Multiple myeloma (MM) is a heterogeneous disease for which, despite the continuing advances in existing therapies such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), there is currently no cure.1–3 MM treatment strategies continue to evolve; however, there remains an unmet need to reduce disease burden, improve tolerability of treatments and achieve long-lasting improvements in patient outcomes.3,4 In this article we review the latest data on the factors that affect patient outcomes in MM, and explore the optimal therapeutic goals in the management of this disease and the treatment approaches that could help make long-term MM disease control a reality for patients.
Drivers of poor prognosis: lessons from
Line of therapy and relapsed/refractory MM disease status
The treatment course of active MM is characterised by remission and subsequent relapse, during which the disease will inevitably become refractory to treatment.4 Several recent studies have started to characterise the real-world clinical progression of relapsed/refractory (RR) MM.5–7 In a study of 2513 patients enrolled in the Registry of Monoclonal Gammopathies database of the Czech Myeloma Group, median overall survival (OS) decreased from 50.3 months (95% confidence interval [CI] 46.1–54.5) at diagnosis to 47.5 months (95% CI 43.1–52.0) at first-line and 13.2 months (95% CI 11.3–15.2) at third-line therapy (Figure 1).5 Similar findings were reported in a US study that used electronic medical records to evaluate progression-free survival (PFS) and OS in 628 newly-diagnosed MM patients as they progressed through the treatment pathway.7 In this study, the difference in OS between second-line and fourth-line therapies was 16.2 months. As well as worsening survival outcomes, the US study also found that successive fixed-dose regimens resulted in shorter time to next treatment in the RRMM population.7 Specifically, time to new treatment or death decreased as RRMM patients progressed from second-line therapy to third-line and fourth-line therapy (15.1 months to 7.8 and 6.9 months, respectively).7
In a recent European study including the UK, in patients with MM, the effect of treatment response on costs to the healthcare system was evaluated.8 It found that the mean monthly costs for patients with MM achieving a deeper response were lower than for those patients who had a lesser response. This may be related to lower hospitalisation rates seen in the deeper responders. In the UK, the mean costs per month from beginning of treatment of MM patients to progression were €4342 for patients achieving at least a very good partial response, €6031 for patients achieving a partial response (PR) and €5924 for patients with stable or progressive disease.8
Real-world studies have also attempted to distinguish between patients with MM who fail to respond to treatment and those who relapse. Compared with the relapsed population, refractory MM patients are more likely to have high-risk cytogenetics (16.9% versus 3.2%, respectively), renal impairment (RI; 52.8% versus 37.9%), anaemia (65.2% versus 45.3%), hypercalcaemia (15.7% versus 3.7%) and bone disease (30.3% versus 23.7%); at the start of second-line therapy, these refractory patients with increased disease burden were also more likely to switch to a therapy with a different mode of action to their primary treatment.9
Building on the importance of patient-related factors rather than treatment responses, it is also possible to differentiate subgroups with poor prognosis based on patient frailty – taking into account age, comorbidities and disabilities – and cytogenetic status, gene-expression profile (GEP) and the revised International Staging System (R-ISS).10–16
Frailty, comorbidity and disability are terms that are commonly and interchangeably used in relation to the fitness and vulnerability of elderly patients; however, these factors are distinct and their relationship to age and each other is becoming more apparent.16 It has long been recognised that older patients with MM have a poorer prognosis and this continues to be true today.14,17 Mortality in the first few months after diagnosis is under-recognised in patients with myeloma and better real-world data are required around this issue.18 It is important, however, to not use age to assess treatment decisions, but to assess patients based on frailty, Eastern Cooperative Oncology Group (ECOG) performance status and comorbidities; this is being recognised as increasingly important in delivering tolerable and effective treatments. Poorer outcomes are in part related to the increased frequency of adverse prognostic factors such as high ISS scores and poorer ECOG performance status, increased comorbidities, and increased frailty.17 Patients can also experience age-related deterioration in organ function, which impacts on the pharmacokinetics/pharmacodynamics of drugs (and thereby on the maximum efficacy and tolerability of a given agent).16 In effect, a retrospective analysis of US electronic medical records data also suggests that newly-diagnosed older MM patients (aged ≥75 years) receive suboptimal treatment that adversely impacts survival.14 Results showed that younger patients, compared with older patients, were two-fold more likely to receive an intensive PI plus IMiD-based combination therapy at first-line (21.8% versus 10.8%, respectively) and in second-line (11.1% versus 5.2%) therapy.
