Seminar
Multiple myeloma Christoph Röllig, Stefan Knop, Martin Bornhäuser
Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future.
Epidemiology Multiple myeloma is the malignant counterpart of long-lived plasma cells with a strong tropism for bone and bone marrow. Among other plasma cell dyscrasias, such as Waldenström’s macroglobulinaemia and primary amyloidosis, multiple myeloma is the second most frequent haematological malignancy with an age-adjusted incidence of six per 100 000 per year in the USA and Europe. The incidence of multiple myeloma is two to three times higher in African Americans, making it the most common haematological malignancy in this ethnic group.1 The median age at diagnosis of multiple myeloma is 69 years, with three-quarters of patients being diagnosed above the age of 55 years and two of three patients being men.2 With the advent of more effective therapeutic strategies and improvements in supportive care, the median survival has increased from 3 years to 6 years in the past two decades. The age-adjusted death rate for men and women between 2006 and 2010 in the USA was 3·4 in 100 000.2
Pathogenesis Multiple myeloma cells are similar to long-lived, post-germinal centre plasma cells, and are characterised by strong bone marrow dependence, extensive somatic hypermutation of immunoglobulin genes, and absence of IgM expression. However, multiple myeloma cells differ from healthy plasma cells because they retain the potential to return to a lower proliferative state.3
Role of the microenvironment Current research on the interaction between multiple myeloma cells and their bone marrow microenvironment focuses on cell–cell and cell–matrix interactions, and growth factors and cytokines. Cellular components of the microenvironment include bone marrow stromal cells, osteoblasts, endothelial cells, and cells of the innate and adaptive immune system, including regulatory T cells. Crosstalk between multiple myeloma and its www.thelancet.com Vol 385 May 30, 2015
microenvironment seems to be bidirectional—eg, in the case of tumour-promoting myeloid-derived suppressor cells, which on the one hand induce the growth of multiple myeloma cells by suppressing immune effector cells but on the other hand are increased in number by multiple myeloma cells.4
Myeloma progenitors and stem cells
Lancet 2015; 385: 2197–208 Published Online December 23, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60493-1 Medizinische Klinik und Poliklinik I, Universitätsklinikum, Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany (C RÖllig MD, Prof M Bornhäuser MD); and Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany (S Knop MD) Correspondence to: Dr Christoph Röllig, Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany christoph.roellig@ uniklinikum-dresden.de
Because all therapies established so far, including stem cell transplantation, do not cure multiple myeloma, research is ongoing to identify a way to target and eradicate the subset of tumour cells that replenishes the tumour, even after high-dose melphalan therapy. With the use of serial transplantation models and clonogenic in-vitro assays, it has been suggested that the multiple myeloma stem cell is part of a subset of CD38CD19+CD27+ B cell precursors that do not express the classic multiple myeloma markers CD38 or CD138.5 So far, these investigations have not led to a clear structure of the multiple myeloma stem and progenitor cell network, which would however be necessary before specific therapies targeting multiple myeloma stem cells can be used.
Clonal evolution of multiple myeloma Comprehensive high-resolution genomic studies have shed new light on the clonal composition of multiple myeloma at diagnosis and during disease progression.6,7 By contrast with what was postulated one or two decades ago, tumours including multiple myeloma are not derived from one single tumour stem cell, but composed of clonally diverse subsets of tumour cells harbouring an immense genetic diversity (figure 1). This theory is supported by the clinical occurrence of biclonal disease or even a class switch in the monoclonal immunoglobulin in relapsing multiple myeloma patients. The waves of different multiple myeloma clones evolving during the natural course of disease and the shifts in dominant and subdominant clones during therapy and relapse are a fascinating area for novel research. 2197
Seminar
Monoclonal gammopathy of unknown significance
Myeloma
Progenitor clones competing for bone marrow niche
Relapse or plasma cell leukaemia
Dominant diagnostic clone Mutation x Therapy
Tumour initiating cell
Mutation x (A) clone with unique mutations = diagnostic clone
Mutation x
Mutation xy Minor diagnostic subclone
Mutation z
Mutation xy (B) dominant clone already detectable as minor subclone at diagnosis
Mutation z (C) clone with unique mutations = diagnostic clone
Figure 1: Clonal composition of multiple myeloma during disease progression and therapy During the progression from monoclonal gammopathy to multiple myeloma, tumour initiating cells can give rise to subclones that are predominantly detected in diagnostic samples and harbour unique mutations, x, which might also be detectable later on in relapsed disease. (A) Especially in high-risk disease, minor subclones that might have been hardly detectable at the time of initial diagnosis might acquire additional driving mutations, xy, during therapy, which later dominate the clonal composition at relapse. (B) Subclones derived from tumour-initiating cells not detectable at the time of initial diagnosis might awake from dormancy at a later point in time and evolve as the dominating clone at relapse with a different founding mutation, z. (C) Whereas clones with unique non-linear mutations x or z are supposed to be more susceptible to salvage therapy, subclones driven by newly acquired mutations (xy) are likely to be resistant to conventional therapies.
Test Blood
Serum protein electrophoresis and immunofixation Serum immunoglobulins quantitative Serum free light chain assay Total serum protein, serum albumin, creatinine, calcium, electrolytes, lactate dehydrogenase, β2-microglobulin Haemoglobin, white blood cell count, differential count, platelet count
Urine
Urine protein electrophoresis and immunofixation 24 h urine for total protein, light chains
Bone marrow
Aspirate and biopsy for plasma cell count, morphology, amyloid* Cytogenetic evaluation and fluorescence in-situ hybridisation for the detection of del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q+
Bones
Skeletal survey (conventional x-ray) or low-dose CT scan without contrast
Whole body
MRI*, PET-CT* Tissue biopsy for solitary or extraosseous plasmacytoma*
*Useful under some circumstances.
