Managing multiple myeloma in the elderly: are we making progress?

Abstract

Treatment of multiple myeloma has evolved rapidly over the last decade due to novel therapeutic agents. Improved upfront and salvage options have resulted in enhanced survival; however, this has been less pronounced in elderly patients compared with their younger counterparts. Indeed, treatment-related toxicities in older patients may have subverted the survival benefit made by newer treatment modalities. However, owing to the immaturity of current published data, the true survival impact made by novel agents in the elderly patient subgroup is far from being fully appreciated. Improved responses, along with increased salvage options, imply that progress for elderly patients is being made. The current challenge to improve survival for elderly patients not only rests with continued research into tolerable novel treatment regimens, but also, scrupulous supportive care and the judicious use of current novel agents in appropriate dosing, combinations and sequence. Here, we review the outcomes of elderly patients with multiple myeloma over recent years and focus on the current treatment options available for this group.

Keywords::

• elderly
• multiple myeloma
• progress

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Release date: 14 June 2011; Expiration date: 14 June 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe advances in treatment and survival for patients with MM over the past decade

• • Identify predictors of short- and long-term outcomes in patients with MM

• • Compare best upfront treatment options for older patients with MM

• • Describe best options for treatment of MM in older patients with poorer prognosis

• • Describe factors in the elderly that reduce benefits of MM treatments compared with younger patients

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Désirée Lie, MD, MSEd

Clinical Professor, Director of Research and Faculty Development, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Désirée Lie, MD, MSEd, has served as a nonproduct speaker for: “Topics in Health” for Merck Speaker Services.

AUTHORS AND CRENDENTIALS

Hang Quach

Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia; Monash Medical Centre, Clayton, Victoria, Australia; Malignant Hematology and Stem Cell Transplantation, Alfred Health-Southern Health Hematology Consortium, Victoria, Australia; Department of Medicine, University of Melbourne, Victoria, Australia.

Disclosure: Hang Quach has disclosed no relevant financial relationships.

H Miles Prince

Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia; Department of Medicine, University of Melbourne, Victoria, Australia; Hematology Service, Peter MacCallum Cancer Centre, Victoria, Australia.

Disclosure: H Miles Prince has disclosed no relevant financial relationships.

Andrew Spencer

Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia; Malignant Hematology and Stem Cell Transplantation, Alfred Health-Southern Health Hematology Consortium, Victoria, Australia.

Disclosure: Andrew Spencer has disclosed no relevant financial relationships.

Over the last decade, new therapeutic options together with improved supportive care in autologous stem-cell transplantation (ASCT) have substantially increased the survival expectations for patients with multiple myeloma (MM). Patients diagnosed within the last 10 years can now expect to live for a median of approximately 5–8 years, compared with less than 3 years several decades ago [1,2]. Improvement in survival has certainly been more pronounced in the younger population, compared with the elderly subgroup, in whom only a minor improvement has been documented over the last decade, as reported in recent cohort studies [1,3]. Despite this, no convincing evidence exists to suggest that MM is biologically different in the elderly [4,5]. Thus, the apparent lack in survival progress in older patients over the last decade [1,3] may relate to a combination of treatment-related toxicities and the inability to deliver effective therapy. On the other hand, given the immaturity of published data on novel treatment regimens for elderly patients and their only recent routine use in the clinical setting in this patient subgroup, the true survival impact made by novel agents may have yet to be fully appreciated. Nonetheless, significant progress in the treatment of elderly patients is already evidenced by our ability to induce better quality responses with newer therapeutic modalities that, in turn, correlate with better clinical outcomes [6,7]. Older patients are no longer necessarily assigned to a palliative treatment approach and the therapeutic goal of attaining a state of minimal residual disease can now be feasibly applied to patients irrespective of age group or transplant eligibility [8]. With increasing upfront treatment and salvage options, the challenge of treating elderly patients with MM rests with juggling the different therapeutic combinations and sequence of novel agents, so as to maximize survival outcome and minimize treatment-related toxicities, while offering concurrent best supportive care. Here, we review the outcomes of elderly myeloma patients over the last decade and focus on the current treatment options available for this group of patients.

Survival outcomes for elderly patients

The incidence of MM is approximately five cases per 100,000 persons/year [9]. MM is a disease of the elderly, with a median age of onset of 65–70 years, with one study reporting an increase of median age at diagnosis from 70 to 74 years over the last 50 years [10]. Several reports have noted the increased incidence of MM over time [10,201]. Whilst these data may be prejudiced by improved reporting strategies from cancer registries and better healthcare access, the increasing incidence seen in elderly patients are probably real, given the improved life expectancy of the normal population.

