ABSTRACT: No survival advantage of autologous stem cell transplantation (ASCT) has been documented for patients older than 65 years, and in the era of thalidomide(Drug information on thalidomide) (Thalomid), bortezomib(Drug information on bortezomib) (Velcade), and lenalidomide (Revlimid), ASCT has a diminished role in the front-line treatment of older patients with myeloma. For these individuals and for those who cannot or choose not to undergo ASCT, the initial treatment regimens now recommended by both the National Comprehensive Cancer Network and the International Myeloma Working Group are melphalan(Drug information on melphalan) (Alkeran)/prednisone/thalidomide (MPT), bortezomib/melphalan/prednisone (VMP), and lenalidomide/low-dose dexamethasone(Drug information on dexamethasone). Melphalan/prednisone should no longer be considered the reference treatment, although it may be appropriate for a small number of patients with serious comorbidity and/or poor performance status. Advantages of VMP over MPT include rapid response, high rates of complete response, patient compliance, and more extensive evidence of efficacy in patients with certain cytogenetic abnormalities. Lenalidomide/low-dose dexamethasone is particularly appropriate for patients with preexisting neurotoxicity and those who wish to postpone ASCT. Toxicity profiles differ among the newly established and emerging regimens, and oncology teams must take care to apply the appropriate risk management measures, including dose reduction where necessary.
Supported by an educational grant from Millennium Pharmaceuticals, Inc.
Multiple myeloma is predominantly a disease of the elderly. In the United States, two-thirds of patients are ≥ 65 years old at diagnosis and 85% of all patients are ≥ 55 years old. Recent studies have documented improved survival of myeloma patients, but mainly in younger patients.[2-4] In the United States, the 5-year survival rate for patients diagnosed at ≥ 65 years old is still unacceptably low: 27%, compared with 49% for patients diagnosed at younger ages.
Fortunately, the range of treatment options for older patients has expanded in recent years. This is due to the changing definition of who qualify as “elderly”; the introduction of the novel agents thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid); and the continued safety optimization of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). New guidelines from the International Myeloma Working Group (IMWG) recommend reduced dose intensity ASCT for patients 65 to 70 years of age. National Comprehensive Cancer Network (NCCN) guidelines do not specify an age limit for ASCT in myeloma patients, and patients as old as 80 have participated in trials and institutional protocols of ASCT in the United States. Even so, no survival advantage of ASCT has been documented for patients > 65 years old. Particularly now that thalidomide, bortezomib, and lenalidomide are available, ASCT has a diminished role in the front-line treatment of older patients with myeloma.
It is well established that chronologic age alone is not reliable in estimating life expectancy, functional reserve, or the risk of complications from cancer chemotherapy. The NCCN guidelines on treating older adults with cancer recommend using Comprehensive Geriatric Assessment tools to assess the patient’s likely tolerance of treatment by formally assessing comorbidities, functional status, geriatric syndromes, polypharmacy, nutrition, socioeconomic status, and personal preferences, in addition to life expectancy. Of these, functional status is perhaps the most important. In elderly persons, dysfunction in instrumental activities of daily living is independently predictive of death, and functional measures contribute prognostic information that is independent of that obtained by evaluating comorbidity.[8,9]
Once a patient with previously untreated myeloma is deemed ineligible or chooses not to undergo ASCT, a number of treatment options are available. The purpose of this review is to compare safety and efficacy data on the standards of care (Table 1)[5,6] as well as several emerging regimens.
Regimens Incorporating Newer Agents
For patients unable or unwilling to undergo early ASCT, thalidomide plus dexamethasone (thal/dex) has been compared with dexamethasone monotherapy and with melphalan (Alkeran)/prednisone (MP). When compared with dexamethasone alone, thal/dex resulted in significantly higher response rates (Table 2),[10-19] but grade ≥ 3 adverse events were more common. In the comparison with MP, grade 3/4 toxicity was greater with thal/dex and overall survival (OS) was significantly shorter (Table 2).
