Issue 3: Real-world insights into the unmet needs in multiple myeloma
Myeloma Hub Connect is an educational resource for healthcare professionals. This edition of Myeloma Hub Connect was co-produced by Succinct Medical Communications and Takeda Oncology. Myeloma Hub Connect is edited and published by Succinct Medical Communications Ltd. on behalf of Takeda Oncology.
Dr Matthew Jenner, MBBS, MRCP, FRCPath, Consultant Haematologist, University Hospital Southampton NHS Foundation Trust
The landscape for multiple myeloma (MM) has shifted dramatically over the last decade. There have been major advances in the understanding of the pathophysiology of MM, including the significance of recurrent genetic events and their impact on clinical behaviour, as well as the techniques used to evaluate these. The so-called ‘novel agents’, thalidomide and bortezomib, and use of autologous stem cell transplantation for all suitable patients are now fully incorporated into routine clinical practice both at diagnosis and disease progression. Supportive care, including prevention and treatment of infection, is also well established. All of these factors have resulted in improved outcomes for patients diagnosed today with MM; 1-year survival rates have more than doubled between the early 1970s and 2010 (1-year overall survival [OS]: 37.2% in 1971–72; 76.6% in 2010–11), however 5-year OS remains at less than 50%.1
The exciting array of newer agents, both in development and currently licensed, poses a number of challenges. Whilst randomised phase 3 clinical trials remain the ’gold standard’ for determining the efficacy and safety of newer agents and combinations, clinical trials, particularly licensing studies, may need to exclude certain patient subgroups in order to generate consistent data. As a result, such trials cannot always inform us of the optimal way to use a combination, which subgroups may have the greatest response, or how best to dosemodify to take account of comorbidities. MM remains a disease predominantly of the elderly and it is acknowledged that many licensing trials will tend to include a predominantly younger, more fit cohort.
There remains an important role for national multi-centre investigator-initiated studies with sufficient power to answer both clinical and biological questions in a comprehensive manner. For example, the NCRI Myeloma IX and XI studies have not only helped to evaluate the optimal induction and maintenance approaches for MM but, due to integration of clinical and biological data, have provided insight into genetic subgroups in whom a particular strategy may or may not be effective. In addition, the UK has specific requirements in relation to not only marketing authorisation but funding for new drugs. NICE require an assessment to be made of not just the clinical effectiveness but also cost effectiveness of new treatments in comparison with UK- appropriate comparators.
Other sources of data are therefore increasingly important in determining real-world outcomes. This real-world evidence can capture a more representative demographic, take more account of comorbidities, dosing strategies and potentially health resource utilisation. This is particularly important given the trend towards continuous therapies rather than fixed-duration treatments. These continuous therapies have both financial and quality of life implications.
As we enter the era of genomic medicine, this article outlines some of the key ongoing challenges and reviews the data that already exist, as well as where further information is needed to help guide treatment approaches for patients with MM.
Real-world evidence demonstrates unmet needs in multiple myeloma
MM is a heterogeneous disease that, despite recent advances, remains incurable, resulting in an ongoing high unmet need. This is particularly pronounced outside the context of clinical trials.2–5 In addition, due to an aging demographic, MM predominantly remains a disease of the elderly.3,6 Innovations in MM care and the evolution of new treatment combinations have led to a two-fold increase in survival of elderly patients. This allows physicians to tailor treatment approaches to the individual by taking into account their clinical and biological features as well as personal preferences.7 The pathogenesis of this disease is not yet fully understood and its heterogeneous presentation emphasises the importance of prognostic stratification, treatment monitoring and different therapeutic approaches.2,8 It remains crucial to optimise ways of improving treatment tolerability, achieving