Although comorbid conditions are common among patients with MM, many of whom are in advanced age, the impact of these comorbidities on clinical outcomes has not been studied in detail in the real-world.15 Among a US population of 628 RRMM patients with a median age of 69 years, almost half (48%) of patients had comorbid renal dysfunction (RD) and/or cardiovascular disease (CVD) before beginning first-line treatment, and this proportion increased to 68% before second-line treatment.15 Time to new treatment or death after second-line therapy was markedly shorter for RRMM patients with these comorbidities; 12.3 months for patients with RD and CVD, 13.7 for patients with RD only, and 14.3 months for patients with CVD only, compared with RRMM patients without these comorbidities (20.1 months). The presence of comorbid conditions in patients with RRMM was also associated with reduced survival at 1- and 2-years after initiation of second-line therapy (72.7–77.8% and 51.6–64.1%, respectively) versus patients with no comorbid RD and/or CVD (88.2% and 78.4%, respectively; p<0.05).
The revised International Staging System, cytogenetic profile and gene-expression profiling
High-risk cytogenetics and GEPs are associated with poor prognosis in patients with MM.10–15,19,20 The R-ISS updated the previous International Staging System (ISS), which incorporated β2-microglobulin and albumin, to now include lactate dehydrogenase (LDH) and adverse cytogenetic features.21 Patients with high-risk fluorescence in situ hybridisation (FISH) status, defined as the presence of the chromosomal deletion (del[17p]) or one of the t(4;14), t(14;16) and t(14;20) translocations, have significantly poorer OS when compared with standard-risk patients; the median OS for these groups from time of diagnosis was 3.5 years and not reached, respectively (p<0.001) (Figure 2).22,23 Importantly, patients with more than one adverse cytogenetic risk feature do much worse than those with a single cytogenetic risk feature. Other adverse cytogenetic risk features also exist; for example, patients with gains in chromosome 1q have inferior OS outcomes compared with 1q-negative patients (hazard ratio 2.00; p<0.001) (Figure 2).23 Recent analyses of 1q21 gains in symptomatic newly-diagnosed MM patients have also shown its association with shorter PFS (17 versus 25 months; p=0.01).12 In accordance with these findings, high-risk chromosomal abnormalities are included in the R-ISS Stage III disease of MM; patients in this group have 40% and 24% 5-year OS and PFS rates, respectively.21
In patients with standard-risk cytogenetics, factors including age older than 65 years at diagnosis, <20% plasma cells in bone marrow and hypodiploid clone karyotype are all associated with poorer survival.11 Although advanced age is also associated with poor outcomes in patients with high-risk cytogenetics, ISS Stage III disease and elevated baseline LDH are additional characteristics that have been shown to confer poor survival in this patient population.12 A significant proportion (10–24%) of real-world RRMM patients are classified as having high-risk disease based on their ISS stage and cytogenetic profile; survival outcomes in this population are particularly poor.24 GEP can also be used to identify a group of high-risk patients that are not categorised as having high-risk cytogenetics by FISH, as there is only partial overlap between patients with an adverse GEP and patients with adverse cytogenetics by FISH. In the future, GEP may be used in addition to FISH to more comprehensively identify a group of patients with high-risk myeloma.19,20 Currently, there is a lack of global standardisation with regards to cytogenetic testing as well as a lack of prospective studies looking at treatment options and respective outcomes in patients with high-risk cytogenetic disease.
There is a continuing unmet need within MM for new therapeutic options to improve patient outcomes, particularly in high-risk patient subgroups with one or more factors associated with poor prognosis
Optimising treatment response in the context of current treatment strategies
Recent real-world data suggest that RRMM patient outcomes may be improved and long-term disease control can be achieved through optimisation of response to therapy.7,9,14
Variable patient responses to therapy necessitate consideration of both depth and duration when defining an optimal treatment response. Complete response (CR), defined by negative immunofixation and bone marrow plasma cell number below 5%, is an established measure of the depth of response to treatment and is deemed clinically relevant as a marker for survival.25,26 However, the presence of residual disease is not detected within these standard response measurements and definitions; suggesting that efficacy goals beyond CR should be considered.3
A deeper measure of response than CR is termed minimal residual disease (MRD) and is measured either by flow cytometry or by next-generation sequencing, ideally using a cut-off of 10−5 cellular level for being MRD negative (Figure 3).3,27 Lower levels of MRD correlate with improved PFS and OS, with data from the Medical Research Council (MRC) Myeloma IX trial showing a 1-year survival benefit per log depletion of MRD levels.27,28 MRD will become a primary endpoint of trials of newly-diagnosed MM patients as a surrogate marker of PFS and OS. Increasingly OS is becoming a more difficult measure for trials for newly-diagnosed MM patients as survival times continue to improve.29 Apart from assessment of response, how we use MRD to alter therapy is still unclear, but in theory it may have value in determining the escalation or de-escalation of treatment.
