High-dose (HD) chemotherapy followed by autologous stem cell transplant (ASCT) has dramatically improved the care of patients with multiple myeloma (MM).1 In recent years, induction therapy with novel agents followed by ASCT has emerged as an optimal treatment pathway.2 Not every myeloma patient, however, can receive the benefits of transplant. Unfortunately, vulnerable and compromised patients, often those older than 65 years, may not be eligible for transplant because they cannot tolerate the toxicities associated with the HD/ASCT process.3 However, these patients may benefit from novel agents developed and approved over the past decade. Bortezomib, lenalidomide, or thalidomide combined with established forms of cytotoxic chemotherapy or steroids are now recommended by evidence-based guidelines for initial therapy of the newly diagnosed nontransplant patient.2,4 These agents may also play a key role in maintenance therapy for patients ineligible for transplant and can be used in the relapsed and/or refractory settings.3
In this typically older population, the adoption of newer therapies has improved outcomes but has not produced the very dramatic improvements in survival seen in younger MM patients.3 For example, in a 2008 publication, Kumar and colleagues reported significantly greater median overall survival (OS) among a cohort of patients diagnosed from 1997 to 2006 (N=1051) compared with patients diagnosed from 1971 to 1996 (N=1930).5 Median survival for those diagnosed from 1997 to 2006 was 44.8 months, significantly better than the 29.9 months for those diagnosed from 1971 to 1996 (P<.001). Stratification by age, however, showed that the subset of patients younger than 65 years contributed most to this overall improvement in survival. In these patients, median survival was 60 months for those diagnosed from 1997 to 2006 versus 33 months for those diagnosed from 1971 to 1996. In patients 65 years or older, the improvement in median survival between these time periods was more modest (32 months vs 26 months, respectively). Reasons for this age-related survival difference may include a greater incidence of medical comorbidity, frailty, and other forms of vulnerability among older patients.3
These findings have broad implications for value-based care. Since 75% of men and 79% of women with MM are older than 70 years,2 comorbid conditions or lower performance status may preclude them from being eligible for transplant. As the US population ages,6 there will be more patients of this description in the healthcare system. Thus, the identification of high-value therapies has become an increasingly critical component of effective myeloma care.
Initial Therapy for the Newly Diagnosed Patient
The National Comprehensive Cancer Network (NCCN) guidelines recommend 5 preferred regimens and 5 other regimens as initial therapy for patients with MM who are not eligible for transplant (Table 1).2 Four of these regimens—melphalan, prednisone, and thalidomide (MPT), lenalidomide plus low-dose dexamethasone (Rd), bortezomib, melphalan, and prednisone (VMP), and lenalidomide, melphalan, and prednisone (MPR)—are category 1 recommendations, based on the most robust evidence.2
MPT has been compared with MP alone in 6 randomized clinical trials aggregated in a systematic review and meta-analysis published in 2011 by Fayers and colleagues.7 The impact of treatment on OS varied across trials, but the meta-analysis, encompassing 1685 patients, reported a survival benefit with the 3-drug regimen: median OS was 39.3 months among MPT-treated patients compared with 32.7 months among MP-treated patients (6.6-month difference; P=.004). In addition, Crusoe and colleagues recently presented preliminary data that demonstrated improved progression-free survival (PFS) with MPT or a regimen of cyclophosphamide, dexamethasone, and thalidomide compared with thalidomide plus dexamethasone alone in 60 newly diagnosed nontransplant patients with MM.8
Rd as initial therapy for nontransplant candidates is supported by results of the phase 3 ECOG E4A03 trial conducted by Rajkumar and colleagues.9 This study of 445 patients—50% of whom were aged 65 years or older—reported that lenalidomide plus a lower (less frequent) dose of dexamethasone was associated with significantly better 1-year OS and a more favorable toxicity profile than lenalidomide plus a higher (more frequent) dose of dexamethasone. Greater toxicity in the high-dose dexamethasone group appeared to be responsible for excess mortality.