long-lasting, positive outcomes and reducing the clinical and psychosocial burden of myeloma.9,10 Furthermore, outcomes are typically worse in the real-world compared with those observed in a controlled clinical trial setting with a highly-selected patient population.5 Patients in the real-world are more likely to suffer from high-risk disease than those enrolled in clinical trials, and thus have poorer outcomes; survival rates of under a year after first relapse have been reported in these patients.11 Survival outcomes relating to the revised international staging system (R-ISS) have also been confirmed as poor in the real-world as compared with data from clinical trials.12 As the evidence base of real-world data grows, it is crucial to understand how these insights into patient outcomes and treatment decisions can inform future clinical practice.10
Many of the factors that influence outcome and duration of treatment are more prevalent outside the clinical trial setting.13 Despite this, real-world data in relapsed/refractory MM (RRMM) patients have been limited.13 Recent evidence suggests that outcomes in this group are suboptimal.13-19 This places a burden on the healthcare system and, despite availability of novel agents, MM remains a disease with unacceptable patient burden and outcomes.13-19
It is recognised that with each line of therapy, both depth and duration of response is reduced. Two retrospective US cohort studies of newly diagnosed MM patients demonstrated that whilst it would be expected that overall survival (OS) duration is shorter with each line of therapy, successive lines of therapy also yielded progressively shorter times to next treatment (TTNT) compared with first-line treatment (Table 1).15,20 Supporting these data, the PREAMBLE study demonstrated that rate of progression/death in patients with MM is associated with the number of lines of treatment discontinued due to progression, overall number of treatment lines and disease stage (Figure 1).18
These results are also comparable to those seen in a Czech retrospective analysis, which demonstrated considerably poorer real-world outcomes in symptomatic MM patients compared with those reported in clinical trials. In addition, a decrease in OS and progression-free survival (PFS) was also observed with each successive treatment line (Table 1).16 Beyond traditional outcomes such as OS and PFS, real-world data highlight the burden of disease that still exists in the MM population. Although first-line lenalidomide has been shown to improve outcomes in elderly MM patients (FIRST clinical trial),21 real-world data show that MM patients refractory to first-line lenalidomide present with higher disease-related symptom burden at the start of second-line therapy compared with relapsed patients (renal impairment 52.8% vs. 37.9%, anaemia 65.2% vs. 45.3%, hypercalcaemia 15.7% vs. 3.7% and bone disease 30.3% vs. 23.7%).19 In addition, refractory patients treated more aggressively in second-line therapy are more likely to switch to PI-based therapy compared to those with relapsed disease.19 Evidence from the real-world has therefore shown that despite advances in treatment, patients continue to exhibit disease burden, and that there is a need for strategies to overcome this.
Disease heterogeneity and comorbidities impact treatment decisions and outcomes
The course of MM is highly variable; clinical presentation is heterogeneous due to the underlying biology of the tumour, extent of disease and patient-specific factors (age, biology, comorbidities, frailty).8,22
Older age and frailty
MM typically presents in older patients, with a median age at diagnosis of around 70 years, and approximately a quarter of patients are older than 75 years.8,23 A key consideration in the treatment decision for this elderly patient population is that they are a heterogeneous group, often physically frail, and may suffer from multiple comorbidities such as arthritis, dementia, diabetes, renal impairment, and cardiovascular disease.7 However, frailty score has been shown to better predict OS in young MM patients (<65 years) than in elderly patients.24 The G8 geriatric assessment screening tool has been shown to be an independent factor for survival (hazard ratio [HR]: 4.7, p=0.004), providing important prognostic information related to the risk of early mortality and OS independent of disease characteristics and treatment type.25 There is therefore a need for a unified approach to be able to compare clinical outcomes between studies and translate these into real-world practice.