Until the turn of the century, no improvement was made with respect to overall survival (OS) in patients with MM. In fact, an increased mortality rate was generally observed over time [11–13]. A modest improvement in survival was achieved upon the introduction of high-dose melphalan with ASCT in the 1990s. Although MM remained incurable, ASCT improved median OS for younger patients in the order of 4–5 years [14,15], while OS for elderly patients remained unsatisfactory at 2–3 years [16]. The next wave of substantial improvement in long-term prognosis occurred upon the introduction of thalidomide in the 1990s, followed by bortezomib in 2003 and lenalidomide in 2005 [1,17]. However, in the elderly patient subgroup, the impact on survival appeared to be more modest, according to recent reports [1,3]. Recently, Kumar and colleagues attributed the clear improvement in OS from both initial diagnosis (44.8 vs 29.9 months; p < 0.001) and time of relapse (23.9 vs 11.8 months; p < 0.001) to novel therapeutic agents in 2981 patients diagnosed with MM after the year 2000 [1]. However, the degree of improvement in survival over the last 10 years appeared to progressively diminish when assessed according to increasing age group; the greatest increase in 10-year relative survival was seen in patients younger than 50 years of age, whereas only a modest increase was seen in patients 60–69 years of age and virtually no improvement in survival was seen in patients aged 70 years or over. Similarly, via a novel model-based projection method using epidemiological data from 1973 to 2005, one group reported much lower 5- and 10-year relative-survival projections for elderly patients compared with young patients diagnosed with MM between 2006 and 2010 [3]. Of note, the aforementioned analysis for survival improvement in elderly patients with MM was extrapolated from data from the first half of this decade, when in fact the widespread and routine use of novel therapeutic agents in the upfront treatment of MM in elderly patients has only occurred in the latter half of this decade. As such, these survival estimates may not adequately reflect the survival expectations for elderly patients diagnosed in the current era.

Many clinical trials utilizing novel therapeutic agents demonstrate improvements in clinical outcomes irrespective of age [18,19]. Despite this, the application of innovative treatment strategies in elderly patients has generally lagged behind that of young patients in recent years. This, combined with the tendency to opt for a nonintensive or palliative approach in older patients, has led to a proportion of patients being undertreated [20]. Conversely, with improved supportive care, the upper age limit criteria for intensive treatments have progressively increased [21–23]. In addition, we now have a number of trials showing that tolerance to novel therapeutic agents is similar between young and elderly patients [18,19,24]. One would hope that with time, the delivery of a new standard of care, such as chemotherapy with novel agents, will not be compromised by age. Indeed, it will be some time before any survival advantage is fully appreciated.

Importance of complete response with upfront treatment: does this apply to the elderly population?

The achievement of complete response (CR) in MM, has so far been difficult with conventional-dose chemotherapy and its positive correlation with improved survival has been difficult to establish. CR rates were typically in the order of 5% with conventional-dose chemotherapy, and many studies historically demonstrated no correlation between depth of response and long-term survival [25,26]. The potential prognostic impact of CR (as stringently defined by immunofixation negativity as per either the European Bone Marrow Transplant [EBMT] [27] or International Response Criteria [28]) was realized when such a depth of response became more achievable with high-dose therapy (HDT) and ASCT [29–33] and even more so with the incorporation of novel therapeutic agents [34–36]. Indeed, a recent review of 4990 patients confirmed that achievement of CR translated to improved long-term outcome [37]. This holds true in the era of novel agents in both the upfront and relapse setting; CR has emerged as a predictor for longer progression-free survival (PFS) and, in some cases, OS [6,7,18,34–36,38,39]. It now represents an important goal in the treatment of MM [7]. However, does such an endeavor carry the same degree of importance for elderly patients in whom treatment-related mortality might subvert the survival benefit conferred by the achievement of CR?

Recent clinical trials that have focused on elderly patients demonstrate the benefit in achieving a CR with respect to PFS and treatment-free interval (TFI), but not necessarily OS. In the Phase III Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone (VISTA) trial, where a combination of bortezomib, melphalan and prednisone (VMP) was compared with melphalan and prednisone (MP) in a group of patients with a median age of 71 years [18], CR was associated with longer time to progression (TTP; hazard ratio [HR]: 0.45; p = 0.004) and TFI (HR: 0.38; p < 0.0001) [6]. The numerical improvement in OS in patients who achieved CR (HR: 0.87; p = 0.54) was not statistically significant [6]. Possible reasons include short follow-up period and a small number of deaths in each arm. Nonetheless, the significant prolongation of TFI in the VMP arm (from 15 months [MP] to 30 months [VMP]) is itself an important clinical benefit and could be argued as a justification for a more intensive approach in elderly patients [8]. In studies that have much longer follow-up, such as the recent analysis of 1175 patients who received MP in combination with thalidomide (MPT), achievement of a CR was an independent predictor of longer PFS and OS, regardless of age. Patients aged above 75 years derived similar survival benefits from the achievement of CR [40].

In other studies, the potential survival benefit conferred by a higher rate of CR was counterbalanced by a higher rate of toxicity-related deaths in elderly patients. This was observed in a randomized trial comparing thalidomide and dexamethasone (TD) with MP in a group of 289 patients aged over 65 years [41]. Despite a higher proportion of CR/very good partial response (VGPR) in the TD group (26 vs 13%; p = 0.006), OS was slightly shorter in the TD group due to a higher rate of toxicities, especially in patients above 75 years of age with poor performance status.

Irrespective of age, the impact of CR on survival is not pronounced in patients whose symptomatic MM has progressed from monoclonal gammopathy of uncertain significance (MGUS) or smouldering myeloma [42–44]. Via microarray analysis, one group demonstrated that MM patients with MGUS-like molecular signatures had prolonged survival despite a lower incidence of CR following intensive therapy with tandem transplantation [43]. Similarly, the impact of CR on survival was not seen for International Staging System stage I disease in the long-term analysis of the Intergroupe Francophone du Myelome (IFM) trials, in which patients underwent tandem ASCT [44]. This may relate to the inherently indolent biology of these subgroups such that a ‘reversal back to their smouldering state’ is sufficient to achieve a durable response.