Table 1: Diagnostic workup for multiple myeloma
Symptoms, diagnostic workup, and disease monitoring The most common clinical manifestations of symptomatic multiple myeloma are anaemia, infections, lytic or osteopenic bone disease, or renal failure, but patients with multiple myeloma might be diagnosed at an asymptomatic stage by chance. Generally, multiple myeloma is diagnosed at an earlier stage today than in the past.8 Back pain, particularly in older patients, or unclear anaemia should prompt screening for the presence of multiple myeloma. 2198
The standard screening workup includes total serum protein, serum and urine protein electrophoresis (SPEP and UPEP), immunofixation in serum and urine, detection of immunoglobulin free light chains (FLC) in serum, and the following additional parameters: complete blood count, serum creatinine, and electrolytes including calcium, lactate dehydrogenase, and β2 microglobulin. In a patient with suspected multiple myeloma, a bone marrow sample should be obtained by aspiration or by doing a biopsy. If a monoclonal protein is detected through SPEP, UPEP, or by pathological FLC ratio and the plasma cell count is higher than or equal to 10%, a diagnosis of multiple myeloma is made. The same applies to patients with less than 10% plasma cells but with a monoclonal protein of more than or equal to 3 g/100 mL.9 In patients with non-secretory multiple myeloma, the diagnosis is based on the presence of more than 30% bone marrow plasma cells or the detection of plasmacytoma in a biopsy.10 A singular plasma cell lesion in the bone or at an extraosseous site with less than 10% plasma cell infiltration in the bone marrow and low monoclonal protein is defined as solitary plasmacytoma, a disorder distinctively different from systemic multiple myeloma both in terms of prognosis and treatment. In patients diagnosed with multiple myeloma, development of end-organ damage is the indication for treatment. Multiple myeloma without end-organ damage is referred to as smouldering multiple myeloma. Multiple myeloma patients should have a full radiographic skeletal www.thelancet.com Vol 385 May 30, 2015
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survey done to detect lytic lesions, severe osteopenia, or pathological fractures.9 MRI or PET-CT can be used when symptomatic areas show no abnormality on routine radiographs.11 Table 1 summarises the diagnostic workup for patients with multiple myeloma. Patients with monoclonal gammopathy but with less than 10% bone marrow plasma cells or low M-protein are diagnosed with monoclonal gammopathy of unknown significance, and do not need treatment but do need regular follow-up because of the potential for progression to multiple myeloma; however, the risk of progression is only 1% per life-year.9 Disorders such as nephrotic syndrome and heart failure, neuropathy in non-diabetic patients, left ventricular hypertrophy on echocardiography without consistent electrocardiographic evidence or low limb lead voltages, hepatomegaly with normal imaging, or albuminuria should be assessed carefully to not overlook light-chain amyloidosis caused by free light-chain secretion.12,13 The appendix shows the diagnostic criteria for monoclonal gammopathy of unknown significance, smouldering and active multiple myeloma. To measure treatment response and monitor disease activity, the serum M-protein is the preferred surrogate marker. In patients with light chain secretion, the Bence-Jones proteinuria in a 24 h urine specimen should be used to monitor disease activity, and for patients with oligosecretory multiple myeloma, the FLC assay is useful to monitor disease activity, provided the FLC ratio is abnormal and the involved FLC level is at least 100 mg/L.14 In the rare non-secretory multiple myeloma, only the plasma cell count in the bone marrow and monitoring of clinical manifestations of organ damage can be used for response assessment and to monitor disease.15 Other techniques such as flow cytometry, fluorescent in-situ hybridisation or PCR using allele-specific oligonucleotides can contribute information on minimal residual disease in myeloma, refine the complete remission definition, and distinguish two response groups (minimal residual disease positive and negative) with clear differences in progression-free and overall survival.16
Disease management Indication for treatment Patients with smouldering multiple myeloma have no treatment indication and should be monitored for disease progression because early treatment with conventional therapy has shown no benefit.17–19 The risk of progression is highest in the first 5 years and decreases subsequently. The overall risk of progression is 10% per year for the first 5 years, about 3% per year for the next 5 years, and 1% per year for the next 10 years.17 Patients with high-risk smouldering multiple myeloma should be enrolled onto clinical trials End-organ damage is defined mainly by the CRAB criteria—hypercalcaemia, renal failure, anaemia, or bone lesions, which are related to a plasma cell proliferative disorder and cannot be explained by another unrelated www.thelancet.com Vol 385 May 30, 2015
disease or disorder. The appendix provides additional information about criteria for active multiple myeloma. Moreover, progressive myeloma-induced renal insufficiency should trigger initiation of treatment even before the creatinine threshold of 2 mg/dL (177 μmol/L) has been reached. Acute renal failure due to multiple myeloma can be reversible if treated early. After the confirmation of an underlying cast nephropathy, appropriate treatment should be initiated without delay.20,21 Once patients with renal impairment have achieved a remission, their outcomes are similar to patients with no renal insufficiency.22
Local disease control and systemic treatment Solitary osseous and extraosseous plasmacytomas are treated with curatively intended radiation therapy to the involved field with cumulative doses of 45 Gy or more.23,24 Additionally, if necessary, extraosseous lesions can be resected surgically. Although cure is the primary goal of treatment in solitary plasmacytoma, a progression to systemic multiple myeloma is possible and occurs in 30–60% of cases, therefore requiring regular follow-up.25 Patients diagnosed with systemic active multiple myeloma characterised by end-organ damage should be treated with systemic chemotherapy to prevent progression and reduce disease-induced symptoms. A very good partial remission or complete remission after systemic treatment is associated with an improved long-term outcome. Therefore, the aim of new treatment approaches is to increase response rates in all patients. In elderly patients, this concept should be considered in relation to possible side-effects and quality of life because improved response rates do not necessarily translate into a survival benefit.26–30 Surgery or radiotherapy might be necessary if bone-related complications are present.