The NCCN lists thal/dex among the options for front-line treatment of transplant-ineligible myeloma, although not with its highest level of evidence or consensus (Table 1). The IMWG recommends against using thal/dex as standard therapy for elderly patients ineligible for ASCT, especially at higher doses, mainly due to its major toxicities of peripheral neuropathy (PN) and sedation.
MP + Thalidomide
Three published phase III trials have investigated MP + thalidomide (MPT) regimens of various dose and duration as initial therapy for myeloma (Table 2). All of them have demonstrated improved response rates with MPT compared with MP, but not necessarily improved OS rates.
The first of these, by the Italian Multiple Myeloma Study Group (GIMEMA), found that adding thalidomide to MP significantly improved the complete response (CR) rate and overall response rate (ORR; defined here as at least partial response [PR]) in patients 60 to 85 years old (Table 2). However, there was no significant advantage with respect to OS after a median follow-up of 38 months (Table 2). Survival from progression or relapse was significantly better in patients who received MP at diagnosis and then received thalidomide- or bortezomib-based salvage therapy, compared with those who received MPT initially. Rates of selected grade 3/4 adverse events with MPT in this and the other studies discussed in this article are given in Table 2.
The IFM (Intergroupe Francophone du Myélome) 99-06 trial, on the other hand, showed that MPT significantly extended survival for older patients (65–75 years of age) with previously untreated multiple myeloma. The MPT regimen was better than MP in terms of CR and OS (Table 2) as well as progression-free survival (PFS). Median follow-up (51.5 months) was substantially longer than that in the Italian study discussed above, and other differences included patient age (no patient older than 75 vs 25% patients of advanced age in the Italian study), number of MP cycles (12 vs 6), thalidomide dose (up to 400 mg/d vs 100 mg/d), and use of maintenance thalidomide in the Italian study. At the time of first relapse, about 15% of patients were unable to receive salvage therapy; as the investigators noted, this strongly suggests that optimum front-line treatment is of major importance in elderly patients with myeloma.
In the more recent IFM 01/01 trial, limited to patients ≥ 75 years of age, MPT as initial therapy again significantly prolonged OS and PFS compared with MP. At the time of relapse, 81% of patients in the MP group and 53% of those in the MPT group received thalidomide, bortezomib, and/or lenalidomide, and survival time after progression was similar in the two groups. Again, as the researchers note, this finding emphasizes the need for the best possible front-line treatment in elderly patients.
MP + Bortezomib
The major investigation of MP + bortezomib (VMP) for myeloma patients not undergoing ASCT was VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone(Drug information on prednisone)). This phase III trial enrolled patients who were ineligible for ASCT due to age ≥ 65 years or coexisting conditions. The trial was stopped by monitoring committee recommendation after the third interim analysis (at median follow-up of 16 months), which determined that VMP was superior to MP across all prespecified efficacy endpoints: time to progression (TTP) (the primary endpoint), CR, ORR, time to subsequent therapy, and OS (Table 2). Time to response was 1.4 months vs 4.2 months with MP.
Longer follow-up (26 months) confirmed that VMP was superior for all efficacy endpoints. Median OS was not reached in either arm; the 3-year OS rate was 72% for VMP and 59% for MP. Overall survival was not affected by renal impairment at baseline or by the prognostically adverse cytogenetic abnormalities t(4;14), t(14;16), or del(17p). Initial treatment with VMP did not preclude successful use of thalidomide- or lenalidomide-based therapy at relapse, or successful retreatment with bortezomib. In a recent update to the VISTA trial which further extended these observations after a median follow-up of 36.7 months, a 35% reduction of risk of death with VMP vs MP (hazard ratio [HR] 0.653, P = .0008) was reported. Based on these findings, the US Food and Drug Administration (FDA) has approved a supplemental new drug application (SNDA) for bortezomib, which expands the label to include these long-term overall survival data and provides specific dosing recommendations for patients with hepatic impairment.
The VISTA investigators determined that quality of response improves with prolonged VMP treatment. Median times to first response, best response, and CR were 1.4, 2.3, and 4.2 months, respectively, vs 4.2, 4.9, and 5.3 months with MP. Prolonged therapy also maximized CR achievement with VMP in that 28% of CRs as best response occurred during cycles 5 to 9. Compared with PR or very good partial response (VGPR), CR was associated with significantly longer TTP, as well as a significantly longer treatment-free interval—a measure of clinical benefit that is important to many patients.