Overall, the two groups that may not derive a significant survival advantage from achieving CR are frail elderly patients with poor performance status and patients who have progressed from prior MGUS/smouldering myeloma or International Staging System stage I disease. For the remainder of the elderly population, with improved supportive therapy, CR may still be a valid endeavor, especially with the advent of less toxic but more efficacious treatment options.

Upfront treatment options for elderly patients

It has been increasingly recognized that chronological age does not always reflect biological age and, as such, the traditional blanket omission of HDT for patients aged over 65 years has been superseded by a risk-adapted approach based on biological assessments [45]. The options for induction therapy in elderly patients have expanded over the last decade to incorporate novel therapeutic agents, with or without consolidative HDT and ASCT postinduction therapy.

Elderly patients eligible for HDT & ASCT

Currently, HDT and ASCT are valid upfront treatment strategies for elderly patients who are deemed suitable based on good performance status and limited comorbidities. Generally, such patients are limited to those under the age of 70 years. Although younger patients have better OS with ASCT, age per se is not an independent prognostic variable with ASCT [46]. Thus, older patients may stand to benefit as much from ASCT as younger patients [46,47]. Treatment-related mortality appeared to be reduced with the use of lower-dose melphalan conditioning (100–140 mg/m²) in elderly patients [23,48] and has rendered this treatment modality feasible in selected patients between the ages of 65 and 70 years, especially with the improvement in supportive care. Patients eligible for ASCT should receive stem cell-sparing induction therapy (i.e., regimens not containing melphalan) for three to four cycles prior to stem cell collection. This generally consists of a combination of one or two chemotherapy agents with or without corticosteroids and novel therapeutic agents including thalidomide, lenalidomide or bortezomib [49–55]. The choice often depends on local treatment guidelines and access to novel agents.

Given the efficacy of novel agent-containing induction regimens for MM, the role of ASCT has been questioned, especially when the IFM99 study demonstrated superior OS with MPT compared with vincristine, doxorubicin and dexamethasone induction therapy followed by ASCT for elderly patients [39]. However, the question remains as to whether ASCT will further improve the outcome for patients receiving induction therapy that incorporate novel agents upfront. Indeed, thalidomide, lenalidomide or bortezomib-based induction therapy have achieved impressive CR rates in the order of 20–44% [32,33,55,56], a result comparable to, if not better than, that seen post-ASCT in the era of conventional-dose chemotherapy with infusional vincristine, doxorubicin and dexamethasone. These promising results have led to the current era of trials comparing novel induction agents with or without consolidative ASCT [55,57]. In the subset of patients who achieve CR post-novel agent-based induction therapy, the question of whether deferring ASCT until relapse will result in similar survival outcomes remains uncertain. The depth of CR in such patients may be further improved with ASCT; indeed, early data seem to suggest that such patients still benefit further with HDT and ASCT in consolidation [58,59].

Elderly patients not eligible for HDT & ASCT

In patients not eligible for ASCT, the addition of thalidomide, lenalidomide and bortezomib to conventional MP have improved response and survival outcomes (Table 1). Results from the six studies comparing MPT with MP are outlined in Table 2. In all six studies, MPT resulted in a significantly superior PFS, TTP and event-free survival compared with MP. However, the Italian [19,38] and Nordic [60] studies, which utilized ongoing thalidomide maintenance, did not demonstrate superiority in OS in the MPT arm compared with MP. There are at least two reasons for the lack of OS benefit: first, the successful salvage with thalidomide or other novel agents in the MP group upon progression, and second, patients in the MPT group appeared to be more resistant to salvage therapy upon relapse. By contrast, the two French trials (IFM 99 [39] and IFM 01 [61]), in which thalidomide maintenance was not incorporated, did demonstrate superiority in both PFS and OS in the MPT arm compared with MP. This differs to recent results from the Turkish group [62], which showed that eight cycles of MPT, without ongoing thalidomide maintenance, resulted in a superior overall response rate (ORR) and disease-free survival, but not OS, compared with MP in patients aged over 55 years. The median follow-up of this study was a short 23 months. Overall, a meta-analysis of all six trials recently confirmed HRs for PFS and OS of 0.68 and 0.80, respectively, in favor of MPT [63]. The superior efficacy of MPT comes at a cost of greater toxicity; mainly myelosuppression, thromboembolism and peripheral neuropathy. Higher doses of thalidomide, up to 400 mg, as used in the Nordic trial, resulted in greater toxicity, whereas lower doses (100–200 mg) were better tolerated and did not compromise survival outcome [60]. As such, there is a move towards lower doses of thalidomide (50–100 mg) and melphalan when MPT is applied to patients 75 years of age or older [63].