See Online for appendix
Autologous stem cell transplantation Because myeloablative high-dose therapy with autologous stem cell transplantation prolongs survival substantially compared with conventional cytostatic treatments, it has become an essential part of multiple myeloma management.31,32 Because of its toxic effects and the advanced age of many multiple myeloma patients, the thorough assessment of eligibility is crucial.33 The most commonly used criteria for eligibility are the patient’s preference, a biological age up to 65–70 years, the absence of substantial heart, lung, kidney, or liver dysfunction, or other uncontrolled comorbidities such as diabetes. Eligible patients should receive myeloablative treatment with melphalan 200 mg/m² after remission induction by standard first-line treatment. Older patients or patients with substantially impaired organ function might receive reduced doses of melphalan (100–140 mg/m²) before infusion of autologous stem cells.34,35 Investigators in France showed that tandem transplantation was superior to single transplantation in a randomised trial; however, this benefit was restricted to 2199
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Age 75 years and dose level –2
Bortezomib
1·3 mg/m² on days 1, 4, 8, and 11 every 3 weeks
1·3 mg/m² on days 1, 8, 15, and 22 every 5 weeks
1·0 mg/m² on days 1, 8, 15, and 22 every 5 weeks
Cyclophosphamide
300 mg/m² orally on days 1, 8, 15, and 22 every 4 weeks
50–100 mg/m² orally on days 1, 8, 15, and 22 every 4 weeks
50 mg/m² orally every other day on days 1–21 every 4 weeks
Dexamethasone
40 mg on days 1–4 and 15–18 or on days 1, 4, 8, 15, and 22 every 4 weeks
20–40 mg on days 1, 4, 8, 15, and 22 every 4 weeks
10–20 mg on days 1, 4, 8, 15, and 22 every 4 weeks
Lenalidomide
25 mg on days 1–21 every 4 weeks
15 mg on days 1–21 every 4 weeks
10 mg on days 1–21 every 4 weeks
Melphalan
0·25 mg/kg on days 1–4 every 4–6 weeks
0·18 mg/kg on days 1–4 every 4–6 weeks
0·13 mg/kg on days 1–4 every 4–6 weeks
Prednisone
50 mg every other day
25 mg every other day
12·5 mg every other day
Thalidomide
200 mg/day continuously
100 mg/day continuously
50 mg/day continuously
Data from Ludwig and colleagues43 and Palumbo and Anderson.44
Table 2: Dose-adjustment recommendations depending on age and tolerability
patients who did not achieve at least a very good partial remission after the first transplantation.36 The pooled results from a systematic review showed no significant difference between tandem and single autologous stem cell transplantations for the outcome of overall survival, but a superior event-free survival and response rate with tandem transplantation.37 Current practice in most centres is to do only one autologous stem cell transplantation initially. A reason for the use of this strategy is that the proportion of patients achieving complete remission after one high-dose chemotherapy has doubled in the era of novel compounds used during induction therapy. Moreover, stem cell transplantation might again be effectively done in relapse, as suggested by data from several non-randomised trials.38 Because the benefit of high-dose treatment has been shown before the use of novel drugs and meta-analyses showed an event-free survival advantage, but no clear overall survival benefit,39 the value of autologous stem cell transplantation has been a matter of debate for years. However, preliminary results from randomised comparisons incorporating novel drugs have shown the importance of high-dose treatment for sustained progression-free survival.40 Although immediate autologous stem cell transplantation in first-line treatment is the standard of care, retrospective analyses suggest that in the era of novel drugs its use could be postponed until the time of first relapse with no prognostic disadvantage for patients.41 Currently, two large randomised trials (NCT01191060, NCT01208766) are comparing immediate versus delayed transplantation at the time of first relapse or disease progression.
First-line treatment in patients not eligible for transplantation Most multiple myeloma patients will not be eligible for high-dose therapy because of their older age. In this patient group, emphasis should be placed on tolerability of treatment to minimise excessive morbidity and mortality. Treatment should be given for several cycles because 2200
response quality often increases over time.42 Generally, however, this is only possible for treatments that have a favourable tolerability profile. Quality of life is also a major issue, particularly in a non-curable disease such as multiple myeloma. To prevent excessive treatment toxic effects and improve tolerability, age-adjusted dose reductions, modified application schedules (table 2), and adequate supportive measures are important considerations. Figure 2 shows an overview of treatment approaches used in newly diagnosed multiple myeloma patients. Standard treatment options combine traditional drugs such as melphalan and prednisone with novel treatments such as immunomodulatory drugs and proteasome inhibitors. The addition of the immunomodulatory drug thalidomide to melphalan and prednisone has been shown to increase response rates, progression-free survival, and potentially overall survival in several trials and a meta-analysis.45 Data from a large international trial showed that the combination of the proteasome inhibitor bortezomib and melphalan and prednisone had a statistically significantly higher efficacy than melphalan and prednisone alone and led to improved survival outcomes.46 No data from randomised trials comparing melphalan, prednisone, and thalidomide and melphalan, prednisone, and bortezomib regimens are available. However, findings from a recent meta-analysis suggested higher response rates with the melphalan, prednisone, and bortezomib regimen compared with the melphalan, prednisone, and thalidomide regimen, but there were no significant differences between the treatment regimens in progression-free survival and overall survival.47 Another indirect meta-analysis of this comparison showed no difference between melphalan, prednisone, and bortezomib and melphalan, prednisone, and thalidomide for all outcomes but a statistically significant benefit for complete response and grade 3 or 4 adverse events for melphalan, prednisone, and bortezomib.48 On the basis of the survival benefit, compared with the melphalan and prednisone combination, the combinations of melphalan, prednisone, and thalidomide and melphalan, prednisone, and bortezomib are the www.thelancet.com Vol 385 May 30, 2015
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Patient with newly diagnosed multiple myeloma
CRAB criteria?
No
Watch and wait
Yes Symptomatic osseus or extraosseous lesion?