Although advances in care for elderly MM patients have been significant, recent studies have shown that outcomes can be improved upon. A retrospective analysis of US electronic medical records revealed that MM patients aged ≥75 years receive suboptimal treatment, which adversely impacts survival.26 Similarly, a retrospective analysis of the Dutch PHAROS MM registry confirmed that older age is associated with poorer outcomes (Table 2), and that OS decreases and resource use rises (as measured by inpatient stays) with increasing number of treatment lines.14 This negative association between age and survival outcomes, regardless of confounders such as gender, cytogenetic risk, comorbidities and prior regimen type, was further confirmed in an analysis of the Swedish Multiple Myeloma Register.17
Future management strategies should therefore take into account the frailty of the elderly population and provide treatments that are tolerable and balanced with efficacy; geriatric assessment tools may help achieve these goals.27
MM is associated with significant comorbidities due to disease pathology, age and treatment toxicity.7 It is therefore crucial that comorbidities are considered when making treatment decisions. A study of 628 RRMM patients from a US national database revealed that almost half (48%) of patients suffered from comorbid renal dysfunction† and/or cardiovascular disease before their first treatment, and that this proportion increased to 68% before second line treatment.28
The negative impact of these comorbidities was also demonstrated; shorter time to new treatment and lower 1- and 2-year OS probabilities were observed in RRMM patients with renal dysfunction† and/or cardiovascular disease relative to those without (Table 3).28 These data are further supported by analysis from a population-based registry, which showed that patients presenting with renal failure*, pathological fracture or constitutional syndrome had a poor outcome in terms of early mortality and OS (Table 4).29
†Criteria for renal dysfunction and renal failure vary across studies
Genetic risk stratification as a strategy to improve outcomes
Clonal evolution and cytogenetics analysis
The myeloma genome is heterogeneous and undergoes a number of genetic changes over time.2 Based on these features, cytogenetic analysis can be utilised as a prognostic tool in MM; patients with high-risk cytogenetic profiles (presence of del[17p], t[4;14], t[14;16], t[14;20] or chromosome 1q gains, as identified by fluorescence in situ hybridisation) have significantly worse OS outcomes than standard-risk patients.30,31 Whilst these are independent prognostic markers, outcomes are influenced by other patient specific or biological factors. Advanced age, extent of bone marrow involvement and specific clonal abnormalities are associated with poor 3-year OS in MM patients with standard risk (Table 5) whilst age >65 years, higher ISS score and elevated baseline (LDH) are associated with adverse outcomes in MM patients with high-risk cytogenetics (Table 6).32,33 These data illustrate the importance of identifying reliable predictors of poor clinical outcomes and the role of risk stratification in the MM patient population.
Clonal evolution of myeloma cells can be stimulated by tumour-, host-, environmental- or treatment-related factors, meaning that selective pressures can lead to several evolutionary paths and the dominance of different clones over time.8,34,35 The number of acquired mutations increases with disease progression, and high-risk mutations can appear at relapse even if not present at diagnosis.8,36,37 The high level of variability in MM has clear therapeutic implications; understanding the clonal composition of the tumour at each treatment phase can be used to guide treatment and to identify combinations effective against multiple targets rather than a single genomic anomaly.2,8,38
Treatment strategies for high-risk cytogenetics MM
Personalised induction and maintenance therapy according to genetic risk stratification is an active area of research that may offer insights into a promising new treatment approach.
One study investigating the use of a proteasome inhibitor (PI) during induction and post-transplantation maintenance reported significantly improved PFS and OS in the newly-diagnosed MM patient population. In particular there was improvement in the subgroup of patients with high-risk cytogenetics, compared with a thalidomide maintenance regimen.39 Another study of patients with del(17p) supported the use of a PI-based induction followed by autologous stem cell transplant (ASCT) and maintenance therapy in this subgroup of high-risk patients.33 Long-term data on the inclusion of maintenance PI therapy as a single agent or within immunomodulatory drug (IMiD)-containing combinations have further demonstrated survival benefits in patients with MM, including those with high-risk cytogenetics.40
The current management approach of patients with MM who relapse after induction therapy is treatment with bortezomibor IMiD-based combinations, however research has shown that suboptimal sequencing can negatively affect outcomes.41
Bortezomib followed by chemotherapy or thalidomide was found to result in poor second PFS compared with a bortezomib-melphalan-prednisone combination treatment. This impact of sequencing was also apparent in patients with high-risk cytogenetics.41 Novel combination treatments, such as those studied in recently reported Phase 3 trials, have however shown promise in this high-risk patient population.42-47 Favourable benefit-risk profiles of triplet regimens have been demonstrated in these studies across patients with standard- and high-risk cytogenetics.42-47 Combining treatments with different modes of action, including PIs and/or monoclonal antibodies (mAbs), are therefore particularly important therapeutic options in this subset of patients.
