International Myeloma Working Group recommendations … · International Myeloma Working Group recommendations for global myeloma care H Ludwig1, JS Miguel2, ... Giessen, Germany;

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International Myeloma Working Group recommendations forglobal myeloma careH Ludwig1, JS Miguel2, MA Dimopoulos3, A Palumbo4, R Garcia Sanz5, R Powles6, S Lentzsch7, W Ming Chen8, J Hou9, A Jurczyszyn10,K Romeril11, R Hajek12, E Terpos3, K Shimizu13, D Joshua14, V Hungria15, A Rodriguez Morales16, D Ben-Yehuda17, P Sondergeld18,E Zamagni19 and B Durie20

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma(MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including informationabout cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effectivedrugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but alsopose new challenges for the prevention and management of their specific side effects. Given these various new options andchallenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the mostsophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possibleoptions for diagnosis, monitoring and treatment of patients with multiple myeloma.

Leukemia advance online publication, 1 November 2013; doi:10.1038/leu.2013.293

Keywords: myeloma care; global perspective; management of myeloma-related side effects

INTRODUCTIONMultiple myeloma is the second-most common cancer of theblood and accounts for 1% of all malignancies. Extrapolating thesefigures to the estimated incidence of cancer yields a globalincidence of roughly 120 000 cases per year. With a median age of70 years at diagnosis and a rapidly aging world population, thesefigures likely will rise significantly to about 350 000 cases by theyear 2050. Although age-standardized incidence rates vary withethnicity from 3.9/100 000 in Chinese to 12.7/100 000 in Africanindividuals (SEER data),1 the figures indicate that multiplemyeloma (MM) poses a substantial global health problem.

During recent years, many improvements in our understandingof the biology2 and in the management of the disease have beenmade.3 Although the basic criteria for establishing a diagnosishave not changed since the first descriptions in the early sixties,4

the techniques available for assessing the cytogenetic andgenetic characteristics and for the evaluation of bone and softtissue manifestations of the disease have been improvedsignificantly. Staging and prognostication5 can be upgraded bycomplementing the International Staging System with additionalinvestigations, such as positron emission tomography, magneticresonance imaging and cytogenetics.6 The treatment has beenmarkedly improved with the introduction of a first wave of novelagents and will continue to be developed further, with manytrials investigating agents with new modes of action currently

ongoing.7 Improvement in supportive care has led to a moresophisticated symptom control and has saved many lives bybetter prophylactic strategies and more efficient management ofcomplications of the disease and of therapy.

Given the plethora of novel developments, the issue of minimalrequirements for the management of this complex diseasebecomes highly relevant. The IMWG convened at the occasionof the European Hematology Association meeting in Amsterdamin June 2012 to address, among various other topics, thisimportant issue. The current manuscript contains the summaryand recommendations of the working group on ‘Global MyelomaCare’ and represents an international perspective, with the aim ofproviding relevant information and recommendations for clin-icians across the globe. Because of substantial differences inhealthcare systems, approval status of different agents, andeconomic constraints, the recommendations given may notalways be feasible. With this consideration in mind, alternativeoptions have been provided where possible.

ESTABLISHING A DIAGNOSIS OF ACTIVE MULTIPLE MYELOMAThe diagnosis of MM is based on the presence of monoclonalplasma cells, monoclonal protein and myeloma-related organ andtissue impairment including bone lesions.8 Monoclonal plasmacells must be documented in all patients, whereas myeloma-