Yes
Consider radiotherapy or surgical treatment
No Systemic treatment
Assess comorbidities, age, patient’s preference
Transplantation-eligible patient
Three-drug regimen Bortezomib, cyclophosphamide, and dexamethasone Bortezomib, doxorubicin, and dexamethasone* Bortezomib, lenalidomide, and dexamethasone* Bortezomib, thalidomide, and dexamethasone*
Transplantation-ineligible patient
Two-drug regimen Lenalidomide and dexamethasone* Bortezomib and dexamethasone*
Three-drug regimen Melphalan, prednisone, and bortezomib* Melphalan, prednisone, and thalidomide*
Two-drug regimen Lenalidomide and dexamethasone* Bortezomib and dexamethasone* Melphalan and prednisone*† Bendamustine and prednisone*† Dexamethasone†
Single autologous SCT*‡
Consider maintenance
Figure 2: Clinical management of patients with newly diagnosed multiple myeloma The listed therapy combinations are selected and not inclusive of all regimens. *Treatment combinations with evidence from randomised-controlled trials. †Melphalan + prednisone, bendamustine + prednisone, or dexamethasone can be used if novel drugs are not available or contraindicated. ‡Consider allogeneic stem-cell transplantation in young patients with deletion 17p and HLA-identical siblings.
preferred first-line treatments if available and tolerated. Data from two studies have shown that the combination of lenalidomide and dexamethasone is an effective treatment in elderly multiple myeloma patients.49,50 Preliminary data from a large randomised controlled trial suggest higher response rates and similar progression-free survival after first-line treatment with lenalidomide plus low-dose dexamethasone for a fixed number of cycles compared with melphalan, prednisone, and thalidomide.51 Prophylactic antithrombotic measures should be taken when thalidomide or lenalidomide are given,52,53 whereas prophylactic aciclovir is recommended in patients receiving bortezomib for the prevention of zoster reactivation.54,55 Careful clinical monitoring and dose adaptation is advisable to minimise the toxic effects of treatment, ensure adherence to treatment and, hence, provide the greatest opportunity for achievement of high response rates and long-term remission. To minimise toxicities of multiple myeloma treatments, dose reduction might be necessary in patients receiving thalidomide and lenalidomide, whereas laxatives might be needed for patients receiving thalidomide. Moreover, there are three main preventive strategies for bortezomib-induced polyneuropathy: expansion of the application intervals www.thelancet.com Vol 385 May 30, 2015
from days 1, 4, 8, and 11 to days 1, 8, 15, and 22 per cycle; use of the subcutaneous administration route as opposed to intravenous application; and dose reduction.
First-line treatment in patients eligible for transplantation Patients eligible for high-dose treatment of multiple myeloma tend to be younger and fitter than those who are not eligible. Because there seems to be a positive correlation between depth of response and survival,56–62 the goal with primary therapy is to achieve a maximum response before high-dose treatment that translates into even higher remission rates after autologous stem cell transplantation. Accordingly, more effective and intensive treatments are used to improve outcomes. Similarly to non-transplantation-eligible patients, the combination of novel drugs thalidomide,63 bortezomib,64 or lenalidomide49 with standard drugs for multiple myeloma treatment has resulted in higher response rates than the historical standard of vincristine plus doxorubicin (adriamycin) plus dexamethasone.65,66 Therefore, combinations with novel drugs should be used for primary treatment, provided that they are available and not medically contraindicated (figure 2). The triple combination including either one or two novel drugs results in higher 2201
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response rates than the combination of two drugs—eg, bortezomib plus dexamethasone plus either cyclophosphamide67–70 or doxorubicin71,72 or thalidomide27,73 or lenalidomide.69,74 The addition of a fourth drug to primary treatment does not seem to further increase response rates.28,69 On the basis of these findings, experts and guidelines preferentially recommend the use of a triple combination or if contraindications exist, a double combination for three to six cycles for primary treatment in transplant-eligible patients.43,44,65,75,76 There is a need for high-level evidence from randomised-controlled trials comparing different first-line regimens and two-drug versus three-drug combinations, not only regarding progression but also overall survival.
Consolidation and maintenance To further reduce the tumour burden after autologous stem cell transplantation, a limited number of treatment cycles can be administered afterwards. This treatment is referred to as consolidation and can improve the depth of response.77,78 However, the emergence of novel agents with a lower toxic effect profile than with more traditional anti-multiple myeloma drugs led to a renaissance in the concept of continuous treatment or maintenance. Historical approaches with steroids79,80 or interferon81,82 showed little efficacy and serious limitations because of long-term side-effects and low tolerability. As thalidomide was the first of the novel drugs, the largest number of patients has received thalidomide continuously. Three meta-analyses of trial results in transplantation-eligible patients showed a benefit in progression-free survival and overall survival when thalidomide maintenance was compared with no maintenance.83–85 These positive results should be considered in relation to substantial long-term toxic effects, leading to a short treatment, mainly as a result of peripheral polyneuropathy. In the large MRC IX trial of thalidomide maintenance, patients with high-risk cytogenetics had a statistically significantly shorter overall survival after thalidomide maintenance than did those without maintenance. This difference was caused by a higher incidence of resistant disease that did not respond to salvage treatment in the thalidomide maintenance group.86 In four clinical trials administering thalidomide after melphalan, prednisone, and thalidomide in elderly patients,87–90 only one trial showed a small statistically significant benefit in overall survival.88 The maintenance of lenalidomide, the second novel drug, has been extensively studied in three large randomised trials. As opposed to thalidomide, longterm application is feasible because of a more favourable toxicity profile with mainly haematological side-effects. The IFM 2005-0278 and CALGB 10010491 trials applied lenalidomide maintenance after high-dose treatment in a randomised placebo-controlled design until disease progression. With a median follow-up of 45 months in the IFM 2005-02 trial, progression-free survival was 2202
significantly prolonged with lenalidomide versus placebo (41 months vs 23 months; p
Multiple myeloma Christoph Röllig, Stefan Knop, Martin Bornhäuser
Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future.