Like MPT, combination VMP is impressive. An initial interim analysis of the randomized Phase III VISTA trial showed convincing superiority of VMP compared with MP with regards to ORR (70 vs 44% in the MP arm), CR (35 vs 4%), TTP (24 vs 16 months) and 2-year OS (83 vs 70%) [18]. A more recent report showed that the quality of responses improved with prolonged VMP treatment, with 28% of CRs achieved during cycles five to nine [6]. Importantly, the superior efficacy of VMP was demonstrated in poor prognostic groups, including patients with high-risk cytogenetics, renal impairment and advanced age. However, this was not confirmed in the Spanish study comparing VMP with bortezomib, thalidomide and prednisone (VTP) in patients aged 65 years or older [32]. Here, patients with high-risk cytogenetics (t4;14, t14;16 or del17p) had shorter OS, despite a similar ORR compared with patients with standard-risk cytogenetics. There was no difference in efficacy between VMP and VTP, with impressive CR rates of 20 and 28%, respectively, postinduction therapy (p = 0.2). VTP was associated with a higher rate of serious adverse events – in particular, 8% of serious cardiac events, leading to discontinuation. Importantly, the rate of CR was further improved with ongoing bortezomib and prednisone or bortezomib and thalidomide (VT) maintenance therapy, to 39 and 44%, respectively. Weekly dosing of bortezomib (as opposed to twice weekly in the classic scheduling of day 1, 4, 8 and 11 every 21 days) appears to reduce bortezomib-induced peripheral neuropathy, constipation and thrombocytopenia [32,64] and should be considered for elderly patients.

The main contender for MPT and MPV as upfront treatment for elderly patients is MP combined with lenalidomide (MPR; Revlimid™). In an interim report of the international Phase III randomized trial (MM-015) comparing MPR with MPR followed by lenalidomide maintenance (MPR-R) and MP, the response was highest in the MPR-R arm (MP: ORR 77 vs 50%, p < 0.001; MP: ≥VGPR 32 vs 12%, p < 0.001) [65]. Ongoing therapy with lenalidomide (i.e., MPR-R) resulted in a 69% risk reduction of progression (p < 0.001) compared with MPR alone. Grade 3 or 4 neutropenia, thrombocytopenia and anemia occurred in 71, 38 and 24% of patients, respectively. However, the incidence of myelosuppression was low during single-agent lenalidomide maintenance therapy.

Other non-melphalan-containing induction regimens could also be used in patients not eligible for ASCT. However, these have yet to demonstrate superior survival compared with MPT. In the Phase III Eastern Cooperative Oncology Group E4A03 trial [55], lenalidomide and dexamethasone (len–dex) combination appeared efficacious as induction therapy. However, the use of lenalidomide with high-dose dexamethasone (RD; dexamethasone 40 mg daily on days 1–4, 9–12 and 17–20 every 28 days) was more toxic compared with lenalidomide and low-dose dexamethasone (Rd; dexamethasone 40 mg weekly). This was especially true for patients aged over 65 years, in whom increased early deaths, venous thromboembolism (VTE) complications and other serious adverse events were encountered. The increased treatment-related mortality in the high-dose dexamethasone plus lenalidomide arm resulted in an inferior OS despite a superior response rate [55]. A study comparing MPT with len–dex, MM-020, is nearing completion. It is worth reiterating that unlike len–dex, combination TD has only modest efficacy as an induction therapy, with an ORR between 64 and 76% [66–68] and an inferior OS compared with MP in elderly patients [41].

Combinations of two novel agents with chemotherapy, such as the addition of thalidomide to VMP (VMPT) followed by maintenance VT, appear to induce an impressive response, with a CR rate of 38% [33,64] and superior PFS compared with VMP (p = 0.008) However, toxicities were significant, with rates of grade 3 and 4 hematological and nonhematological toxicities being up to 45 and 51%, respectively. Similarly, lenalidomide, bortezomib and dexamethasone is emerging as an effective combination for elderly patients [56,57]. Preliminary data from a Phase I/II trial [57], which included patients up to the age of 86 years, showed an ORR of 100%, with a CR of 37%. The incidence of grade 3 or 4 neutropenia and thrombocytopenia were 10% each and nonhematological toxicities were low. This non-chemotherapy-containing regimen is impressive, but requires further study to ascertain the outcome in the elderly-patient subgroup in the ongoing Phase II trial.

Maintenance treatment

Maintenance therapy postinduction or ASCT aims to improve PFS and OS, but must be weighed up against the potential treatment-related toxicities in a group that would otherwise enjoy a treatment-free period of remission. Furthermore, the potential resistance to subsequent salvage therapy as a result of ongoing drug exposure remains an unresolved issue [19].

In the setting of post-ASCT, thalidomide maintenance has shown a trend towards improvement in OS in one meta-analysis [69]. Two [70,71] out of the five randomized studies [70–74] of thalidomide maintenance following ASCT have shown benefits with respect to OS. However, these studies pertain to a younger patient population and are extrapolated to older patients undergoing ASCT. Thalidomide maintenance, especially when applied to elderly patients, is not without side effects, which include lethargy, sedation, peripheral neuropathy and constipation. The incidence of thalidomide-induced neuropathy is both cumulative and dose-related and, generally, patients only tolerate lower doses of thalidomide (∼100 mg) for 12–24 months. The benefit of maintenance therapy with other novel agents such as lenalidomide [75] or bortezomib [76] following ASCT is being evaluated in ongoing trials.