Optimisation of multiple myeloma therapy
Emerging treatment strategies
The high rates of toxicities associated with combination cytotoxic regimens have historically precluded the use of both continuous and/or combination therapies in RRMM.48 However, the advent of newer drugs with different mechanisms of action and favourable toxicity profiles— such as PIs, mAbs, IMiDs, and histone deacetylase (HDAC) inhibitors—have revolutionised the MM landscape.48
Continuous therapy is an alternative treatment approach that aims to continuously suppress the survival and proliferation of tumour cells; this is supported by the rationale that residual disease remains even in patients with complete response.3,40 Safety is an important factor in continuous therapy, because it is both undesirable for patients to experience long-term adverse events and due to the compromised efficacy of regimens if patients cannot tolerate their treatment. Several studies are currently ongoing that examine tolerability in a maintenance setting.49
Continuous treatment options
Thalidomide has been investigated as part of a continuous treatment regimen where it is believed to play both a maintenance role and exert a consolidation effect,50 however adverse effects have been reported in patients with high-risk cytogenetics.51 Similarly, lenalidomide has demonstrated significant improvements in PFS and OS rates in transplant-ineligible, but only in standard-risk cytogenetics.21,52,53 Continuous versus an 18-cycle regimen of lenalidomide-dexamethasone has also demonstrated PFS benefits and a delayed time to second treatment in transplant-ineligible, newly diagnosed MM patients (FIRST clinical trial).54 Lenalidomide has further been shown to be a highly effective maintenance therapy in over 1,500 MM patients of all ages and across risk subgroups (Myeloma XI clinical trial).55 Bortezomib maintenance has shown benefit in both standard- and high-risk cytogenetics patients, however, treatment-related peripheral neuropathy as well as the practicalities of administering an intravenous or subcutaneous drug in the long term have limited this option in this setting.39 As such, future options for continuous therapy should not only address high-risk cytogenetics but also take into account long-term symptom burden, quality of life and practicality of administration.
Evidence from the real-world has shown that patients continue to exhibit disease burden despite advances in treatment, and that there is a need for strategies to address these suboptimal outcomes. It is essential to better understand the biological heterogeneity of MM in order to optimise prognostic stratification, treatment approaches and assessment of response.2
Superiority of triplet versus doublet therapies in MM has been demonstrated by the addition of a novel agent, such as second generation PIs or mAbs, to the standard lenalidomide- or bortezomib-dexamethasone regimens in recent Phase III trials.42-44,46,56 In these trials, significant reductions in the risk of disease progression were demonstrated with triplet regimens compared with a doublet regimen.42-44,46,56 These benefits were observed in both standardand high-risk cytogenetic patients.42-44,46,47
Combination therapy, with the aim of attaining a deep and durable response through the synergy of multiple mechanisms of action, has shown promise in the clinical trials mentioned above, as well as in other trials combining different and/or newer agents. Results of a multi-centre, dose-escalation, Phase I study of pomalidomide-bortezomib-dexamethasone in PI-exposed and lenalidomide-refractory patients has shown positive results, with an overall response rate of 65% and a median duration of response of 7.4 months; all patients achieved at least stable disease and the combination was generally well tolerated.57Further positive results of triplets in RRMM are emerging from Phase Ib trials of oprozomib-pomalidomide-dexamethasone, venetoclax-bortezomib-dexamethasone, isatuximab-lenalidomide-dexamethasone and afuresertib-bortezomib-dexamethasone, and a Phase II study of lenalidomide-bendamustine-prednisolone.58-62
Although studies have demonstrated deep and durable responses with dual- and more recently triple-combination regimens (such as combinations with IMiDs, PIs, mAbs and HDAC inhibitors), there remains a need to better define the optimal therapeutic options to improve outcomes for MM patients in relation to their heterogeneity, be that clinical or biological.48,63-65 Treatments that are not only effective, but also well tolerated and easy to administer are further requirements to deliver the positive outcomes observed in clinical trials in the real-world.
New treatment approaches must address current challenges
Despite the promising results of combination and continuous therapy in RRMM, there are a number of challenges that must be considered, including efficacy and tolerability of agents, emergence of cumulative toxicities, convenience of regimens to patients, and pressure on healthcare resources.40,66-69 Treatment to progression may be compromised by the need to adjust dosing in vulnerable patient populations such as the frail, elderly and/or those with renal or hepatic impairment.68,70 Furthermore, adverse events and cumulative toxicities also have an impact and may lead to discontinuation or dose reduction of the agent, which can shorten the length of treatment and reduce survival.70 These aspects of long-term treatment can negatively influence patient quality of life and therefore appropriate management and long-term supportive care is needed during continued treatment.27,71 However, if patients are to benefit from long-term treatment without adverse effects on quality of life, better therapies with an improved safety profile are needed.72
Another aspect that must be considered in assessing the efficacy of newer treatment is the measurement of quality of life outcomes in the study design of clinical trials. Patient-reported outcomes may be subjective and impacted by patient expectations of treatment efficacy.73 In recently reported Phase 3 trials, no significant detriment to overall health-related quality of life was seen with the addition of novel agents to the lenalidomide-dexamethasone backbone.43,44,56 However attention should be paid to the potential bias added in open-label as opposed to double-blinded trial designs. Relevant comparisons must also be investigated to fully understand the impact of regimens on patients’ quality of life. For example, the effect of an all-oral combination regimen assessed against combination treatment using an intravenous agent.44
The advances in MM treatment means that patients are living longer with the disease, and as such health-related quality of life is becoming an increasingly important aspect of care; trials of new therapies must therefore ensure that these outcomes are accurately measured and reported.74
New treatment approaches must also consider the burden placed on healthcare resources. Recent real-world studies demonstrate that there is a significant economic and human burden associated with MM.72 However, data also indicate that outpatient treatment, very good partial responses or better, and deeper responses reduce the burden on the healthcare system.75,76 This highlights the need for newer treatments to provide both efficacy and logistical benefits so that economic as well as patient outcomes are optimised.