Epidemiology Multiple myeloma is the malignant counterpart of long-lived plasma cells with a strong tropism for bone and bone marrow. Among other plasma cell dyscrasias, such as Waldenström’s macroglobulinaemia and primary amyloidosis, multiple myeloma is the second most frequent haematological malignancy with an age-adjusted incidence of six per 100 000 per year in the USA and Europe. The incidence of multiple myeloma is two to three times higher in African Americans, making it the most common haematological malignancy in this ethnic group.1 The median age at diagnosis of multiple myeloma is 69 years, with three-quarters of patients being diagnosed above the age of 55 years and two of three patients being men.2 With the advent of more effective therapeutic strategies and improvements in supportive care, the median survival has increased from 3 years to 6 years in the past two decades. The age-adjusted death rate for men and women between 2006 and 2010 in the USA was 3·4 in 100 000.2
Pathogenesis Multiple myeloma cells are similar to long-lived, post-germinal centre plasma cells, and are characterised by strong bone marrow dependence, extensive somatic hypermutation of immunoglobulin genes, and absence of IgM expression. However, multiple myeloma cells differ from healthy plasma cells because they retain the potential to return to a lower proliferative state.3
Role of the microenvironment Current research on the interaction between multiple myeloma cells and their bone marrow microenvironment focuses on cell–cell and cell–matrix interactions, and growth factors and cytokines. Cellular components of the microenvironment include bone marrow stromal cells, osteoblasts, endothelial cells, and cells of the innate and adaptive immune system, including regulatory T cells. Crosstalk between multiple myeloma and its www.thelancet.com Vol 385 May 30, 2015
microenvironment seems to be bidirectional—eg, in the case of tumour-promoting myeloid-derived suppressor cells, which on the one hand induce the growth of multiple myeloma cells by suppressing immune effector cells but on the other hand are increased in number by multiple myeloma cells.4
Myeloma progenitors and stem cells
Lancet 2015; 385: 2197–208 Published Online December 23, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60493-1 Medizinische Klinik und Poliklinik I, Universitätsklinikum, Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany (C RÖllig MD, Prof M Bornhäuser MD); and Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany (S Knop MD) Correspondence to: Dr Christoph Röllig, Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany christoph.roellig@ uniklinikum-dresden.de
Because all therapies established so far, including stem cell transplantation, do not cure multiple myeloma, research is ongoing to identify a way to target and eradicate the subset of tumour cells that replenishes the tumour, even after high-dose melphalan therapy. With the use of serial transplantation models and clonogenic in-vitro assays, it has been suggested that the multiple myeloma stem cell is part of a subset of CD38CD19+CD27+ B cell precursors that do not express the classic multiple myeloma markers CD38 or CD138.5 So far, these investigations have not led to a clear structure of the multiple myeloma stem and progenitor cell network, which would however be necessary before specific therapies targeting multiple myeloma stem cells can be used.
Clonal evolution of multiple myeloma Comprehensive high-resolution genomic studies have shed new light on the clonal composition of multiple myeloma at diagnosis and during disease progression.6,7 By contrast with what was postulated one or two decades ago, tumours including multiple myeloma are not derived from one single tumour stem cell, but composed of clonally diverse subsets of tumour cells harbouring an immense genetic diversity (figure 1). This theory is supported by the clinical occurrence of biclonal disease or even a class switch in the monoclonal immunoglobulin in relapsing multiple myeloma patients. The waves of different multiple myeloma clones evolving during the natural course of disease and the shifts in dominant and subdominant clones during therapy and relapse are a fascinating area for novel research. 2197
Seminar
Monoclonal gammopathy of unknown significance
Myeloma
Progenitor clones competing for bone marrow niche
Relapse or plasma cell leukaemia
Dominant diagnostic clone Mutation x Therapy
Tumour initiating cell
Mutation x (A) clone with unique mutations = diagnostic clone
Mutation x
Mutation xy Minor diagnostic subclone
Mutation z
Mutation xy (B) dominant clone already detectable as minor subclone at diagnosis
Mutation z (C) clone with unique mutations = diagnostic clone
Figure 1: Clonal composition of multiple myeloma during disease progression and therapy During the progression from monoclonal gammopathy to multiple myeloma, tumour initiating cells can give rise to subclones that are predominantly detected in diagnostic samples and harbour unique mutations, x, which might also be detectable later on in relapsed disease. (A) Especially in high-risk disease, minor subclones that might have been hardly detectable at the time of initial diagnosis might acquire additional driving mutations, xy, during therapy, which later dominate the clonal composition at relapse. (B) Subclones derived from tumour-initiating cells not detectable at the time of initial diagnosis might awake from dormancy at a later point in time and evolve as the dominating clone at relapse with a different founding mutation, z. (C) Whereas clones with unique non-linear mutations x or z are supposed to be more susceptible to salvage therapy, subclones driven by newly acquired mutations (xy) are likely to be resistant to conventional therapies.
Test Blood
Serum protein electrophoresis and immunofixation Serum immunoglobulins quantitative Serum free light chain assay Total serum protein, serum albumin, creatinine, calcium, electrolytes, lactate dehydrogenase, β2-microglobulin Haemoglobin, white blood cell count, differential count, platelet count
Urine
Urine protein electrophoresis and immunofixation 24 h urine for total protein, light chains
Bone marrow
Aspirate and biopsy for plasma cell count, morphology, amyloid* Cytogenetic evaluation and fluorescence in-situ hybridisation for the detection of del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q+
Bones
Skeletal survey (conventional x-ray) or low-dose CT scan without contrast
Whole body
MRI*, PET-CT* Tissue biopsy for solitary or extraosseous plasmacytoma*
*Useful under some circumstances.