1Department of Medicine I, Center of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria; 2Clinica Universidad de Navarra, Pamplona, Spain;3Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece; 4Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy;5Servicio de Hematologia, Hospital Universitario de Salamanca, Salamanca, Spain; 6Parkside Cancer Centre, London, UK; 7Columbia University Medical Center, New York, NY, USA;8Chaoyang Hospital, Capital Medical University, Beijing, China; 9Shanghai Chang Zheng Hospital, Shanghai, China; 10Department of Hematology, University Hospital, Cracow,Poland; 11Haematology Department, Wellington Hospital, Wellington, New Zealand; 12Department of Internal Medicine, University of Ostrava, Ostrava, Czech Republic;13Nagoya City Midori General Hospital, Nagoya, Japan; 14Institute of Hematology, Royal Prince Alfred Hospital, Sydney, Australia; 15Santa Casa de Sao Paulo, Sao Paolo, Brazil;16Bonco Metro Politano de Sangre, Caracas, Venezuela; 17Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 18University of Giessen,Giessen, Germany; 19Istituto di Ematologia Seragnoli, Universita degli Studi di Bologna, Bologna, Italy and 20Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA.Correspondence: Professor H Ludwig, Department of Medicine I, Center of Oncology, Hematology and Palliative Care, Wilhelminenspital, Montleartstrasse 37, Vienna, 1160,Austria.E-mail: [email protected] 25 July 2013; revised 17 September 2013; accepted 23 September 2013; accepted article preview online 9 October 2013

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specific bone lesions are detected in about 80% of patients at thetime of diagnosis and 1–3% of patients present with oligo- ornonsecretory myeloma. Of note, MM must be distinguished fromMGUS and smoldering myeloma and other variants of clonalplasma cell expansion need to be considered, such as solitaryplasmacytoma of the bone with or without detectable dissemina-tion of monoclonal cells, extramedullary plasmacytoma, primaryamyloidosis and light-chain deposition disease.

A diagnosis of monoclonal plasma cell proliferation is usuallymade by bone marrow aspiration and/or bone marrow biopsy.Both techniques are recommended, although bone biopsy is notconsidered essential by some experts. Bone marrow aspirationoffers the advantage of further characterization of the monoclonalcell population by immunophenotyping, fluorescence in situhybridization, cytogenetics and conventional karyotyping. Fluor-escence in situ hybridization using probes for poor-risk abnorm-alities that include del17p13, t(4; 14), t(14; 16), amplification 1q21and del 1p, as well as conventional karyotyping, which enables aseparation between hypodiploid and hyperdiploid myeloma,offer prognostic information.9 However, neither these tests norimmunophenotyping is considered mandatory at present. A bonebiopsy provides more accurate information about the degree ofbone marrow infiltration, other bone marrow cells and, in addition,allows the immunophenotypic characterization of plasma cells.It is also a useful baseline for future comparison. The absoluteminimal requirement is bone marrow aspiration and, in caseof solitary plasmocytomas, fine needle aspiration, although ahistological specimen is preferred.

For the detection and characterization of monoclonal immu-noglobulin, both serum and urine need to be assessed. In morethan 80% of patients, a monoclonal paraprotein will easily bedetected using serum electrophoresis, but in 16–18% of cases onlyfree light chains can be detected either in serum10 and urine or inurine only, and in a few patients monoclonal proteins can bedetected neither in serum nor in urine. All patients should havea serum protein electrophoresis, a urine protein electrophoresisof a 24-hour urine specimen (if needed of a concentrate),immunofixation in serum and urine, as well as determination ofserum free light-chains and their ratio. Quantification of serumparaproteins may be hampered or impossible by serum proteinelectrophoresis when myeloma proteins co-migrate with otherproteins such as transferrin, �-lipoprotein and C3 toward theanodal region, making nephelometry the preferred method,particularly in patients with IgA M-proteins.

A whole skeletal bone survey by conventional radiography,including the spine, skull, shoulders, thoracic cage, pelvis and longbones of arms and legs, is still considered standard for the initialworkup. Results of the conventional bone survey are needed toapply the staging system described by Durie and Salmon,11 andare used in many clinical studies for the evaluation of bonedisease. It also provides an evaluation for the risk of imminentpathological fracture, which may require radiotherapeutic orsurgical intervention. Newer techniques, such as computedtomography, magnetic resonance imaging and positronemission tomography, have greatly increased the sensitivity forthe detection of myeloma-specific bone lesions. The former twotechniques can either be used to evaluate specific areas of interestor for whole-body scanning. Combining those methods withpositron emission tomography seems to be particularly useful forthe detection of extra-skeletal masses, but the routine use of thesetechniques is not recommended at present.12 Clinicians need tobe aware that osteoporosis may be the only bone finding inmyeloma, and usually it is not possible to distinguish myeloma-induced osteoporosis form bone loss due to other causes.