Beyond consideration of the depth of response, longer duration of response has also been shown to correlate with improved survival. A study of 668 patients with MM showed that achieving a sustained CR at 3 years was associated with significantly longer median survival when compared with not achieving CR or achieving and subsequently losing CR status (p<0.0001) (Figure 4).30 Importantly, median survival at the 3-year landmark analysis was significantly greater in patients who never achieved CR, compared with those who initially achieved deeper CR but then lost it (p<0.0001).30 The presence of persistent MRD alongside high-risk cytogenetic features is associated with loss of CR, reinforcing the importance of both factors in achieving long-term disease control.31
Evidence from recent studies reinforces the potential benefits of a longer and deeper response to treatment in patients with RRMM.8,32,33 One US study of RRMM patients showed that the odds of 1-year survival were 1.2 times higher for each additional month of second-line treatment received.33 Therefore, in addition to achieving depth of response, maintaining treatment response and staying on treatment are key aims for the management of patients with RRMM.34
Long-term disease control, as evidenced by durable treatment responses, leads to improved patient outcomes in RRMM 8,32,33
Acheiving long-term disease control
The concept of clonal heterogeneity and the presence of high variability in genomic architecture in MM has clear therapeutic implications; understanding the clonal composition of the tumour at each treatment phase could be used to guide treatment and to identify combinations effective against multiple targets rather than a single genomic anomaly.1,35,36 However, using genetic data in this way to guide therapy is still an aspirational goal.
The synergistic effect of combining therapies with different mechanisms of action (eg IMiDs and PIs, histone deacetylase [HDAC] inhibitors and PIs) may lead to a deeper and more durable response. This has been studied in vitro, with results suggesting that the different classes of MM agents are likely to exert multiple, but overlapping, effects that lead to disruption of tumour cell growth and survival.38,39
Combining PIs with IMiDs and corticosteroids has shown promise in patients with MM.38–41 In newly-diagnosed and RRMM patients, triple combination therapy with PIs, IMiDs and corticosteroids improved CR rates by 13% to 24% and prolonged PFS at 2 years compared with double combinations without a PI or IMiD.38–40 Recent phase 3 studies of new agents in MM have also shown consistent benefits in PFS associated with the use of triplet versus doublet regimens, with OS gains observed where mature data are available.41–47
The presence of residual disease even in patients with CR supports the rationale for continuous treatment versus fixed-duration therapy, with the aim of continuously suppressing the survival/proliferation of tumour cells.4,34 The results of a phase 3 randomised trial of continuous versus fixed-duration therapy in 820 newly-diagnosed MM patients suggest that thalidomide modifies the residual cells in the bone marrow and, therefore, plays a maintenance role as well as exerting a consolidation effect.48 Importantly, however, thalidomide maintenance had an adverse effect for patients with poor-risk cytogenetics in the MRC Myeloma IX trial.49 Continuous lenalidomide plus dexamethasone given until disease progression provided a significant improvement to PFS and OS rates in newly-diagnosed MM patients who were ineligible for stem cell transplantation,50 however this benefit is mainly due to the effect on standard-risk patients; patients with high-risk cytogenetic features do not show improved survival outcomes on lenalidomide treatment.51,52
In a front-line setting, prior to the novel agent era, continuation of conventional chemotherapy agents such as interferon or single-agent corticosteroids did not prove to be effective in maintaining a response.34 The outcomes of novel agents in the maintenance setting have also been studied in the post-transplantation setting. Treatment with lenalidomide after high-dose (HD) autologous stem cell transplantation (ASCT) has been linked to significant improvements in time-to-progression and PFS, with varying effects on OS as compared with placebo.34,49,53 A meta-analysis of three trials also found that lenalidomide maintenance post-ASCT provides 5-, 6- and 7-year improvements in OS.53 However, treatment with lenalidomide was associated with increased rates of toxicity and a small risk of secondary cancers.53 Consolidation with a PI and IMiD combination after ASCT improved the quality of response in approximately 40% of patients with MM, and lengthened time-to-progression.54