Table 1: Diagnostic workup for multiple myeloma
Symptoms, diagnostic workup, and disease monitoring The most common clinical manifestations of symptomatic multiple myeloma are anaemia, infections, lytic or osteopenic bone disease, or renal failure, but patients with multiple myeloma might be diagnosed at an asymptomatic stage by chance. Generally, multiple myeloma is diagnosed at an earlier stage today than in the past.8 Back pain, particularly in older patients, or unclear anaemia should prompt screening for the presence of multiple myeloma. 2198
The standard screening workup includes total serum protein, serum and urine protein electrophoresis (SPEP and UPEP), immunofixation in serum and urine, detection of immunoglobulin free light chains (FLC) in serum, and the following additional parameters: complete blood count, serum creatinine, and electrolytes including calcium, lactate dehydrogenase, and β2 microglobulin. In a patient with suspected multiple myeloma, a bone marrow sample should be obtained by aspiration or by doing a biopsy. If a monoclonal protein is detected through SPEP, UPEP, or by pathological FLC ratio and the plasma cell count is higher than or equal to 10%, a diagnosis of multiple myeloma is made. The same applies to patients with less than 10% plasma cells but with a monoclonal protein of more than or equal to 3 g/100 mL.9 In patients with non-secretory multiple myeloma, the diagnosis is based on the presence of more than 30% bone marrow plasma cells or the detection of plasmacytoma in a biopsy.10 A singular plasma cell lesion in the bone or at an extraosseous site with less than 10% plasma cell infiltration in the bone marrow and low monoclonal protein is defined as solitary plasmacytoma, a disorder distinctively different from systemic multiple myeloma both in terms of prognosis and treatment. In patients diagnosed with multiple myeloma, development of end-organ damage is the indication for treatment. Multiple myeloma without end-organ damage is referred to as smouldering multiple myeloma. Multiple myeloma patients should have a full radiographic skeletal www.thelancet.com Vol 385 May 30, 2015
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survey done to detect lytic lesions, severe osteopenia, or pathological fractures.9 MRI or PET-CT can be used when symptomatic areas show no abnormality on routine radiographs.11 Table 1 summarises the diagnostic workup for patients with multiple myeloma. Patients with monoclonal gammopathy but with less than 10% bone marrow plasma cells or low M-protein are diagnosed with monoclonal gammopathy of unknown significance, and do not need treatment but do need regular follow-up because of the potential for progression to multiple myeloma; however, the risk of progression is only 1% per life-year.9 Disorders such as nephrotic syndrome and heart failure, neuropathy in non-diabetic patients, left ventricular hypertrophy on echocardiography without consistent electrocardiographic evidence or low limb lead voltages, hepatomegaly with normal imaging, or albuminuria should be assessed carefully to not overlook light-chain amyloidosis caused by free light-chain secretion.12,13 The appendix shows the diagnostic criteria for monoclonal gammopathy of unknown significance, smouldering and active multiple myeloma. To measure treatment response and monitor disease activity, the serum M-protein is the preferred surrogate marker. In patients with light chain secretion, the Bence-Jones proteinuria in a 24 h urine specimen should be used to monitor disease activity, and for patients with oligosecretory multiple myeloma, the FLC assay is useful to monitor disease activity, provided the FLC ratio is abnormal and the involved FLC level is at least 100 mg/L.14 In the rare non-secretory multiple myeloma, only the plasma cell count in the bone marrow and monitoring of clinical manifestations of organ damage can be used for response assessment and to monitor disease.15 Other techniques such as flow cytometry, fluorescent in-situ hybridisation or PCR using allele-specific oligonucleotides can contribute information on minimal residual disease in myeloma, refine the complete remission definition, and distinguish two response groups (minimal residual disease positive and negative) with clear differences in progression-free and overall survival.16
Disease management Indication for treatment Patients with smouldering multiple myeloma have no treatment indication and should be monitored for disease progression because early treatment with conventional therapy has shown no benefit.17–19 The risk of progression is highest in the first 5 years and decreases subsequently. The overall risk of progression is 10% per year for the first 5 years, about 3% per year for the next 5 years, and 1% per year for the next 10 years.17 Patients with high-risk smouldering multiple myeloma should be enrolled onto clinical trials End-organ damage is defined mainly by the CRAB criteria—hypercalcaemia, renal failure, anaemia, or bone lesions, which are related to a plasma cell proliferative disorder and cannot be explained by another unrelated www.thelancet.com Vol 385 May 30, 2015
disease or disorder. The appendix provides additional information about criteria for active multiple myeloma. Moreover, progressive myeloma-induced renal insufficiency should trigger initiation of treatment even before the creatinine threshold of 2 mg/dL (177 μmol/L) has been reached. Acute renal failure due to multiple myeloma can be reversible if treated early. After the confirmation of an underlying cast nephropathy, appropriate treatment should be initiated without delay.20,21 Once patients with renal impairment have achieved a remission, their outcomes are similar to patients with no renal insufficiency.22
Local disease control and systemic treatment Solitary osseous and extraosseous plasmacytomas are treated with curatively intended radiation therapy to the involved field with cumulative doses of 45 Gy or more.23,24 Additionally, if necessary, extraosseous lesions can be resected surgically. Although cure is the primary goal of treatment in solitary plasmacytoma, a progression to systemic multiple myeloma is possible and occurs in 30–60% of cases, therefore requiring regular follow-up.25 Patients diagnosed with systemic active multiple myeloma characterised by end-organ damage should be treated with systemic chemotherapy to prevent progression and reduce disease-induced symptoms. A very good partial remission or complete remission after systemic treatment is associated with an improved long-term outcome. Therefore, the aim of new treatment approaches is to increase response rates in all patients. In elderly patients, this concept should be considered in relation to possible side-effects and quality of life because improved response rates do not necessarily translate into a survival benefit.26–30 Surgery or radiotherapy might be necessary if bone-related complications are present.