The following additional laboratory tests are required for theassessment of the extent and level of activity of the disease:Albumin and �2-microglobulin are needed for InternationalStaging System. In addition, an analysis of the complete blood

count, as well as of the levels of calcium, creatinine andlactate dehydrogenase, is recommended. A determination ofC-reactive protein levels is not mandatory, but may behelpful when an infection is suspected. The same applies tovitamin D levels, which are decreased in about 20% of myelomapatients.13

In addition, both myeloma and host-related issues need to beconsidered. An assessment of the overall state of the patient,including age, performance status, organ function (renal, cardio-vascular, bone marrow, pulmonary, cognitive) and dental evalua-tion, will help identify potential comorbidities and guidetreatment decisions. Table 1 contains a summary of essentialprocedures to establish a diagnosis of MM.

PARAMETERS FOR THE INITIATION OF THERAPYTreatment should be initiated in all patients with active myelomafulfilling the CRAB criteria, namely presenting with one or more ofclinically relevant bone lesions, anemia (Hbo10 g/dl), myeloma-induced renal impairment (creatinine42.0 mg/ml) and hypercal-cemia (411.0 mg/dl), as well as in those symptomatic owing tothe underlying disease. In patients with smoldering MM historical,small randomized trials comparing an early initiation of treatmentwith a deferred start once patients became symptomatic orotherwise at risk for severe myeloma-induced complications wereunable to show a survival advantage for an early onset of therapy.This standard is presently being challenged by data from aSpanish trial showing a significant prolongation of progression-free and overall survival (OS) in patients with high-risk smolderingmyeloma subjected to immediate, as compared with deferred,myeloma therapy.14 For the time being, and before results havebeen confirmed by other trials, starting treatment when patientsbecome symptomatic because of myeloma and/or fulfill the CRABcriteria is considered standard, although initiation of therapy mayalso be considered for prevention of imminent disease-relatedcomplications such as increasing deterioration of renal function,but not having reached the cutoff level of 2 mg/dl creatinine.

MONITORINGPatients on treatment should be carefully monitored for responseto therapy, for symptoms of their disease and for any toxic sequelsof therapy. After the initiation of therapy, patients should bemonitored monthly, or more frequently if clinically indicated,whereas during follow-up or maintenance the frequency ofmonitoring can be reduced to every 2–3 months. In addition toclinical evaluation, the following should form a part of routinemonitoring: a full blood count, creatinine and/or glomerularfiltration rate, calcium, albumin, lactate dehydrogenase, M-proteinquantification using electrophoresis and nephelometry for IgAparaproteins, keeping in mind that in IgG and in the rare case ofIgM myeloma the amount of paraprotein may be overestimatedby nephelometry.15 The serum free light-chains should bemeasured particularly in patients with oligo- or nonsecretory MM.An increase in the involved free light-chain accompanied bychanges in the serum free light-chains ratio indicates progressivedisease. This refers also to patients with light-chain escape, whereprogressive disease is not reflected in changes in the heavy-chainlevel. Twenty-four-hour urine M-protein excretion should beincluded in case of light-chain myeloma and measurable urinespike, as well as in patients with suspected renal amyloidosis orlight-chain escape. Monthly assessment of serum and urineprotein is recommended during active therapy, but intervals canbe prolonged markedly once the disease enters a plateau phasewhen the decision regarding the frequency of assessment shouldbe left at the discretion of the treating physician. Response shouldbe evaluated according to the criteria issued by the IMWG16,17

IMWG global myeloma careH Ludwig et al

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Leukemia (2013) 1 – 12 & 2013 Macmillan Publishers Limited

and, if minor response should be evaluated in the relapsed/refractory setting, by the definition released by the EBMT group.18

The bone marrow should be assessed as a routine by aspirateand/or biopsy at the time of a suspected complete response,usually at complete disappearance of the monoclonal component.In nonsecretory MM, the assessment of the bone marrow isrequired to evaluate the quality of response. For transplantpatients 2–4 months after autologous stem cell transplantation(ASCT) and for conventionally treated patients 4–6 months afterstart of therapy may be appropriate time points. During follow-up,re-biopsies should be scheduled individually and be performedwhenever the patient becomes symptomatic or if bone marrow

failure develops, whereas in asymptomatic patients without newbone lesions and laboratory abnormalities (normal hemoglobin,renal function, calcium and lactate dehydrogenase levels) biopsiescan be withheld.