Most recently, the VISTA investigators reported reassuring data about PN, which was grade 3 in 13% of patients and grade 4 in < 1%. Overall, 79% of all events improved by ≥ 1 grade within a median of 2 months, including 60% that completely resolved within a median of 6 months. The only baseline factor associated with worsening of PN was preexisting ≥ grade 1 PN.
No head-to-head study has compared MPT and VMP, but a recent meta-analysis of the phase III studies determined that better response rates could be expected with VMP than with MPT. In comparing data on MP, MPT, and VMP, Yeh and colleagues calculated an 81% probability that VMP was the most efficacious in terms of ORR and > 99% probability that VMP was the most efficacious in terms of CR. The investigators estimated that a patient was twice as likely to achieve CR with VMP than with MPT. The VMP and MPT regimens were similar with regard to OS and PFS.
Noting that it remains to be seen whether an alkylating agent or an immunomodulatory drug is the optimal partner for bortezomib, the Spanish PETHEMA/GEM group is conducting a phase III trial comparing VMP with bortezomib/thalidomide/prednisone (VTP) in patients > 65 years of age. In this study VMP is being modified: patients receive only six cycles and bortezomib is given on a weekly schedule after cycle 1. Patients in the VTP arm receive the same bortezomib and prednisone regimen as patients in the VMP arm, but instead of melphalan, they receive continuous thalidomide at 100 mg/d. On initial analysis, no significant differences between arms were observed with respect to the primary endpoint, ORR, or the CR rate (Table 2).
As with thalidomide, the initial approach to using lenalidomide in the treatment of newly diagnosed patients was to pair it with dexamethasone. In a phase II trial, lenalidomide/dexamethasone (Rev/dex) induced responses in 91% of 34 patients, including CR in 6%, similar to response to thal/dex. This trial was not limited to transplant-ineligible patients, and a more recent analysis distinguishes between the 13 patients who discontinued Rev/dex to proceed to ASCT and the 21 who continued on Rev/dex for a median of 19 cycles. (The latter group included two patients who died before a decision about ASCT could be made.) As in the overall cohort, the depth of remission in the no-transplant group improved over time. After four cycles of therapy, 44% of the entire cohort had at least VGPR; over time, that rate improved to 56% for the entire cohort and 67% for the no-transplant group.
The most common grade 3/4 nonhematologic toxicities with Rev/dex were fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash (6%). These toxicities were similar to those noted in the dexamethasone-only arm of a phase III trial that evaluated thal/dex as pretransplant induction therapy. Concerned that high-dose dexamethasone might be greatly contributing to the toxicity of Rev/dex, the Eastern Cooperative Oncology Group (ECOG) initiated the phase III E4A03 trial to compare lenalidomide plus standard high-dose pulse dexamethasone (RD) against lenalidomide plus low-dose weekly dexamethasone (Rd).[19,29] This trial was not limited to transplant-ineligible patients.
In the primary analysis of response and safety after four cycles, neither the CR rate nor the ORR was significantly better with Rd than with RD (Table 2). However, among patients > 65 years of age, the probability of survival in the Rd group was significantly greater than that in the RD group at both 1 and 2 years. Moreover, in the entire cohort, the lower dexamethasone dose was associated with substantially less deep-vein thrombosis/pulmonary embolism, infection/pneumonia, any grade ≥ 3 nonhematologic toxicity, any grade 4/5 toxicity, and risk of death within 4 months.
The ECOG investigators performed a landmark analysis of 142 patients in the E4A03 trial, median age 66 years, who did not undergo ASCT and continued on Rd for more than four cycles. Continued Rd was highly active in these patients (Table 2). In fact, the 2-year OS rate was comparable with that of the original intent-to-treat population that received Rd and with that of the patients who received RD or Rd for four cycles before proceeding to ASCT.
Table 3[5,10,13,15,16,24,26,29-48] provides guidance for using standard anti-myeloma regimens in the nontransplant setting.