MPR also appears to be effective for the treatment of newly diagnosed MM patients who are aged 65 years or older.10 Data strongly indicate, however, that the efficacy of this regimen is maximized when continuous maintenance lenalidomide follows initial cycles of MPR (see discussion of maintenance therapy later in this article).10
The addition of bortezomib to MP was shown to enhance efficacy in the phase 3 VISTA trial, which enrolled 682 newly diagnosed transplant-ineligible myeloma patients.11-13 At a median follow-up of 16.3 months, investigators reported that VMP produced significantly longer time to progression, a higher rate of complete response (CR), and superior OS compared with MP alone. In 2011, investigators presented long-term results from this trial.13 After 5 years of follow-up, median OS was 56.4 with VMP versus 43.1 months with MP (13.3-month difference, P=.0004), yielding a 31% reduced risk of death with VMP (Figure). Five-year OS rates were 46.0% with VMP and 34.4% with MP. Investigators asserted that the findings compared favorably with the 6.6-month increase in median OS in the meta-analysis of MPT versus MP.7 The OS benefit with VMP was seen across most patient subgroups, including those aged 75 years and older. Time to next treatment and treatment-free interval were significantly longer with VMP compared with MP, and there was no difference in the risk of secondary malignancy between treatment groups.
Munshi and colleagues reported that the combination of bortezomib plus dexamethasone (VD) was effective and well tolerated in 50 elderly patients (median age, 71 years) with significant comorbidities, including 86% with cardiovascular disease and 67% with diabetes.14 In this study, overall incidence of peripheral neuropathy (PN), a known adverse event of bortezomib, was 20% (10/50), but the rate of grade 3 PN was relatively low, at 2.4%. A trial presented by Berdeja and colleagues showed promising interim results in 18 newly diagnosed, transplant-ineligible MM patients treated with a regimen of bendamustine, bortezomib, and dexamethasone.15 A Canadian National Trial reported that the combination of bortezomib, cyclophosphamide, and prednisone was effective in 27 newly diagnosed, nontransplant patients with unfavorable prognosis due to translocation t(4;14), yielding 2-year PFS and OS rates of 47.7% and 76.8%, respectively.16
Following initial treatment, maintenance regimens containing novel agents have emerged as an important component of therapy in the nontransplant population.2 Recently, however, data have suggested that thalidomide-based maintenance in elderly, transplant-ineligible patients may not improve OS and may be associated with increased toxicity.17 Current NCCN guidelines contain discussions of lenalidomide and bortezomib, but not thalidomide, for maintenance therapy tailored specifically to nontransplant patients.2
An important evaluation of lenalidomide maintenance in the nontransplant population was conducted by Palumbo and colleagues, who compared MP, MPR, and MPR plus continuous lenalidomide maintenance (MPR-R) in 459 elderly MM patients.10 Data from the phase 3 MM-015 trial, which were presented initially in 2010, showed that MPR-R resulted in higher PFS than did MP. Moreover, when MPR-R was compared with MPR, the inclusion of lenalidomide maintenance therapy in MPR-R resulted in a 69% reduced risk of progression compared with MPR plus placebo (P<.001). In 2011, updated and expanded findings in patients aged 65 to 75 years confirmed that MPR improves outcomes versus MP and that MPR-R confers additional outcome benefit (Table 2).18
Bortezomib-based maintenance therapy in nontransplant myeloma patients has been the subject of several recent trials. Mateos and colleagues assessed 2 maintenance regimens—bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP)—in an elderly population of 178 patients initially treated with VMP or bortezomib, thalidomide, and prednisone.19 Both the VT and the VP maintenance regimens elevated the CR rate, from 24% immediately after initial therapy to 42% after a median follow-up of 34 months. Median PFS in patients treated with maintenance therapy was 35 months; median OS was 60 months. A trend toward somewhat longer PFS was seen with VT versus VP, but VT was associated with a higher incidence of nonhematologic adverse events.
