvage option, and these patients will have few alternatives left. Probably the best option will be to include them in an experimental trial, providing they meet the inclusion criteria for such a trial. Unfortunately, many experimental trials are very restrictive for patients with a previous allogeneic SCT.
MM is predominantly a disease of the elderly (median age at diagnosis is 66 years). With increasing survival duration, a higher proportion of the relapsed/refractory population will be in the older age group. However, elderly patients generally have poorer overall health status and more severe disease, making secondary treatment difficult.[62,63] Moreover, clinical trial data in elderly patients, particularly those who are also weak or ailing, are limited, making evidence-based treatment recommendations difficult. Physicians should base treatment decisions for older patients not just on the patient's chronologic age but also on his or her performance status, comorbidities, psychological state, and available social support.[2,63]
Treatment options for elderly patients are suggested in the Figure. Consideration should be given to dose-adjusted regimens such as low-dose dexamethasone or, preferably, prednisone in combination with oral cyclophosphamide or lenalidomide, with the alternative of thalidomide or weekly bortezomib.
In patients with relapsed/refractory MM, one of the most relevant questions is whether to use all of the active drugs at the same time or sequentially. Moreover, it needs to be proved that the combination of a PI plus one IMiD is superior to the combination of either of the two drugs plus an alkylating agent or anthracycline with corticosteroids. In relapsed/refractory MM, four key factors should be assessed to determine the optimal treatment approach.
First, a comprehensive analysis of the patient's previous lines of therapy is vital. This should include the types of drugs and combinations used (eg, alkylating agents, immunomodulators, PIs), the degree and duration of response obtained, and adverse events experienced by the patient. This will allow decisions about the possibility of retreatment with the same drug (alone or in combination, based on previous sensitivity) and avoid the use of agents with little or no effect and those with a known potential for toxicity in that patient. Second, the type of relapse should be considered: is this an aggressive or EM relapse? In those cases a more intensive therapeutic approach would usually be recommended. Third, the clinical situation (particularly comorbidities) and the patient's demographic and socioeconomic situation must be considered. Treatment of relapsed/refractory MM is particularly challenging because of the reemergence or worsening of disease-related complications, patient comorbidities, and cumulative toxicities resulting from previous lines of therapy. Therefore, it is important to take into account any comorbidities (eg, diabetes), performance status/quality of life, bone marrow reserve, renal function, previous toxicities (eg, peripheral neuropathy, VTE), age, life expectancy, insurance coverage, distance from hospital, and living situation (eg, availability of supportive care at home). Fourth, future treatment options should be taken into consideration. For instance, how many treatment lines and new experimental agents are available at the local center or at the referral site for this patient? Also, the patient's cytogenetic profile may be considered, but current evidence for cytogenetic-based therapy in the context of relapsed MM is limited and is sometimes conflicting.
We recently proposed a management algorithm for patients with relapsed/refractory MM that takes into account many of these factors (see Figure). In elderly patients, considerations of quality of life and cost constraints should be carefully weighed. At the initial relapse, the first choice should be to use a new class of drug or a drug combination that is different from the one used for induction, unless the first remission was long enough (progression-free interval > 6 to 9 months) to merit consideration of retreatment with the same regimen. In patients under treatment with a single agent (eg, maintenance with low-dose lenalidomide) who are showing nonaggressive disease progression, the possibility of adding another agent (eg, dexamethasone ± an alkylating agent) before switching to another class of drug can be considered. At second or subsequent relapse, usually after a patient has been treated with bortezomib and at least one IMiD, enrollment in a clinical trial with experimental agents should be encouraged. If the patient is not a candidate for active therapy, palliative treatment with oral cyclophosphamide (50 mg daily) and prednisone (30 mg on alternating days) could be considered.
Choosing an appropriate treatment for patients with relapsed/refractory MM is a complex task requiring consideration of numerous patient-, treatment-, and disease-related factors. Disease- and treatment-related complications, patient comorbidities, and patient age can all affect treatment choices, as can the magnitude and duration of response to previous therapies. Novel agents have transformed the range of treatment options available, and new agents under development offer the opportunity to further expand these choices and improve the therapeutic options for patients with relapsed/refractory MM.
Acknowledgments:The authors would like to thank Catherine Rees, PhD, and Yvonne Yarker, PhD, on behalf of Fishawack Communications for their assistance with manuscript development. This editorial support was funded by Onyx Pharmaceuticals.
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