A skeletal survey using radiography or magnetic resonance imagingor computed tomography in case of plasmacytoma, extramedullarydisease or a suspected spinal cord compression is generallyrecommended.19 During active therapy, a skeletal survey should beconducted only at the time of the appearance of new skeletal-relatedsymptoms or suspected progressive disease using appropriate imagingtechniques. It is important to select the technique that is most suitedfor the investigation of particular symptoms. Nevertheless, the same

Table 1. Essential procedures for the diagnosis and follow-up of multiple myeloma

Parameter of interest Information provided

Monoclonal plasma cells

Bone marrow aspiration and/or bone biopsy

BaselineBMPC infiltration, enables FISH cytogenetics, immunophenotyping, immunocytochemistry, conventional karyotyping, gene arrays

Follow up For documentation of CR and of PD

Monoclonal protein

Serum electrophoresis Baseline

M-component, possible suppression of non-paraprotein immunoglobulins; emergence of a new M-component (rare)

Follow upRegularly when M-component detectable and in longer intervalsin initially serum M-component negative patients

Urine electrophoresis(24-hour urine)

Baseline M-component, indicates glomerular damage when albumin present (amyloidosis).

Follow up Regularly when urine M-component detectable and in longer intervals in initially urine M-component negative patients

Nephelometry of serum immunoglobulins

BaselineMeasurement of IgA, overestimates the M-component concentration in patients with IgG and IgM myeloma. Provides information about suppression of non-involved immunoglobulins

Follow up Regularly when M-component (IgA) detectable and in longer intervals in initially serum M-component negative patients

Immunofixation electrophoresis

BaselineIdentifies isotype and light chain type, confirms CRat baseline in serum and in urine in those with proteinuria

Follow upFor confirmation of CR and for early detection of reappearance of the M-component

Free light chain Measurement(Serum)

BaselineM-component in patients with light chain and oligo secretory myeloma, supports disease monitoring in all patients

Follow upFor monitoring of disease, particularly in those with light chain or oligo secretory myeloma

Myeloma specific bone lesions

Skeletal bone survey by conventional radiography

BaselineAssessment of extent of bone disease, and of progressive bone disease

Follow up During FU in those with suspected new bone disease

CT, MRI, PET, PET/CT,PET/MRI

BaselineHigher sensitivity for myeloma specific bone lesions Assessment of extramedullary disease, PET provides information about activity of the disease

Follow up Presently only recommended for detection of extramedullary disease or suspected spinal cord compression

Additional laboratory parameters

Albumin, �2-microglobulin, blood count, calcium, creatinine, LDH, total protein, , Liver function tests (CRP, vitamin D, not obligatory)

Baseline

Provides information about organ function and aggressiveness of the disease (LDH), bacterial infections (CRP)Follow up

Abbreviations: CT, computed tomography; CR, complete response; CRP, C-reactive protein; FISH, fluorescence in situ hybridization; FU, follow-up; LDH, lactatedehydrogenase; MRI, magnetic resonance imaging; PD, progressive disease; PET, positron emission tomography.