In patients not proceeding towards ASCT, the ability of maintenance therapy post-induction treatment to improve OS is still unclear in the era of novel therapeutic agents. In a randomized comparison between maintenance thalidomide (100 mg/day) plus dexamethasone (20 mg daily on days 1–4 every 28 days) or interferon three-times weekly, following induction with thalidomide, dexamethasone and pegylated liposomal doxorubicin, Offidani and colleagues demonstrated a superior 2-year PFS and OS with thalidomide-based maintenance (PFS 63 vs 32%; p = 0.02; OS 84 vs 68%; p = 0.03) [77]. However, in the setting of MPT, survival postrelapse appeared to be shorter in patients with ongoing thalidomide maintenance compared with patients who received MP [19]. This was not observed in MPT trials that ceased thalidomide after induction therapy [39], raising the question of whether thalidomide maintenance could induce drug resistance, which would potentially compromise duration of response and survival postrelapse.

Like thalidomide, maintenance therapy with bortezomib [32] or lenalidomide [78] post-induction appears to improve responses, but the impact on OS remains to be seen. On preliminary analysis, the randomized trial of MPR with or without lenalidomide maintenance versus MP alone, showed that the addition of lenalidomide maintenance improved the quality of responses and reduced the risk of progression (HR: 0.42; p < 0.001) [65]. Similarly, in a recent Spanish study, ongoing maintenance with VT after induction with VTP or VMP improved CR rates from 24% after induction to an impressive 42% in patients randomized to the maintenance arm [32]. This was echoed by the recent Italian study, which showed that maintenance therapy for at least 6 months with VT after VMPT induction further improved the CR rate from 58 to 62% [33]. Such a CR rate is unprecedented for elderly patients with MM and will hopefully translate to improve OS with longer-term follow-up. Importantly, maintenance with VT was well tolerated with a low incidence of grade 3 and 4 toxicity including peripheral neuropathy [32].

Treatment of relapsed elderly patients with myeloma

The principles guiding the choice and sequence of salvage therapy for elderly patients, like young patients, are dependent on the nature and response to past treatments and speed of relapse, but with emphasis placed on current comorbidities that may impinge on treatment tolerance. Many effective salvage options have emerged that combine one or more of thalidomide, lenalidomide and bortezomib, with or without chemotherapy and with or without corticosteroids [51,54,79–85]. Owing to the heterogeneity and effectiveness of salvage therapy at subsequent relapses, it is difficult to compare OS outcome between different treatment regimens. However, incorporation of novel agents at first relapse appears to produce superior outcomes compared with their use as later lines of salvage treatment [86,87].

Often, the choice of which novel agent to use at relapse not only depends on availability, but also on individual preference (oral vs intravenous route of administration) and, importantly, comorbidities. In patients with pre-existing neuropathy, exacerbation may occur with bortezomib or thalidomide. Peripheral neuropathy is dose related and is usually reversible if prompt dose reduction or temporary cessation of bortezomib or thalidomide is applied upon the onset of grade ≥2 severity [88,89]. For patients with a previous history of VTE or who are at high risk of VTE events, thalidomide and lenalidomide, although not absolutely contraindicated, should be avoided if alternate effective options are available. VTE risks are highest when these immunomodulatory drugs are used with high-dose dexamethasone or anthracycline chemotherapy. Prophylactic or therapeutic-dose anticoagulation should therefore be instituted as appropriate [90]. Lenalidomide is cleared via the renal route and is not generally the first choice of treatment in patients with moderate-to-severe renal impairment. Thalidomide or bortezomib are preferred in such patients, especially as the latter has been shown to potentially reverse the poor prognosis implicated by renal impairment [18].

In patients with rapidly progressive disease, intensive regimens combining novel agents with chemotherapy can be considered in selected elderly patients with good performance status and organ function [54,79,81–83]. By contrast, patients with slow disease progression may do well with single-agent novel therapy with or without dexamethasone, especially if they cannot tolerate more intensive treatment. Similarly, HDT and ASCT could be considered at early relapses for a selected group of well-functioning elderly patients, particularly as this option is not viable with the decline in performance status and advancing age at subsequent relapses. If relapse occurs over 6 months following cessation of the last treatment regimen, the same regimen can be reconsidered, however, an inferior duration and quality of response is to be expected. When all different novel agent combinations have been exhausted, conventional moderate doses of cyclophosphamide [91], nonmyeloablative doses of melphalan [92] or low-to-modest doses of corticosteroids remain viable options, as is palliation in patients who cannot tolerate any further therapy.

Special treatment considerations for elderly patients

The management of elderly patients with MM must focus on issues beyond that of disease control given the likelihood of multiple comorbidities. The chance of succumbing to any complications is higher and the stepwise clinical deterioration associated with each complication is often substantial, underlining the importance of preventative and supportive therapy. For instance, elderly patients, especially those with concomitant cardiorespiratory disease, tolerate anemia poorly. Apart from blood transfusions, recombinant human erythropoietin is beneficial and has been shown to improve fatigue score and quality of life in patients with MM [93]. Vigilance regarding VTE risks is warranted, especially when recombinant human erythropoietin is used in combination with thalidomide or lenalidomide. VTE prophylaxis with either aspirin, prophylactic-dose low-molecular-weight heparin or therapeutic-dose warfarin should be used according to VTE risk stratification [90].

Infectious complications can result in significant clinical decline and must be treated promptly if not prevented. Elderly patients are more susceptible to varicella-zoster virus reactivation, which can potentially result in debilitating post-herpetic neuralgia. Patients treated with bortezomib should be on prophylaxis against Varicella Zoster virus with aciclovir, especially when used in combination with high-dose corticosteroids [94]. Prophylaxis against Pneumocystis jirovecii (carinii) with trimethoprim and sulfamethoxazole should be considered in patients receiving high-dose corticosteroids. In patients with recurrent pneumonia and marked hypoglobulinemia, monthly infusions of intravenous immunoglobulin may help to prevent infections. Impaired renal function is more common in elderly patients, necessitating the dose reduction of medications that are renally cleared, such as lenalidomide.

