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  • 21ST EHA Annual Meeting & Exposition

    June 9–12 2016 Copenhagen, Denmark

    Click here for more

Multiple myeloma: a complex and challenging disease

Multiple myeloma (MM) is a B-cell malignancy characterised by a monoclonal expansion and accumulation of abnormal plasma cells in the bone marrow compartment. It is the second most common cancer of the blood and accounts for 1% of all malignancies.1

The past few years have seen substantial progress in this area of oncology. A better understanding of disease biology, combined with the development of novel targets for therapy, have enabled the advancement of more tailored treatment approaches in MM, which have led to dramatic improvements in survival rates across all age groups.2 Nevertheless, MM remains an incurable disease and relapse is common, with a 5-year survival rate of around 45%.3

Survival rates have improved dramatically in the era of novel therapies2
Graph: proportion surviving / follow up from diagnosis Graph: proportion surviving / follow up from diagnosis

*Bortezomib, lenalidomide or thalidomide as part of initial therapy.

A paradigm shift in multiple myeloma diagnosis

CT, computed tomography; IMWG, International Myeloma Working Group; LLN, lower limit of normal; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-CT; ULN, upper limit of normal.

Diagnostic criteria for MM have, until recently, focused on the need for overt clinical manifestations of serious end-organ damage before treatment can be initiated.4 However, as data for novel agents are now available, demonstrating that early intervention in some asymptomatic patients can extend survival,5 new criteria have been developed enabling treatment initiation before the development of end-organ damage.6

In addition, newer diagnostic and imaging techniques are beginning to be integrated into the diagnosis and follow up of MM patients on top of standard techniques such as x-ray skeletal surveys.7 These new modalities include whole body computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography and CT scanning (PET/CT).7


The use of modern imaging methods will enable the diagnosis of myeloma to be made before serious complications can develop and will help to assess treatment response at follow up7

The evolution of response assessment in multiple myeloma

It is now widely accepted that achievement of a complete response (CR) or a very good partial response (VGPR) are positive prognostic indicators for improved survival in the frontline and relapsed settings.8-12 However, several studies have suggested that CR may not necessarily be a prerequisite for survival benefits, and that this may potentially be explained by the heterogeneity of risk and of the methods used to define CR.10

Using current methods of detection, significant disease burden still exists in patients with CR (known as minimal residual disease [MRD]),13 and its persistence after therapy may lead to relapse.14 Newer, more sensitive diagnostic modalities, including multiparameter flow cytometry and polymerase chain reaction, can now quantify disease burden more accurately, and this in turn has led to the development of more sensitive definitions of CR.10

These may prove to be better predictors of outcome than previous definitions, and future strategies may therefore focus on achievement of molecular remission as a new therapeutic target in clinical practice.10 As evidence continues to build, what is clear is that achieving and sustaining high-quality responses should be one of the key priorities in the treatment of patients at all stages of MM.8,15

More sensitive definitions of CR may prove to be better predictors of outcome10,11
graph disease burden graph disease burden

Balancing high-quality responses with quality of life

Outcome is influenced by multiple factors in patients with multiple myeloma22
model factors influencing quality of life model factors influencing quality of life

As with many disease areas in oncology, the advances in treatment seen in MM have generated significant debate over whether the disease should be treated with an aggressive multi-drug strategy or a sequential disease control approach that emphasises quality of life (QoL) as well as overall survival (OS).16,17 Additionally, the ability to modify the biology of MM has raised the question of whether a change in the treatment paradigm towards continuous, 'chronic' therapy is warranted to sustain or even improve responses.18 Although OS remains a primary goal in MM, longer survival times, as a result of more efficacious chemotherapy and other treatment approaches, and potentially longer treatment durations, have driven QoL to the fore.19

The achievement of symptom reduction and disease control must therefore be effectively balanced by efforts to minimise the adverse effects of potentially long-term treatment, in order to improve patient QoL and promote adherence. In the frontline setting, the first remission is likely to be the period during which patients will experience the best QoL.20 Thus, aiming to achieve a first remission that is as long as possible appears to be a logical approach.20 However, at relapse, the challenge is to select the optimal treatment for each patient while balancing disease control and QoL.20 A number of assessment tools are now available to help physicians categorise patients based on their performance status and frailty, facilitating subsequent treatment decisions in both the frontline and relapse setting.21

Multiple myeloma remains a challenging disease

Despite substantial progress, the majority of patients with MM still fail to achieve optimal responses regardless of treatment regimen. MM currently remains incurable and most patients will relapse despite achievement of CR.14 In addition, as the disease progresses, clinical benefit decreases with each subsequent line of therapy.8

These diminishing responses experienced with successive treatment regimens likely reflect acquired drug resistance to prior therapy and individual disease biology.23 Hence, there continues to be an urgent unmet need for novel therapeutic approaches that provide high-quality responses and symptomatic relief, and maintain a good QoL for patients with relapsed or refractory MM.24

There is a need to create long-term treatment strategies so that patients are offered efficient treatment even in third, fourth and further relapses of multiple myeloma25

Remission duration decreases with each line of therapy25
graph remission duration decreases graph remission duration decreases

MGUS, monoclonal gammopathy of unknown significance.