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imaging technique should be used to assess new lytic lesions in orderto make appropriate comparisons with the baseline data. Initial resultsindicate a significant prognostic impact of negative positron emissiontomography findings after a given number of chemotherapy cycles.20

TREATMENTTransplant-eligible patientsPatients deemed eligible for ASCT should be treated with 3–4cycles of active induction therapy, followed by stem cellcollection and high-dose therapy with stem cell transplantation.Of note, studies aimed at elucidating the optimal number ofcycles before high-dose therapy are not available, and trialsusing more than four cycles have been reported.21 In case of asuboptimal response (less than PR) to four cycles of inductiontherapy, it is recommended to proceed to stem celltransplantation without modification of the original treatmentplan, as the transplant procedure is known to upgraderesponses.22 In case of progressive disease after the first two–three cycles, a change of the type of the induction regimenseems indicated, but the benefit of this approach has notformally been proven.

The most active regimen available should be used forinduction therapy (Table 2). This should include novel drugs.Several studies showed superiority of a three-drug, bortezomib-based regimen over VAD or two-drug combinations, rendering itthe preferred combination for induction therapy.21,23–30

In countries where bortezomib is not available for frontlinetherapy, the use of the CTD regimen (cyclophosphamideþthalidomideþdexamethasone) is an option.29 Two-drugregimens with bortezomib–dexamethasone, lenalidomide–dexamethasone or thalidomide–dexamethasone may also beused, although the latter regimen was found to be markedlyinferior to a VTD combination.21,23 In case neither a bortezomib-based regimen nor CTD or lenalidomideþdexamethasoneregimens are feasible, VAD may be a regimen of choice inselected situations and individual countries, if no other optionsare available.

The conditioning for the transplant procedure should be carriedout with melphalan 200 mg/m2 (MEL200). Attempts to improvethe efficacy of the conditioning regimen by adding busulfan31 or alimited number of bortezomib doses32 to MEL200 have beenreported, but these regimens cannot be considered standard asyet. In general, one transplant procedure should be conducted;however, it is recognized that tandem transplant forms part ofroutine practice in some centers, improves response rates33,34 andmay benefit patients with inferior response to a single transplant27

and also those with high-risk cytogenetics.35

Taken together, the absolute minimum in case of no otheroptions is four cycles of VAD followed by high-dose melphalanand ASCT. At present, a three-drug regimen incorporatingbortezomib followed by one course of high-dose therapy andASCT is recommended.

Frontline nontransplant settingRecommended treatments for patients not eligible for high-dosetherapy, or in case the transplant procedure is not available, includeMPT, MPV and CTD, on the basis of the results of phase 3 studiesthat have demonstrated the superiority of these regimens overconventional chemotherapy (Table 3).36–38 Longer progression-freesurvival (PFS) has also been shown for frontline bendamustine–prednisone compared with MP therapy,39 but, although approvedin Europe, the regimen is only rarely used for frontline treatment.Therapy should be administered until best response for 9–12 cycles.In addition, other regimens such as VCD or VTD and the use of two-drug regimens, such as VD, vD, LD and TD, present effectiveoptions. The doses of dexamethasone and the other agents have tobe adapted according to age and tolerance. Bortezomib should begiven subcutaneously, and a weekly schedule is an attractivealternative over the standard twice-weekly schedule. However, thepanel is aware that accessibility to these treatments will varygeographically and will be influenced by economic situations.Furthermore, the panel recognizes that MP can be a useful optionfor patients with good-risk disease, as well as in those who have noor only minor symptoms when novel agents are not available.In addition, it is acknowledged that new drugs such as carfilzomibare currently being incorporated into first-line treatments andcompared with the established therapies. Preliminary results fromongoing trials indicate that they may supersede the activity of theirclass-specific counterparts.

Elderly unfit and frail patientsScientific data are scarce in this growing subset of patients.Comorbidity correlates with age and with poor prognosis,40–42

and patient status should carefully be assessed before treatmentselection. Elderly myeloma patients should be categorized as ‘fit,’‘unfit’ or ‘frail’.43 Treatment needs to be adapted accordingly; two-drug combinations improve tolerance often without jeopardizingactivity44 and drugs doses should carefully be tapered to thebiological status of the patients.45

In summary, MP is the minimum that should be offered, but ithas to be acknowledged that it will be suboptimal particularly forpatients with poor risk cytogenetics or other poor risk features.A regimen adding a novel drug to the MP backbone or abortezomib- or lenalidomide-based regimen is recommended.