Although a meta-analysis of five post-transplantation studies has identified significant PFS and OS improvements with thalidomide-containing maintenance regimens, these benefits were gained at the expense of a higher-risk of grade 3–4 toxicity.34 It is clear that thalidomide is not well tolerated as a maintenance strategy and that a newer IMiD such as lenalidomide is much more suitable for maintenance strategies. Bortezomib given as monotherapy after HD-ASCT provided a significant PFS benefit when compared with a thalidomide-containing maintenance regimen (p=0.002), and resulted in fewer toxicity events that required treatment discontinuation.55 Furthermore, a phase 3 trial of 1218 newly-diagnosed MM patients (both transplant-eligible and -ineligible) demonstrated that continuous therapy with bortezomib or IMiDs for at least 2 years significantly improved PFS and OS when compared with fixed-duration therapy for up to 1 year (p<0.01) (Figure 5).56
Promising evidence is emerging in support of the individualisation of maintenance therapy according to risk stratification, although further research is needed. In one study, use of a PI as induction and post-transplantation maintenance therapies was associated with significantly improved PFS and OS in an overall population of newly-diagnosed MM patients, as well as among a subgroup of high-risk patients (those with renal failure or deletion of chromosome 17p13 [del(17p)] and/or t[4;14]) compared with a thalidomide maintenance regimen.55 A second and later study specifically selected patients with del(17p) (n=110) to identify prognostic factors for survival and concluded that PI-based induction followed by ASCT and maintenance therapy may be the best treatment option for patients with del(17p).12 Moreover, inclusion of maintenance PI therapy as a single-agent or within IMiD-containing combinations over the long-term (up to 3 years) has been found to yield survival benefits in patients with MM, including those with high-risk cytogenetics.34 Nevertheless, there are challenges to the use of continuous and/or long-term therapies for MM with current agents that need to be considered.
Combination therapies and long-term, continuous therapies are two emerging treatment approaches in RRMM. Recent data have consistently demonstrated the survival benefits of triplet therapies and have also reinforced the conclusion that continuous therapy facilitates long-term disease control in patients with RRMM12,54,57
Challenges to maintaining long-term treatment
Extended duration of therapy is associated with improved clinical outcomes in clinical trials in MM,56,58 and there are several treatment- and patient-related factors to consider when using continuous therapies over long periods (Table 1):16,34,59–61
- Efficacy of the agent or regimen and the ability to maintain efficacious dosing
- Acceptable tolerability
- Emergence of cumulative toxicities
- Convenience of regimen to patients
- Pressure on healthcare resources.
Although many of the factors that influence duration of therapy, including older age and concomitant comorbidities, are more prevalent outside of clinical trials, until recently, real-world data related to duration of therapy among RRMM patients have been limited.62 A recent, retrospective, real-world, cohort study demonstrated that duration of therapy decreases with subsequent lines of therapy and that baseline comorbidities and type of second-line treatment are significantly associated with duration of therapy.62 These results suggest that tailored therapy choices that account for baseline patient comorbidities may mitigate the observed variation in duration of therapy.62 Additional real-world data also indicate that advanced age impacts treatment choice.14
Adverse events (AEs)/cumulative toxicities and the need to dose-adjust in vulnerable patient populations such as the frail, elderly and/or those with RI or hepatic impairment can compromise the ability to maintain efficacious treatment regimens.16,63 Neuropathy can be a serious concern with long-term use of the first generation PIs and/or thalidomide;63–65 whereas fatigue, gastrointestinal AEs, rash and thrombotic complications have been associated with current IMiD therapies.66–68 The risk of toxicities can increase when two or more agents are used; for example the occurrence of venous thromboembolism following triple combination treatment with corticosteroids, conventional chemo-therapies and IMiDs.69 Discontinuation of the agent(s) or dose reductions are two of the strategies that have been implemented to manage such AEs of therapy.63 However, it seems that dose reductions in the early stages may shorten the length of treatment and reduce survival in patients with MM.63
Requirements for dose adjustments in frail patients, such as those with renal and hepatic insufficiency, and/or advanced age, could limit treatment efficacy.16,70 Although there is no need to dose-adjust PIs and thalidomide for RRMM patients with RI, lenalidomide is renally excreted and therefore requires some dose adjustment when initiated in patients who have RI.63,71 Hepatic impairment has been reported to occur in patients taking concomitant medications for pain or comorbid conditions, as well as arising from treatment-related toxicity.71 Impaired hepatic function, as seen for RI, requires dose adjustments,71 but dosing recommendations are not clear for all of the novel agents due to the lack of patient data.