See Online for appendix
Autologous stem cell transplantation Because myeloablative high-dose therapy with autologous stem cell transplantation prolongs survival substantially compared with conventional cytostatic treatments, it has become an essential part of multiple myeloma management.31,32 Because of its toxic effects and the advanced age of many multiple myeloma patients, the thorough assessment of eligibility is crucial.33 The most commonly used criteria for eligibility are the patient’s preference, a biological age up to 65–70 years, the absence of substantial heart, lung, kidney, or liver dysfunction, or other uncontrolled comorbidities such as diabetes. Eligible patients should receive myeloablative treatment with melphalan 200 mg/m² after remission induction by standard first-line treatment. Older patients or patients with substantially impaired organ function might receive reduced doses of melphalan (100–140 mg/m²) before infusion of autologous stem cells.34,35 Investigators in France showed that tandem transplantation was superior to single transplantation in a randomised trial; however, this benefit was restricted to 2199
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Age 75 years and dose level –2
Bortezomib
1·3 mg/m² on days 1, 4, 8, and 11 every 3 weeks
1·3 mg/m² on days 1, 8, 15, and 22 every 5 weeks
1·0 mg/m² on days 1, 8, 15, and 22 every 5 weeks
Cyclophosphamide
300 mg/m² orally on days 1, 8, 15, and 22 every 4 weeks
50–100 mg/m² orally on days 1, 8, 15, and 22 every 4 weeks
50 mg/m² orally every other day on days 1–21 every 4 weeks
Dexamethasone
40 mg on days 1–4 and 15–18 or on days 1, 4, 8, 15, and 22 every 4 weeks
20–40 mg on days 1, 4, 8, 15, and 22 every 4 weeks
10–20 mg on days 1, 4, 8, 15, and 22 every 4 weeks
Lenalidomide
25 mg on days 1–21 every 4 weeks
15 mg on days 1–21 every 4 weeks
10 mg on days 1–21 every 4 weeks
Melphalan
0·25 mg/kg on days 1–4 every 4–6 weeks
0·18 mg/kg on days 1–4 every 4–6 weeks
0·13 mg/kg on days 1–4 every 4–6 weeks
Prednisone
50 mg every other day
25 mg every other day
12·5 mg every other day
Thalidomide
200 mg/day continuously
100 mg/day continuously
50 mg/day continuously
Data from Ludwig and colleagues43 and Palumbo and Anderson.44
Table 2: Dose-adjustment recommendations depending on age and tolerability
patients who did not achieve at least a very good partial remission after the first transplantation.36 The pooled results from a systematic review showed no significant difference between tandem and single autologous stem cell transplantations for the outcome of overall survival, but a superior event-free survival and response rate with tandem transplantation.37 Current practice in most centres is to do only one autologous stem cell transplantation initially. A reason for the use of this strategy is that the proportion of patients achieving complete remission after one high-dose chemotherapy has doubled in the era of novel compounds used during induction therapy. Moreover, stem cell transplantation might again be effectively done in relapse, as suggested by data from several non-randomised trials.38 Because the benefit of high-dose treatment has been shown before the use of novel drugs and meta-analyses showed an event-free survival advantage, but no clear overall survival benefit,39 the value of autologous stem cell transplantation has been a matter of debate for years. However, preliminary results from randomised comparisons incorporating novel drugs have shown the importance of high-dose treatment for sustained progression-free survival.40 Although immediate autologous stem cell transplantation in first-line treatment is the standard of care, retrospective analyses suggest that in the era of novel drugs its use could be postponed until the time of first relapse with no prognostic disadvantage for patients.41 Currently, two large randomised trials (NCT01191060, NCT01208766) are comparing immediate versus delayed transplantation at the time of first relapse or disease progression.
First-line treatment in patients not eligible for transplantation Most multiple myeloma patients will not be eligible for high-dose therapy because of their older age. In this patient group, emphasis should be placed on tolerability of treatment to minimise excessive morbidity and mortality. Treatment should be given for several cycles because 2200
response quality often increases over time.42 Generally, however, this is only possible for treatments that have a favourable tolerability profile. Quality of life is also a major issue, particularly in a non-curable disease such as multiple myeloma. To prevent excessive treatment toxic effects and improve tolerability, age-adjusted dose reductions, modified application schedules (table 2), and adequate supportive measures are important considerations. Figure 2 shows an overview of treatment approaches used in newly diagnosed multiple myeloma patients. Standard treatment options combine traditional drugs such as melphalan and prednisone with novel treatments such as immunomodulatory drugs and proteasome inhibitors. The addition of the immunomodulatory drug thalidomide to melphalan and prednisone has been shown to increase response rates, progression-free survival, and potentially overall survival in several trials and a meta-analysis.45 Data from a large international trial showed that the combination of the proteasome inhibitor bortezomib and melphalan and prednisone had a statistically significantly higher efficacy than melphalan and prednisone alone and led to improved survival outcomes.46 No data from randomised trials comparing melphalan, prednisone, and thalidomide and melphalan, prednisone, and bortezomib regimens are available. However, findings from a recent meta-analysis suggested higher response rates with the melphalan, prednisone, and bortezomib regimen compared with the melphalan, prednisone, and thalidomide regimen, but there were no significant differences between the treatment regimens in progression-free survival and overall survival.47 Another indirect meta-analysis of this comparison showed no difference between melphalan, prednisone, and bortezomib and melphalan, prednisone, and thalidomide for all outcomes but a statistically significant benefit for complete response and grade 3 or 4 adverse events for melphalan, prednisone, and bortezomib.48 On the basis of the survival benefit, compared with the melphalan and prednisone combination, the combinations of melphalan, prednisone, and thalidomide and melphalan, prednisone, and bortezomib are the www.thelancet.com Vol 385 May 30, 2015
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Patient with newly diagnosed multiple myeloma
CRAB criteria?
No
Watch and wait
Yes Symptomatic osseus or extraosseous lesion?