An additional factor to be considered with the use of long-term therapies is patient convenience, as reduced adherence to treatment schedules can compromise the benefits to be gained from efficacious therapies and altogether impact quality of life. Such factors may include the requirement for patients to travel to clinics to collect and receive treatment, which may impact elderly and frail patients, those less able to travel independently, as well as working patients. The impact of the increasing use of combination therapy with novel agents for RRMM management on healthcare resource utilisation and costs should also be taken into account, however these economic calculations have not yet been performed.77
In summary, real-world data confirm that MM is a disease with significant genetic and clinical heterogeneity with a high unmet need. Prognostic factors should therefore be utilised to optimise and individualise treatment. MM is also associated with significant human and economic costs.
Evolving treatment strategies are needed in order to address unmet needs; these include continuous and combination therapies which have been shown to improve long-term outcomes. It is therefore crucial to consider well tolerated regimens tailored to individual patient characteristics, with minimal burden on the patient and healthcare system.
UK/NP/1806/0035ag – July 2018
1. Cancer Research UK. Myeloma (C90): 2010–2011 One-, five- and ten-year net survival (%), adults aged 15-99, England & Wales. 2011. Available at: http://www.cancerresearchuk.org/sites/default/files/cstream-node/surv_1_5_10yr_myeloma.pdf Accessed June 2017.
2. Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 2014; 5: 2997.
3. Borrello I. Can we change the disease biology of multiple myeloma? Leuk Res 2012; 36 Suppl 1: S3-12.
4. Usmani S, Ahmadi T, Ng Y, et al. Analysis of real-world data on overall survival in multiple myeloma patients with ≥3 prior lines of therapy including a PI and an IMiD, or double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Oncologist 2016; Epub ahead of print.
5. Jagannath S, Roy A, Kish J, et al. Real-world treatment patterns and associated progression-free survival in relapsed/refractory multiple myeloma among US community oncology practices. Expert Rev Hematol 2016; 9: 707–717.
6. Girnius S, Munshi NC. Challenges in multiple myeloma diagnosis and treatment. Leuk Suppl 2013; 2: S3–9.
7. Mateos MV, San Miguel JF. How should we treat newly diagnosed multiple myeloma patients? Hematol Am Soc Hematol Educ Program 2013; 2013: 488–495.
8. de Mel S, Lim SH, Tung ML, Chng WJ. Implications of heterogeneity in multiple myeloma. BioMed Res Int 2014; 2014: e232546.
9. Boland EG, Boland JW, Ezaydi Y, et al. Holistic needs assessment in advanced, intensively treated multiple myeloma patients. Support Care Cancer 2014; 22: 2615–2620.
10. Yong K, Delforge M, Driessen C, et al. Multiple myeloma: patient outcomes in real-world practice. Br J Haematol 2016; 175: 252–264.
11. Davis KL, Lin HM, Hui A, Zhang S, Kaye JA. Assessment of real-world treatment patterns and outcomes in relapsed or refractory multiple myeloma: evidence from a brief multi-country survey of European physicians. Value Health 2015; 18: A682.
12. Jimenez-Zepeda VH, Duggan P, Neri P, et al. Revised International Staging System applied to real world multiple myeloma patients. Clin Lymphoma Myeloma Leuk 2016; 16: 511–518.
