Current Challenges in the Management of Patients with Relapsed/Refractory Multiple Myeloma
By Jesús F. San Miguel, MD, PhD1, María-Victoria Mateos, MD, PhD1 |
November 7, 2011
1 Servicio de Hematología, Hospital Universitario de Salamanca, Centro de Investigación del Cáncer (CIC) IBMCC/CSIC, Universidad de Salamanca, Spain
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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on heparin), and those at low risk (≤ 1 VTE risk factor) may receive aspirin(Drug information on aspirin) prophylaxis. The incidence of VTE with bortezomib is low (0.6% to 1.6%) and is unaffected by concomitant dexamethasone or erythropoietin(Drug information on 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(Drug information on 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(Drug information on 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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