Increasingly, it is recognized that dose reduction of many antimyeloma therapies may benefit elderly patients in whom the delivery of standard-dose therapy is difficult. In the MM-009 and MM-010 trials, treatment-related toxicities requiring lenalidomide dose reduction (from a starting dose of 25 mg) were more common in elderly patients and patients with renal impairment. Lower doses of lenalidomide are better tolerated in this patient group. Our preliminary data of 15 mg of lenalidomide in combination with lower-dose dexamethasone (20 mg orally daily on days 1–4, 9–12 and 17–20 every 28 days) appear to reduce myelosuppression, without reduced efficacy in a group of elderly patients with or without renal impairment compared with standard-dose lenalidomide (25 mg) and dexamethasone [95]. Similarly, the use of lower-dose bortezomib (weekly as opposed to twice weekly) appear to result in less neurological and other nonhematological toxicities without compromising efficacy [64]. Dose reduction of corticosteroids is often warranted in elderly patients, in whom diabetes, mood disorders and increased risk of infections are more common [55].

Finally, the issue of polypharmacy and drug interactions is especially relevant to elderly patients. For example, thalidomide-induced constipation may be exacerbated by opiod analgesics; bradycardia associated with both thalidomide and lenalidomide warrants caution when used in conjunction with β-blockers for cardiovascular diseases.

Are we making progress in the treatment of MM for elderly patients?

Undoubtedly, the addition of novel therapeutic agents to conventional therapy and the expansion of effective salvage options have increased the outcome expectation for elderly patients with MM. Unprecedented CR rates can now be achieved in elderly patients, for example, 38% CR with VMPT–VT [33], compared with 24–33% with MPV and <5% within the MP era. Practically however, the standard incorporation of novel agents in the treatment of elderly patients has trailed behind the publications of clinical trials that have shown improved outcome for this older subgroup. Even in so-called developed countries, limitations of access to certain novel agents, either due to economic or regulatory constraints, means that some treatment options are still either restricted to certain phases of disease or not available at all. Thus, survival estimates predicted by clinical trials may not reflect what we see in real-life clinical practice. This partially accounts for the apparent lack of survival improvements in elderly patients in recent reports [3] compared with younger patients in whom clinical trials and the application of innovative approaches have been established much earlier in the historical timeline.

Expert commentary

Increasingly, the clinical approach for older patients with MM requires individualization due to the expanding array of treatment options. ‘Elderly patients’ are no longer synonymous with persons not eligible for HDT and ASCT, given that the enhanced safety of this treatment modality has made it feasible in selected patients up to 70 years of age [47,96]. Indeed, induction therapies that combine novel agents with corticosteroids, with or without chemotherapy, have induced impressive rates of CR even prior to ASCT. Deferring ASCT in this situation is debatable. However, at present, we prefer to proceed to ASCT following up-front induction in eligible patients up to the age of 70 years, as this further improves the depth of responses [59,97] and may not be feasible at future relapse upon declining performance status and further advancing age. In patients not eligible for ASCT, we would use a novel therapeutic agent in combination with chemotherapy and corticosteroids. Currently, either MPT [39,61] or MPV [6] are appropriate induction regimens and are clearly superior to MP. MPR [65], as well as more intensive regimens combining two novel agents [32,33], appears promising and we eagerly await final results. Vigilance regarding treatment-related toxicity is especially relevant in older patients in whom multiple comorbidities may limit the intensity of deliverable treatment. In particular, recognition is required of a small subgroup of elderly patients above 80–85 years of age who cannot tolerate toxicities and in whom reduced doses of MP, monotherapy with novel agents or corticosteroids, or palliation therapy is more appropriate. The wide spectrum of treatment-intensity options for elderly patients with MM is a result of our growing recognition of the clinical heterogeneity of this population. Increasingly, a balancing act is required from the treating physician to recognize on the one hand, ‘fit’ elderly patients who will be potentially disadvantaged by undertreatment and on the other, frailer elderly patients in whom the toxicities of intensive treatment may outweigh any potential survival benefit.

Five-year view

Treatment of MM for elderly patients will continue to evolve over the next 5 years, as long-term data materialize and more clinical trials emerge focusing on this subgroup of patients. Long-term survival data will probably confirm the positive impact on survival in elderly patients with MM, made possible by the use of novel therapeutic agents. Questions regarding the optimal front-line treatment, in particular the role of HDT and ASCT in improving depth of CRs in the era of novel agents, will be elucidated upon longer follow-up and recommendations can then be made based on robust survival data.

Complete response is becoming an increasingly achievable goal for elderly patients [6,32,40] and has emerged as an independent predictor of long-term survival regardless of age [40]. This fact has, and will, prompt further studies utilizing complex combinations of two or more novel agents with or without chemotherapy and maintenance, in an attempt to increase the rate of CR for elderly patients. The future will see fine-tuning of dosage and schedule of such multiple drug combinations to minimize toxicity.