Table 2. Regimens for induction therapy before high-dose chemotherapy and stem cell transplantation

Main components Preferred option – 3-drug, bortezomib-based regimens

2-drug regimens 4-drug regimens

Bortezomib-based PAD, VCD VDBortezomib+IMiD-based

VRD, VTD VRDC, VDTC

Lenalidomide-based LD, LdThalidomide-based TAD, CTD TDIf none of the noveldrugs available

VAD

Abbreviations: CTD, cyclophosphamide with thalidomide plus dexamethasone; LD, lenalidomide with high-dose dexamethasone; Ld, lenalidomide with low-dose dexamethasone; PAD, bortezomib with adriamycin plus dexamethasone; TD, thalidomide with dexamethasone; TAD, thalidomide with adriamycin plusdexamethasone; VCD, bortezomib with cyclophosphamide plus dexamethasone; VD, bortezomib with dexamethasone; VRD, bortezomib with lenalidomideplus dexamethasone; VTD, bortezomib with thalidomide plus dexamethasone; VRDC, bortezomib with lenalidomide plus dexamethasone pluscyclophosphamide; VDTC, bortezomib with dexamethasone plus thalidomide plus cyclophosphamide; VAD, vincristine with adriamycin plus dexamethasone.


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Consolidation and maintenance therapyConsolidation treatment is defined as an intensive therapyadministered for a limited period of time with the main intentof improving the quality of the response and thereby OS.At present, results obtained with bortezomib, lenalidomide–bortezomib–dexamethasone (VRD), lenalidomide–dexametha-sone and VTD or TD are available.46–50 Twenty doses ofbortezomib given during 21 weeks after ASCT resulted in asignificant prolongation of PFS, but a survival gain was notobserved.49 The PFS benefit was only noted in patients with lessthan VGPR before start of consolidation treatment. Consolidationwith VTD after ASCT increased the proportion of patients withPCR-defined molecular remission (minimal residual disease (MRD)negativity).51 Patients who achieved MRD negativity had asignificantly increased PFS, which possibly will translate intolonger OS. Nevertheless, as survival data are not yet available,a definite recommendation for the routine use in clinicalpractice cannot be given at present, but in spite of these factsconsolidation is increasingly being used.

Maintenance therapy is started after a successful inductiontherapy and/or after consolidation therapy, and aims to prolongthe time of remission with a good quality of life, with the ultimategoal of improving OS. Thalidomide maintenance therapy afterautologous transplantation improved PFS in all six trials and OS in3/6 studies,52–57 but tolerance of the agent is a limiting factor.In elderly patients, an improvement in PFS without any benefit forOS has been found with thalidomide maintenance therapy.55–58

Importantly, thalidomide maintenance therapy was even associatedwith inferior OS in high-risk patients.55 Bortezomib has been used assole therapy or in combination with thalidomide after ASCT21,26 andin combination with thalidomide or with prednisone in elderlypatients.59,60 When bortezomib was used in transplant-eligiblepatients both for induction and maintenance, a significantimprovement in PFS and OS was noted as compared withthalidomide, but the design of the trial does not allow for a clearevaluation of the role of bortezomib in the maintenance setting.26

The combination of bortezomib plus thalidomide resulted in asuperior PFS compared with thalidomide or interferon maintenancetherapy alone in younger patients.21 In elderly patients, bortezomibplus thalidomide maintenance was found to yield a longer PFScompared with bortezomib plus prednisone, but, so far, the survivalin both groups is comparable.59 VMPT followed by VT yielded alonger PFS and OS compared with sole VMP induction therapy inelderly patients, but the impact of VT maintenance in this study isdifficult to assess owing to the design of the trial.60

Lenalidomide maintenance has been evaluated in elderly patientsin one trial61 and in younger patients in three trials.46,62,63 All fourstudies showed a striking improvement in PFS with lenalidomidemaintenance therapy, but OS was superior in only two of thethree trials conducted in younger patients.62,63