13. Romanus D, Raju A, Yong C, et al. Duration of therapy in U.S. patients treated for relapsed / refractory multiple myeloma (RRMM) in the real-world. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132850/dorothy.romanus.duration.of.therapy.in.u.s.patients.treated.for.relapsed.html?f=m1 Accessed June 2017.
14. Verelst S, Blommestein H, Gonzalez-McQuire S, et al. Overall survival in patients with symptomatic multiple myeloma in the real-world setting: a retrospective analysis of the PHAROS registry in the Netherlands. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132841/silvia.verelst.overall.survival.in.patients.with.symptomatic.multiple.myeloma.html?f=m1 Accessed June 2017.
15. Romanus D, Raju A, Seal B, et al. The clinical course of relapsed or refractory U.S. multiple myeloma (RRMM) patients receiving two or more lines of therapy. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132836/dorothy.romanus.the.clinical.course.of.relapsed.or.refractory.u.s.multiple.html?f=m1 Accessed June 2017.
16. Hajek R, Jarkovsky J, Maisnar V, et al. Survival and treatment patterns in patients with symptomatic multiple myeloma (MM) in a real-world setting. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132829/roman.hajek.survival.and.treatment.patterns.in.patients.with.symptomatic.html?f=m2 Accessed June 2017.
17. Blimark CH, Genell A, Juliusson G, et al. The Swedish Multiple Myeloma Registry: median survival exceeds 7 years in patients 65 years and younger, population-based data on 3,876 multiple myeloma patients diagnosed 2008-2013. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132814/cecilie.hveding.blimark.the.swedish.multiple.myeloma.registry.median.survival.html?f=m1 Accessed June 2017.
18. Kuter D, Cook G, Goldschmidt H, et al. An ongoing multinational observational study in multiple myeloma (PREAMBLE): preliminary report on progression-free survival. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132810/teresa.zyczynski.an.ongoing.multinationa.observational.study.in.multiple.html?f=m1 Accessed June 2017.
19. Jhaveri M, Romanus D, Raju A, et al. Real-world prescribing patterns in U.S multiple myeloma (MM) patients refractory to lenalidomide in the front-line. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132861/mehul.jhaveri.real-world.prescribing.patterns.in.u.s.multiple.myeloma.28mm29.html?f=m1 Accessed June 2017.
20. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc 2004; 79: 867–874.
21. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014; 371: 906–917.
22. Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 Suppl 6: vi133-137.
23. Raab MS, Cavo M, Delforge M, et al. Multiple myeloma: practice patterns across Europe. Br J Haematol 2016; 175: 66–76.
24. Nikolaou E, Maltezas D, Tzenou T, et al. Assessment of frailty in a multiple myeloma (MM) series. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132852/eftychia.nikolaou.assessment.of.frailty.in.a.multiple.myeloma.28mm29.series.html Accessed June 2017.
25. Dimopoulos M, Gavriatopoulou M, Roussou M, et al. Prospective evaluation of geriatric assessment tools in real-world, unselected, elderly patients with symptomatic myeloma. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132850/dorothy.romanus.duration.of.therapy.in.u.s.patients.treated.for.relapsed.html?f=m1 Accessed June 2017.
26. Romanus D, Raju A, Yong C, et al. Practice patterns and outcomes in elderly U.S. patients with relapsed/refractory multiple myeloma (RRMM). Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132837/dorothy.romanus.practice.patterns.and.outcomes.in.elderly.u.s.patients.with.html?f=p6m3e968o12154 Accessed June 2017.
27. Wildes TM, Rosko A, Tuchman SA. Multiple myeloma in the older adult: better prospects, more challenges. J Clin Oncol 2014; 32: 2531–2540.
28. Yong C, Seal B, Farrelly E, et al. Practice patterns and outcomes in U.S.patients (pts) with relapsed/refractory multiple myeloma (RRMM) and comorbid renal dysfunction (RD) and/or cardiovascular disease (CVD). Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132826/candice.yong.practice.patterns.and.outcomes.in.u.s.patients.28pts29.with.html?f=p6m3e968o12154 Accessed June 2017.
29. Rios-Tamayo R, Sainz J, Alba AM, et al. The impact of the type of myeloma-defining event on early mortality and survival.Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132864/rafael.rostamayo.the.impact.of.the.type.of.myeloma-defining.event.on.early.html?f=p16m3l11449 Accessed June 2017.
30. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014; 28: 1122–1128.
31. Avet-Loiseau H, Attal M, Campion L, et al. Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol 2012; 30: 1949–1952.