Patients with myeloma are susceptible to treatment toxicity – approximately half of frail and comorbid patients have a severe AE in the early cycles of treatment, which may be due to declining physiologic reserve and organ function with age.16,71 To enable patients with MM to receive long-term therapy, a three-step strategy has been proposed for treating physicians to recognise and minimise treatment-related toxicity through evaluating the characteristics and needs of individual patients (Figure 6).2 This enables the most appropriate drug regimen from the available MM agents to be selected and doses adapted accordingly to accommodate physiological changes.2
Quality of life (QoL) is difficult to ascertain, but is influenced by the balance between treatment toxicity and disease symptoms.70 Existing treatments for MM can adversely impact patient QoL, and treatment-related AEs may lead to early discontinuation of therapy and suboptimal outcomes, particularly in frail patients who experience a high treatment toxicity burden.70 It is recognised that the impact of toxicities on patient QoL is an aspect of management that needs appropriate long-term supportive care during continued treatment.66 Over and above supportive care, there is a need for therapies with an improved safety profile if patients are to benefit from long-term treatment without adverse effects on QoL.72
When considering long-term therapies, another factor of importance is patient convenience. The benefits gained from efficacious therapies can be compromised by reduced adherence as a result of the requirement for patients to travel to clinics for treatment and to collect medication. For example, the requirement for injection/infusion of current therapies, such as bortezomib and some emerging therapies (eg carfilzomib, monoclonal antibodies, and oral panobinostat in combination with infused bortezomib)73,74 may impact compliance.73 At a minimum, the need to make frequent visits to the clinic further disrupts the daily life of the patient, in addition to any needs for medication and AE management.
Impact on healthcare resources varies markedly across different healthcare centres and models of care; however, in addition to the cost of the drug, use of agents administered orally or by injection/ infusion can be associated with differential use of day-care resources, pharmacy costs, and laboratory resources.75 Variations in cost can also arise from the impact of treatment (eg neutropenia, neuropathy, worsening performance status) and the comorbidities of patients with myeloma, as well as the sequence of treatment.75 Despite increasing use of combination therapy with novel agents for RRMM management, the cost impact of these combination regimens has not, as yet, been determined.75
Real-world data highlight both the importance, and the challenges, of maintaining long-term treatment in order to achieve long-term disease control in patients with RRMM14,62
Future directions in the management of patients with relapsed/refractory multiple myeloma
Relapse is inevitable in patients with MM, even in those patients initially achieving a CR. There are limitations with the current therapeutic options and more work is needed to overcome the patient- and healthcare-related barriers that prevent the delivery of efficacious therapy over the long-term. Further improvements in patient outcomes are anticipated through the emergence of new generations and/or classes of therapies such as the newer PIs and IMiDs, the monoclonal antibodies elotuzumab76 and daratumumab,77 as well as the HDAC inhibitors; indeed, panobinostat74 has been approved for use in conjunction with bortezomib. Some of these agents are currently intravenously administered by infusion or are given in combination with an injectable agent and might not address the logistical burdens that can limit the practical delivery of continuous therapies.
Strategies are continually evolving in order to address the unmet need for effective therapies to improve clinical outcomes. One potential approach is starting treatment at biochemical relapse (for example the emergence of MRD positivity), which has been shown to delay progression in RRMM patients when compared with initiating treatment at clinical relapse,78 but further studies are needed. Appropriate selection of upfront and first-relapse therapy to improve clinical outcomes is clearly needed because suboptimal sequencing negatively affects patient survival.79 Frail patients with myeloma, in particular, are burdened by additional comorbidities that present a challenge to effective treatment.16,70 Testing of several prognostic tools identified the G8 geriatric assessment screening tool as a simple and informative measure of the risk of early death and OS in patients with MM, allowing it to aid treatment decisions.13 Finally, continuous therapies have been linked to long-term disease control and improved patient outcomes compared with fixed-duration therapies.56 With continuous, long-term treatment approaches it is important to consider efficacy, safety, tolerability and patient burden. Therefore, a key aim for MM agents in the future will be to address the unmet need for therapies that can be taken continuously, and which are efficacious in patients with standard- and high-risk cytogenetics, are well tolerated and minimise the treatment burden on patients and healthcare systems. In this way we can take a step closer to achieving long-term disease control without detrimental effects on patient QoL and healthcare resources.
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