The use of free-light-chain assay, multiparameter flow cytometry and PCR may be incorporated into routine practice in order to detect a deeper level of CR compared with immunofixation [7,32]. This will probably create a new standard of CR and a more ambitious treatment goal for both young and old patients with MM. As these techniques improve, a role for minimal disease detection in deciding treatment intensity and maintenance therapy may emerge.

Finally, new classes of antimyeloma agents will continue to surface. Histone deacetylase inhibitors [98] have already shown potential synergism with bortezomib or lenalidomide [99,100] or chemotherapy [101] in relapsed MM. Other families, including heat shock protein-90 inhibitors [102,103], promise synergistic activities with the current novel therapeutic agents. The side-effect profile of these novel agents, especially when used in combination with currently available therapy, needs to be carefully assessed. Importantly, assessments of quality of life, which hitherto have been lacking in MM studies, need to be incorporated into future studies and are especially relevant for studies involving older patients with MM. Indeed, the challenge in enhancing survival for elderly patients not only rests with ongoing research into tolerable novel treatment regimens, but importantly, scrupulous supportive care and the judicious use of the currently available novel therapeutic agents in appropriate dosing, combinations and sequence, so as to minimize toxicities while maximizing disease control and so improving patient outcome.

Table 1. Examples of induction regimens for elderly patients not eligible for high-dose therapy and autologous stem-cell transplantation.

Regimen	Study	Regimen details	Result	Ref.
MPT	GIMEMA	Melphalan 4 mg/m^2 p.o. daily, days 1–7 Prednisone 40 mg/m^2 daily, days 1–7 Thalidomide 100 mg p.o. daily Cycles repeated every 4 weeks × 6, thalidomide continued until relapse	ORR ∼85%, CR 15.6% Median TTP 24.7 months	[38]
	IFM 99-06	Melphalan 0.25 mg/kg p.o. daily, days 1–4^† Prednisone 2 mg/kg p.o. daily, days 1–4 Thalidomide 200 mg p.o. daily (dose increased as tolerated to maximum 400 mg) Cycles repeated every 6 weeks × 12, then stopped	ORR 76%, CR 13% Median OS 51 months	[39]
MPV	VISTA	Melphalan 9 mg/m^2 p.o. daily, days 1–4 Prednisone 60 mg/m^2 p.o. daily, days 1–4 Bortezomib 1.3 mg iv. days 1, 4, 8, 11, 22, 25, 29 and 32 during cycles 1–4, and on days 1, 8, 22 and 29 during cycles 5–9 Cycles repeated every 6 weeks × 9, then stopped	ORR 76%, CR 30% Median duration of response 19.9 months Median OS not reached at median follow-up of 16 months	[6,18]
VMP versus VTP		Melphalan 9 mg/m^2 p.o. daily, days 1–4 Prednisone 60 mg/m^2 p.o. daily, days 1–4 Bortezomib 1.3 mg/m^2 iv. days 1, 4, 8, 11, 22, 25, 29 and 32 during cycle 1, and on days 1, 8, 22 and 29 during cycles 2–6 versus Thalidomide 100 mg p.o. daily (50 mg days 1–15) Prednisone 60 mg/m^2 p.o. daily, days 1–4 Bortezomib 1.3 mg/m^2 iv. on days 1, 4, 8, 11, 22, 25, 29 and 32 during cycle 1, and on days 1, 8, 22 and 29 during cycles 2–6 After four cycles of induction, patients were randomized to receive VT or VP as maintenance until disease progression	Postinduction (VMP): ORR 80%, CR 20% Postinduction (VTP): ORR 81%, CR 28% No difference in efficacy between VMP and VTP; VMP better tolerated CR rates further improved with maintenance VT (CR 44%) or VP (CR 39%)	[32]
MPR-R	MM-015	Melphalan 0.18 mg/kg p.o. daily, days 1–4 Prednisone 2 mg/kg p.o. daily, days 1–4 Lenalidomide 10 mg p.o. daily Cycles repeated every 4 weeks × 9 ± lenalidomide continued until relapse	MPR-R: ORR 77%, CR 16% Median TTP 24.7 months 2-year OS 86.2%	[65]
VMPT-VT		Thalidomide 50 mg p.o. daily Melphalan 9 mg/m^2 p.o. daily, days 1–4 Prednisone 60 mg/m^2 p.o. daily, days 1–4 Bortezomib 1.3 mg/m^2 iv. daily, days 1, 4, 8, 11, 22, 25, 29 and 32 during cycles 1–4, and on days 1, 8, 22 and 29 during cycles 5–9 Cycles repeated every 6 weeks × 9, followed by maintenance with: Bortezomib 1.3 mg/m^2 iv. every 14 days Thalidomide 50 mg p.o. daily Continued for 2 years or until progression/relapse, whichever is earlier	ORR 89%, CR 38% Responses were superior compared with VMP at the cost of greater toxicity Grade 3 or 4 neutropenia 38% and cardiologic events 10%	[33]
Lenalidomide–bortezomib–dexamethasone		Lenalidomide 25 mg p.o. daily, days 1–14 Bortezomib 1.3 mg/m^2 iv. days 1, 4, 8 and 11 Dexamethasone 20 mg (10 mg for cycles 5–8) p.o. on days 1, 2, 4, 5, 8, 9, 11 and 12 Cycles repeated every 3 weeks × 8 followed by ASCT (after a minimum of four cycles) or further maintenance with: Lenalidomide 25 mg p.o. daily, days 1–4 Bortezomib 1.3 mg/m^2 iv. on days 1 and 8 Dexamethasone 10 mg p.o. on days 1, 2, 8 and 9	Phase II cohort (n = 35): ORR 100%, CR 37%	[57]

Nonmelphalan-containing induction regimens used in patients proceeding to ASCT can also be used in patients not proceeding to ASCT.