32. Binder M, Rajkumar SV, Ketterling RP, et al. Prognostic factors in patients with multiple myeloma and standard-risk cytogenetics. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133553/moritz.binder.prognostic.factors.in.patients.with.multiple.myeloma.and.html?f=m1 Accessed June 2017.
33. Merz M, Hielscher T, Seckinger A, et al. Outcome of myeloma patients with deletion 17p – impact of baseline characteristics, treatment and additional chromosomal changes. Available at: https://learningcenter.ehaweb.org/eha/2016/21st/133538/maximilian.merz.outcome.of.myeloma.patients.with.deletion.17p.impact.of.html Accessed June 2017.
34. Bahlis NJ. Darwinian evolution and tiding clones in multiple myeloma. Blood 2012; 120: 927–928.
35. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.
36. Chavan S, He J, Deshpande S, et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J 2017; 7: e535.
37. Walker BA, Wardell CCP, Melchor L, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 2014; 28: 384–390.
38. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014; 25: 91–101.
39. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 2012; 30: 2946–2955.
40. Ludwig H, Durie BGM, McCarthy P, et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood 2012; 119: 3003–3015.
41. Offidani M, Corvatta L, Bringhen S, et al. Impact of cytogenetic risk on PFS2 of patients treated with different therapy sequences: results of a post-hoc analysis. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133543/massimo.offidani.impact.of.cytogenetic.risk.on.pfs2.of.patients.treated.with.html?f=m1 Accessed June 2017.
42. Dimopoulos M, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375: 1319–1331.
43. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372: 142–152.
44. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 374: 1621–1634.
45. Avet-Loiseau H, Fonseca R, Siegel D, et al. Efficacy and safety by cytogenetic risk status: Phase 3 study (ASPIRE) of carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. Available at: https://learningcenter.ehaweb.org/eha/2016/21st/133551/herv.avet-loiseau.efficacy.and.safety.by.cytogenetic.risk.status.phase.3.study.html?f=m3 Accessed June 2017.
46. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375: 754–766.
47. Avet-Loiseau H, Bahlis N, Chng WJ, et al. Impact of cytogenetic risk status on efficacy and safety of ixazomib-lenalidomide-dexamethasone (IRd) vs placebo-Rd in relapsed/refractory multiple myeloma patients in the global TOURMALINE-MM1 study. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133256/herve.avet-loiseau.impact.of.cytogenetic.risk.status.on.efficacy.and.safety.of.html?f=m3e968 Accessed June 2017.
48. Nooka AK, Lonial S. Novel combination treatments in multiple myeloma. Oncol Williston Park 2016; 30: 451–465.
49. Palumbo A, Gay F, Cavallo F, et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol 2015; 33: 3459–3466.
50. Morgan GJ, Gregory WM, Davies FE, et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012; 119: 7–15.
51. Morgan GJ, Davies FE, Gregory WM, et al. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res 2013; 19: 6030–6038.
52. Avet-Loiseau H, Hulin C, Benboubker L, et al. Impact of cytogenetics on outcomes of transplant-ineligible patients with newly diagnosed multiple myeloma treated with continuous lenalidomide plus low-dose dexamethasone in the FIRST (MM-020) trial. Blood 2015; 126: 730.
53. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol 2016; 34: Suppl Abstr 8001.
54. Facon T, Dimopoulos MD, Catalano J, et al. Final survival analysis from the FIRST trial: lenalidomide plus low-dose dexamethasone until progression (Rd cont) v melphalan, prednisone and thalidomide (MPT), and Rd for 18 cycles (Rd18) for transplant-ineligible (TNE) patients (Pts) with newly diagnosed multiple myeloma. Available at: https://show.jspargo.com/IMW/files/2017IMWAbstractBook.pdf Accessed June 2017.
55. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the Phase III Myeloma XI study. Available at: http://www.bloodjournal.org/content/128/22/1143?sso-checked=true Accessed June 2017.
56. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373: 621–631.
57. Richardson PG, Hofmeister C, Raje NS, et al. Pomalidomide, bortezomib, and low-dose dexamethasone in proteasome inhibitor–exposed and lenalidomide-refractory myeloma: results of a multicenter, dose-escalation, Phase 1 trial (MM-005). Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133541/paul.richardson.pomalidomide.bortezomib.and.low-dose.dexamethasone.in.html?f=m3 Accessed June 2017.