The community-based UPFRONT trial investigated initial therapy with 3 bortezomib-based regimens—VD, VMP, and bortezomib, thalidomide, and dexamethasone (VTD)—followed by maintenance with single-agent bortezomib.20 After a median follow-up of 21.8 months, there was no significant difference in PFS between the 3 initial treatment groups; intergroup data were comparable for 1-year OS: 87.4% (VD), 88.9% (VMP), and 86.1% (VTD). Bortezomib maintenance produced only slight additional toxicity of any kind beyond that incurred with initial therapy.
More research is needed to clarify the role of maintenance therapy in the nontransplant population. According to the International Myeloma Working Group (IMWG) 2012 consensus on maintenance therapy, the choice to use maintenance therapy must balance potential benefits with the risk of adverse events.21 Ultimately, the choice must be highly individualized, since there is as yet no established maintenance standard.
Treatment of Relapsed and/or Refractory MM
For patients with progressive disease who cannot undergo transplant, there are a number of evidence-based drug treatment options.2 If relapse occurs more than 6 months after initial therapy, patients can be rechallenged with the regimen used initially, provided there are no toxicity concerns.2 Various combinations of novel agents are also recommended; currently NCCN category 1 recommendations for salvage therapy in MM are bortezomib alone or combined with liposomal doxorubicin, and lenalidomide plus dexamethasone.2
Additional Impacts on Value-Based Care
Since the nontransplant population is vulnerable to treatment-related toxicities, due to age and comorbidites,3 adverse events of novel agents22-24 need to be considered. Neuropathy induced by bortezomib or thalidomide may pose particular risks in older or diabetic patients. The likelihood of venous thromboembolism associated with thalidomide and lenalidomide is increased in patients with preexisting cardiovascular disease, diabetes, or conditions that reduce mobility.25 Management of adverse events in the nontransplant population affects the value equation. The healthcare system may benefit from developments that reduce risk—such as subcutaneous bortezomib administration26 and once-weekly bortezomib intravenous (IV) dosing (Table 3),27 both of which reduce the incidence of PN in comparison to standard, twice-weekly IV bortezomib.
Another aspect of treatment that affects value is the ability of novel agents to improve myeloma-related renal insufficiency. Bortezomib is very effective for reversing renal failure and can be administered at the full dose and schedule, regardless of the level of impairment.28 The IMWG recommends a regimen of bortezomib plus high-dose dexamethasone to treat patients with renal dysfunction.29 Lenalidomide plus dexamethasone has also demonstrated efficacy in patients with MM who have mild-to-moderate renal insufficiency. In those with severe renal impairment, this agent must be dose-adjusted according to renal function to maintain an acceptable toxicity profile.29,30 Thalidomide may also improve renal function, but data from clinical trials are limited.31 Furthermore, the IMWG suggests that thalidomide-based treatment of renal insufficiency be performed in the context of carefully designed clinical trials, due to the potential for severe hyperkalemia, particularly in patients on dialysis.29
At this time, it is not possible to rank by value the preferred treatments for transplant-ineligible patients, because comparative pharmacoeconomic data are insufficient. A small group of studies, however, have examined the cost-effectiveness or effect on health-related quality of life (HRQoL) of novel agents in the nontransplant setting. In 2010, Wang and colleagues presented a pharmacoeconomic model based on inputs from the VISTA and MM-015 trials suggesting that the VMP regimen is associated with lower cost and improved health outcomes compared with MPR-R.32 Lifetime direct medical costs were $119,102 with VMP and $241,247 with MPR-R, with VMP providing slightly more quality-adjusted life-years.