^†Consider using a lower dose of melphalan (0.18–2.0 mg/kg) and thalidomide (50–100 mg) for patients aged ≥75 years [63].

ASCT: Autologous stem-cell transplantation; CR: Complete response; GIMEMA: Gruppo Italiano Malattie Ematologiche dell’Adulto; IFM 99-06: Francophone Myeloma Intergroup 99-06; iv.: Intravenous; MPR: Melphalan, prednisone and lenalidomide; MPR-R: Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance; MPT: Melphalan, prednisone and thalidomide; MPV: Melphalan, prednisone and bortezomib; ORR: Overall response rate; OS: Overall survival; p.o.: Per oral; TTP: Time to progression; VISTA: Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone; VMP: Bortezomib, melphalan and prednisone; VMPT-VT: Bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance therapy; VP: Bortezomib and prednisone; VT: Bortezomib and thalidomide; VTP: Bortezomib, thalidomide and prednisone.

Table 2. Phase III studies comparing melphalan and prednisone with melphalan, prednisone and thalidomide for the upfront treatment of multiple myeloma.

Study	Regimen	Participants (n)	CR and PR (%)	TTP	OS	Statistical significance for OS	Ref.
GIMEMA	MPT (T maintenance to PD)	129	76	21.8	45		[19]
	MP (no maintenance)	126	48	15.5	47.6	NS
IFM 99	MPT (72 weeks treatment)	191	76	27.5	51.6		[39]
	MP (72 weeks treatment)	124	35	17.8	33.2
	MEL 100	121	65	19.4	38.3
IFM 01	MPT (72 weeks treatment)	113	62	24.1	45.3	p = 0.03	[61]
	MP (72 weeks treatment)	116	31	9	27.7
NMSG	MPT (T maintenance)	148	47 (23% ≥VGPR)	20	29	NS	[60]
NMSG	MP	179	40 (7% ≥VGPR)	18	33
HOVON	MPT (T maintenance)	165	66	PFS: 15	40	p = 0.05	[104]
HOVON	MP	168	45	PFS: 11	31
Beksac et al. (2011)	MPT (eight cycles)	62	58	DFS: 21	26	NS	[62]
	MP (eight cycles)	60	38	DFS: 14	28

CR: Complete response; DFS: Disease-free survival; GIMEMA: Gruppo Italiano Malattie Ematologiche dell’Adulto; HOVON: Dutch–Belgian Hemato-Oncology Cooperative Group; IFM: Francophone Myeloma Intergroup; MEL 100: Melphalan 100 mg/m²; MP: Melphalan and prednisone; MPT: Melphalan, prednisone and thalidomide; NMSG: Nordic Myeloma Study Group; NS: Not significant; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; T: Thalidomide; TTP: Time to progression; VGPR: Very good partial response.

Key issues

• • Improved survival in patients with multiple myeloma is a direct consequence of novel therapeutic agents.

• • Treatment-related toxicities have retrenched this improvement in the elderly patient population.

• • Achievement of a complete response is an independent predictor of long-term survival irrespective of age; however, the goal of achieving complete response must be balanced with treatment-related toxicities for elderly patients; thus, individualization of treatment based on biological age is required.

• • Ongoing research into tolerable treatment regimens, effective supportive care and correct dosing will optimize disease control, minimize toxicities and continue to improve survival for elderly patients with multiple myeloma in the future.

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Managing multiple myeloma in the elderly: are we making progress?

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. A 55-year-old man was diagnosed with multiple myeloma (MM) in 2010. Compared with being diagnosed in 2000, which of the following best describes his expected median survival?

• □ A Similar

• □ B Improved by less than 2 years

• □ C Improved by 2–5 years

• □ D Improved by 6–8 years

2. For the patient in question 1, which of the following is most likely to be predictive of progression-free survival and long-term outcome?

• □ A Complete response

• □ B Performance status

• □ C Presence of comorbidities

• □ D Response to melphalan

3. A 66-year-old woman is diagnosed with MM and has good performance status with one comorbidity. Which of the following is considered the most optimal upfront treatment for her?

• □ A Stem cell-sparing induction treatment followed by ASCT

• □ B High-dose melphalan and dexamethasone

• □ C Conventional dose vincristine and doxorubicin

• □ D All of the above are equally efficacious

4. In a 75-year-old man with high-risk cytogenetics MM and renal impairment, not eligible for ASCT, which of the following is likely to be the most optimal treatment strategy?

• □ A Melphalan and prednisone

• □ B High-dose melphalan, prednisone, and thalidomide

• □ C Bortezomib, melphalan, and prednisone

• □ D All of the above are similar in efficacy and toxicity

5. Beyond disease control, which of the following factor(s) is/are likely to poorly impact outcomes of MM treatment in elderly compared with younger patients?

• □ A Poor tolerance of anemia

• □ B Varicella zoster reactivation

• □ CPneumocystis carinii infection

• □ D All of the above