Yes
Consider radiotherapy or surgical treatment
No Systemic treatment
Assess comorbidities, age, patient’s preference
Transplantation-eligible patient
Three-drug regimen Bortezomib, cyclophosphamide, and dexamethasone Bortezomib, doxorubicin, and dexamethasone* Bortezomib, lenalidomide, and dexamethasone* Bortezomib, thalidomide, and dexamethasone*
Transplantation-ineligible patient
Two-drug regimen Lenalidomide and dexamethasone* Bortezomib and dexamethasone*
Three-drug regimen Melphalan, prednisone, and bortezomib* Melphalan, prednisone, and thalidomide*
Two-drug regimen Lenalidomide and dexamethasone* Bortezomib and dexamethasone* Melphalan and prednisone*† Bendamustine and prednisone*† Dexamethasone†
Single autologous SCT*‡
Consider maintenance
Figure 2: Clinical management of patients with newly diagnosed multiple myeloma The listed therapy combinations are selected and not inclusive of all regimens. *Treatment combinations with evidence from randomised-controlled trials. †Melphalan + prednisone, bendamustine + prednisone, or dexamethasone can be used if novel drugs are not available or contraindicated. ‡Consider allogeneic stem-cell transplantation in young patients with deletion 17p and HLA-identical siblings.
preferred first-line treatments if available and tolerated. Data from two studies have shown that the combination of lenalidomide and dexamethasone is an effective treatment in elderly multiple myeloma patients.49,50 Preliminary data from a large randomised controlled trial suggest higher response rates and similar progression-free survival after first-line treatment with lenalidomide plus low-dose dexamethasone for a fixed number of cycles compared with melphalan, prednisone, and thalidomide.51 Prophylactic antithrombotic measures should be taken when thalidomide or lenalidomide are given,52,53 whereas prophylactic aciclovir is recommended in patients receiving bortezomib for the prevention of zoster reactivation.54,55 Careful clinical monitoring and dose adaptation is advisable to minimise the toxic effects of treatment, ensure adherence to treatment and, hence, provide the greatest opportunity for achievement of high response rates and long-term remission. To minimise toxicities of multiple myeloma treatments, dose reduction might be necessary in patients receiving thalidomide and lenalidomide, whereas laxatives might be needed for patients receiving thalidomide. Moreover, there are three main preventive strategies for bortezomib-induced polyneuropathy: expansion of the application intervals www.thelancet.com Vol 385 May 30, 2015
from days 1, 4, 8, and 11 to days 1, 8, 15, and 22 per cycle; use of the subcutaneous administration route as opposed to intravenous application; and dose reduction.
First-line treatment in patients eligible for transplantation Patients eligible for high-dose treatment of multiple myeloma tend to be younger and fitter than those who are not eligible. Because there seems to be a positive correlation between depth of response and survival,56–62 the goal with primary therapy is to achieve a maximum response before high-dose treatment that translates into even higher remission rates after autologous stem cell transplantation. Accordingly, more effective and intensive treatments are used to improve outcomes. Similarly to non-transplantation-eligible patients, the combination of novel drugs thalidomide,63 bortezomib,64 or lenalidomide49 with standard drugs for multiple myeloma treatment has resulted in higher response rates than the historical standard of vincristine plus doxorubicin (adriamycin) plus dexamethasone.65,66 Therefore, combinations with novel drugs should be used for primary treatment, provided that they are available and not medically contraindicated (figure 2). The triple combination including either one or two novel drugs results in higher 2201
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response rates than the combination of two drugs—eg, bortezomib plus dexamethasone plus either cyclophosphamide67–70 or doxorubicin71,72 or thalidomide27,73 or lenalidomide.69,74 The addition of a fourth drug to primary treatment does not seem to further increase response rates.28,69 On the basis of these findings, experts and guidelines preferentially recommend the use of a triple combination or if contraindications exist, a double combination for three to six cycles for primary treatment in transplant-eligible patients.43,44,65,75,76 There is a need for high-level evidence from randomised-controlled trials comparing different first-line regimens and two-drug versus three-drug combinations, not only regarding progression but also overall survival.
Consolidation and maintenance To further reduce the tumour burden after autologous stem cell transplantation, a limited number of treatment cycles can be administered afterwards. This treatment is referred to as consolidation and can improve the depth of response.77,78 However, the emergence of novel agents with a lower toxic effect profile than with more traditional anti-multiple myeloma drugs led to a renaissance in the concept of continuous treatment or maintenance. Historical approaches with steroids79,80 or interferon81,82 showed little efficacy and serious limitations because of long-term side-effects and low tolerability. As thalidomide was the first of the novel drugs, the largest number of patients has received thalidomide continuously. Three meta-analyses of trial results in transplantation-eligible patients showed a benefit in progression-free survival and overall survival when thalidomide maintenance was compared with no maintenance.83–85 These positive results should be considered in relation to substantial long-term toxic effects, leading to a short treatment, mainly as a result of peripheral polyneuropathy. In the large MRC IX trial of thalidomide maintenance, patients with high-risk cytogenetics had a statistically significantly shorter overall survival after thalidomide maintenance than did those without maintenance. This difference was caused by a higher incidence of resistant disease that did not respond to salvage treatment in the thalidomide maintenance group.86 In four clinical trials administering thalidomide after melphalan, prednisone, and thalidomide in elderly patients,87–90 only one trial showed a small statistically significant benefit in overall survival.88 The maintenance of lenalidomide, the second novel drug, has been extensively studied in three large randomised trials. As opposed to thalidomide, longterm application is feasible because of a more favourable toxicity profile with mainly haematological side-effects. The IFM 2005-0278 and CALGB 10010491 trials applied lenalidomide maintenance after high-dose treatment in a randomised placebo-controlled design until disease progression. With a median follow-up of 45 months in the IFM 2005-02 trial, progression-free survival was 2202
significantly prolonged with lenalidomide versus placebo (41 months vs 23 months; p