Moving toward personalised therapy in multiple myeloma

European Myeloma Network: Prognostic factors in multiple myeloma30
Prognostic determinant Standard risk High risk
Host factors
  • KPS >70%
  • Normal renal function
  • Normal organ function
  • No impairment in GA
  • FCI 0, CCI 0
  • KPS <70%
  • Renal failure (eGFR <30)
  • Other organ impairment
  • GA reduced
  • Advanced age
Tumour burden
  • Durie & Salmon stage I+II
  • Durie & Salmon stage III
Tumour biology (disease aggressiveness)
  • Hyperdiploidy, t(11;14), t(6;14)
  • ISS I+II
  • t(4;14), t(14;16), t(14;20), 17p-, 1q/del1p
  • High LDH
  • ISS III
  • High PC proliferation rate
  • Presentation as PCL
  • Extramedullary disease
  • HR signature on GEP

Adapted from Engelhardt et al.30 CCI, Charlson Comorbidity Index; eGFR, estimated glomerular filtration rate; FCI, Freiburg Comorbidity Index; GA, geriatric assessment; GEP, gene expression profiling; HR, high risk; ISS, International Staging System; KPS, Karnofsky Performance Status; LDH, lactate dehydrogenase; PC, plasma cell; PCL, plasma cell leukaemia.

Despite positive trends in treatment outcomes, it has become apparent that treatment strategies need to be further developed for individual patients with MM.15 Prognosis in MM depends on numerous patient factors (age, performance status, comorbidities), disease stage, disease aggressiveness, and response to therapy.26 The past few years have witnessed a growing ability to identify underlying markers with prognostic significance, based on a variety of techniques, including fluorescence in situ hybridisation (FISH) analysis and gene expression profiling (GEP), in addition to traditionally recognised risk factors.27-30 This has led some centres to propose treatment recommendations based on genetically determined risk stratification.28-30 However, until further evidence is generated, there remains a lack of international consensus as to the optimal treatment approach for different risk groups.

In the future, identification of prognostic markers and/or risk stratification at diagnosis may help direct more tailored efforts towards those patients currently responding poorly, those at risk of significant side effects, or those who may respond better to individual treatments, recognising that it is not necessarily best practice to 'save' particular treatment strategies for later specified time points.20 Strategies to adapt therapy for the individual patient may also include personalised sequencing of novel agents at relapse on the basis of various disease and patient-related factors.31

Each of your multiple myeloma patients needs an individual approach

  SCT Non-SCT Aggressive disease Non-SCT Non-aggressive disease
  SCT patient Non-SCT aggressive disease patient Non SCT non-aggressive disease patient
Personal description
  • 61 years old; married mother of 2 children
  • Successful in her job
  • Never been sick before
  • 69 years old; business owner
  • Good physical fitness
  • 83 years old; retired
  • 6 grandchildren
  • Comorbidities: diabetes
Relapse
  • After 25 months
  • Progressive within 7 months despite treatment
  • 18 months without measurable disease

These patient profiles are fictitious. Any resemblance to real persons, living or dead, is purely coincidental. SCT, stem cell transplant.

Videos

Prof Palumbo at ASH

Listen to Prof. Palumbo on multiple myeloma and quality of life

Prof Mohty at ASH

Listen to Prof. Mohty on multiple myeloma

Dr Mateos at ASH

Listen to Dr. Mateos on multiple myeloma

Prof Ludwig at ASH

Listen to Prof. Ludwig on multiple myeloma

Prof Hajek at ASH

Listen to Prof. Hajek on multiple myeloma

Professor Scheid

Response criteria in multiple myeloma

Professor Lokhorst

Multiple myeloma and quality of life

Professor Gunsilius

Multiple myeloma, the perspective from the patient

Professor Moreau

Multiple myeloma Response criteria – guiding patient management

Downloads

References

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  2. Kumar SK, et al. Leukemia 2014;28:1122–8.
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  6. Hajek R (2013). Strategies for the treatment of multiple myeloma in 2013:
    Moving Toward the Cure. In: Multiple myeloma – a quick reflection on the fast progress. Ed. Hajek R. InTech. Available at:
    http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-on-the-fast-progress/strategies-for-the-treatment-of-multiple-myeloma-in-2013-moving-toward-the-cure. Accessed February 2015.
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