Data presented in 2011 support an overall benefit in HRQoL with both MPR-R and bortezomib-based regimens.33-35 Niesvizky and colleagues, in an analysis of the UPFRONT trial, found a transient decline in QoL with initial bortezomib treatment, most likely related to treatment toxicities, followed by a QoL improvement during bortezomib maintenance therapy.33 Two analyses presented by Dimopoulos and colleagues demonstrated an association between enhanced QoL and 2 favorable clinical outcomes with MPR-R—very good partial response or better and prolongation of PFS.34,35
Two Scandinavian studies yielded conflicting results on the cost-effectiveness of bortezomib versus lenalidomide in the relapsed/refractory setting, with 1 study36 favoring the former treatment and 1 study37 favoring the latter. A Health Technology Assessment from the United Kingdom concluded that the MPT regimen has greater probability of cost-effectiveness than either VMP or cyclophosphamide, thalidomide, and attenuated-dose dexamethasone.38
Future Directions in the Nontransplant Setting
For patients with MM who are not candidates for transplant, identifying high-value treatments may increasingly dovetail with greater personalization of therapy.3 In other words, the value of a regimen will depend on its appropriateness for specific individuals, based on age, comorbid conditions, degree of frailty, and other health-status determinants.3 There is also growing interest in the use of cytogenetic findings to guide the selection of therapy.4 Currently, for patients with high-risk cytogenetics, bortezomib or lenalidomide may offer high-value therapy,11,39-45 but more research is needed to refine drug selection via cytogenetic risk stratification. The value equation may continue to shift with the emergence of new antimyeloma drugs, such as pomalidomide and carfilzomib. In the years ahead, providers and payers will need to adjust the assessment of value in light of clinical advances in the nontransplant setting.
Dana Delibovi contributed to the development of this article.
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- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 1.2012. http://www.nccn.org. Accessed January 26, 2012.
- Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;18:4519-4529.
- Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110.
- Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
- Centers for Disease Control and Prevention (CDC). Public health and aging: trends in aging—United States and worldwide. MMWR Morb Mortal Wkly Rep. 2003;52:101-106.
- Fayers PM, Palumbo A, Hulin C, et al; on behalf of Nordic Myeloma Study Group, Italian Multiple Myeloma Network, Turkish Myeloma Study Group, Hemato-Oncologie voor Volwassenen Nederland, Intergroupe Francophone du Myélome, and European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011;118:1239-1247.
- Crusoe E, Maiolino A, Bittencourt R, et al. A phase III study comparing thalidomide/cyclophosphamide/dexa vs thalidomide/dexa vs thalidomide/melphalan/prednisone in de novo multiple myeloma patients not eligible for ASCT. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 5117.
- Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.
- Palumbo A, Delforge M, Catalano J, et al. A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimens. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 622.
- San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.
- Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266.
- San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 476.
- Munshi N, Lee S, Kambhampati S, et al. Once a week bortezomib with dexamethasone is effective with limited toxicity in newly diagnosed multiple myeloma patients with older age and comorbidities. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3964.
- Berdeja JG, Couriel DR, Murphy P, et al. A phase II trial of combined bendamustine, bortezomib and dexamethasone in newly diagnosed multiple myeloma (MM) patients who are not candidates for high-dose chemotherapy: results of a planned interim safety analysis. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2943.
- Reece DE, Rodriguez GP, Szwajcer D, et al. Bortezomib-based therapy without autologous stem cell transplantation for newly diagnosed multiple myeloma patients with t(4;14): a Canadian National Trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3982.
- Ludwig H, Adam Z, Tóthová E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010;95:1548-1554.
- Palumbo A, Adam Z, Kropff M, et al. A phase 3 study evaluating the efficacy and safety of lenalidomide (Len) combined with melphalan and prednisone followed by continuous lenalidomide maintenance (MPR-R) in patients (pts) ≥65 years (yrs) with newly diagnosed multiple myeloma (NDMM): updated results for pts aged 65–75 yrs enrolled in MM-015. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 475.
- Mateos M-V, Oriol A, Teruel A-I, et al. Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) in elderly myeloma patients included in the GEM2005MAS65 Spanish Randomized Trial. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 477.
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- Niesvizky R, Flinn IW, Rifkin R, et al. Patient-reported quality of life (QoL) in elderly, newly diagnosed multiple myeloma (MM) patients receiving bortezomib-based combinations: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 1864.
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- Dimopoulos MA, Palumbo A, Hajek R, et al. Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance displays treatment characteristic favourable to global quality of life in newly diagnosed multiple myeloma (NDMM) patients ≥65 years. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3988.
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