58. Shah J, Niesvizky R, Stadtmauer E, et al. Oprozomib, pomalidomide, and dexamethasone (OPOMD) in patients (pts) with relapsed and/or refractory multiple myeloma (RRMM): initial results of a Phase 1b study (NCT01999335). Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133258/jatin.shah.oprozomib.pomalidomide.and.dexamethasone.28opomd29.in.patients.28pts29.html?f=m2e968 Accessed June 2017.
59. Moreau P, Chanan-Khan A, Roberts AW, et al. Phase 1b study of venetoclax combined with bortezomib and dexamethasone in relapsed/ refractory multiple myeloma. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133259/philippe.moreau.phase.1b.study.of.venetoclax.combined.with.bortezomib.and.html?f=m3e968 Accessed June 2017.
60. Vij R, Lendvai N, Martin TG, et al. A Phase Ib dose escalation trial of isatuximab (SAR650984, anti-CD38 mAb) plus lenalidomide and dexamethasone (Len/Dex) in relapsed/refractory multiple myeloma (RRMM): interim results from two new dose cohorts. J Clin Oncol 2016;34: Suppl Abstr 8009.
61. Trudel S, Spencer A, Sutherland H, et al. A Phase Ib study of the AKT inhibitor afuresertib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: final results with long term follow-up. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133260/suzanne.trudel.a.phase.ib.study.of.the.akt.inhibitor.afuresertib.in.html?f=m3e968 Accessed June 2017.
62. Beck J, Heyn S, Glaser D, et al. Revlimid, bendamustine and prednisolone(RBP) in relapsed/refractory multiple myeloma: final results of a Phase II clinical trial; OSHO – #077. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132865/juliane.beck.revlimid.bendamustine.and.prednisolone.28rbp29.in.relapsed.html?f=m3e968 Accessed June 2017.
63. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised Phase 3 study. Lancet 2010; 376: 2075–2085.
64. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 2011; 118: 5752–5758.
65. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized Phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2012; 30: 2475–2482.
66. Palumbo A, Niesvizky R. Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Leuk Res 2012; 36 Suppl 1: S19–26.
67. McCarthy PL, Palumbo A. Maintenance therapy for multiple myeloma. Hematol Oncol Clin North Am 2014; 28: 839–859.
68. 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; 118: 4519–4529.
69. Brioli A, Melchor L, Cavo M, Morgan GJ. The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol 2014; 165: 441–454.
70. Mateos MV. How to maintain patients on long-term therapy: understanding the profile and kinetics of adverse events. Leuk Res 2012; 36 Suppl 1: S35-43.
71. Molassiotis A, Wilson B, Blair S, et al. Living with multiple myeloma: experiences of patients and their informal caregivers. Support Care Cancer 2011; 19: 101–111.
72. Singh M, Kay G, O’Rourke J, et al. Burden of illness associated with multiple myeloma. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132992/moushmi.singh.burden.of.illness.associated.with.multiple.myeloma.html?f=m1 Accessed June 2017.
73. Schmidt H, Kogler H, Geier S, et al. Effect size of open-label versus double-blind administration of tiotropium in trials investigating health related quality of life in COPD. Thorax 2014; 69: A186.
74. Kvam AK, Waage A. Health-related quality of life in patients with multiple myeloma – does it matter? Haematologica 2015; 100: 704–705.
75. Romanus D, Byfield SD, Schwartz JS, et al. Healthcare costs among newly diagnosed multiple myeloma (MM) patients undergoing frontline stem cell transplantation in the U.S. – comparison of outpatient versus inpatient-based care. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/133407/dorothy.romanu.healthcare.costs.among.newly.diagnosed.multiple.myeloma.28mm29.html Accessed June 2017.
76. Leleu H, Yong K, Gonzalez-McQuire S, et al. The effect of level of response to treatment on associated costs and healthcare resource utilization: a retrospective chart review study in patients with symptomatic multiple myeloma. Available at: http://learningcenter.ehaweb.org/eha/2016/21st/132859/henri.leleu.the.effect.of.level.of.response.to.treatment.on.associated.costs.html?f=m1 Accessed June 2017.
77. Gaultney JG, Franken MG, Tan SS, et al. Real-world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents. J Clin Pharm Ther 2013; 38: 41–47.