Lenalidomide maintenance treatment is associated with a roughlythreefold increased incidence of secondary primary malignancies,64

but when the risk for dying is analyzed in patients with andwithout lenalidomide maintenance the odds for lower mortalityare clearly in favor of patients on lenalidomide maintenance.Still, at the current time, the panel does not recommend theroutine use of maintenance therapy.65

Treatment of relapsed and refractory diseaseRelapse of myeloma (defined as an increase in the monoclonalprotein by more than 25% and40.5 g/dl) can evolve slowlywithout clinical signs or symptoms or fast with or without clinicalcomplications. Treatment is required in those with symptomsand/or imminent complications. Selection of therapy dependson patient-specific factors, tumor characteristics, such as cyto-genetics, the type, efficacy and tolerance of the previoustreatment, the number of prior treatment lines, the availableremaining treatment options and the interval from the lasttherapy.66,67 Drugs with potential neurotoxicity, such asbortezomib or thalidomide, should be avoided in patients withpolyneuropathy, whereas less myelotoxic drugs should bepreferred in those with compromised bone marrow function. Anoral regimen may be preferred in patients living far away fromtheir myeloma treatment center.68

In young patients, a second ASCT procedure may beconsidered, provided the patient responded well to the previousASCT and had a PFS of more than 12 months at least.69–71

The chance for an excellent response will increase with theduration of the treatment-free interval. Similarly, in elderlypatients, the first-line therapy or, in case of multiple priortreatment lines, even the previous treatment can be repeated,provided it led to a significant tumor response, was well toleratedand PFS lasted for more than 6 months.72

Changing the treatment regimen and drug class (if possible) forsecond or further lines of therapy is recommended in patientswith an insufficient response, a rapid relapse and poor tolerance.Treatment should be continued until best possible response,provided tolerance is adequate. Whether continuation of rescuetreatment until the next relapse or intolerance or whether

Table 3. Regimens for induction therapy for patients not eligible for high-dose therapy and stem cell transplantation

Main components 2-drug regimens 4-drug regimens

Thalidomide MPT, CTD TDBortezomib MPV, VCD VD, vD VMPTThalidomide & Bortezomib

VTD

Lenalidomide LD, LdIf none of the noveldrugs available

MP, BP

Preferred option–3 drug,melphalan-orcyclophosphamide-basedregimens

Abbreviations: BP, bendamustine plus prednisone; CTD, cyclophosphamide with thalidomide plus dexamethasone; LD, lenalidomide with high-dosedexamethasone; Ld, lenalidomide with low-dose dexamethasone; MPT, melphalan with prednisone plus thalidomide; MPV, melphalan with prednisone plusbortezomib; MP, melphalan with prednisone; TD, thalidomide with dexamethasone; VCD, bortezomib with cyclophosphamide plus dexamethasone;VD, bortezomib with dexamethasone; vD, reduced-dose bortezomib with dexamethasone; VMPT, bortezomib with melphalan plus prednisone plusthalidomide; VTD, bortezomib with thalidomide plus dexamethasone.


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maintenance therapy will improve outcome is unknown at present.Parameters relevant for treatment selection are shown in Figure 1.

Recently, new effective agents, such as carfilzomib73 andpomalidomide,74 have been introduced for the treatment ofrelapsed/refractory patients, but these drugs are not yet availablein several parts of the globe. Patients whose disease has becomerefractory to novel agents present a particular challenge. Theymay be enrolled in a clinical trial with novel experimental agentsin case this option is available, or may be offered palliativetreatment using alkylating agents in combination withcorticosteroids, bendamustine-based combinations, high-dosedexamethasone or older regimens, such as the continuousinfusion of DCEP or DT-PACE. Allogeneic SCT should, if at all,only be performed in the context of a clinical trial in highlyexperienced centers and only in patients with good responsebefore transplant, but trials in the relapsed/refractory setting arenot available at present.

SUPPORTIVE CAREPrevention and treatment of bone diseaseBone disease is a hallmark of MM, which may manifest itself asosteoporosis, osteolysis, fractures and, very rarely, osteosclerosis.The substantial loss in bone mass causes devastating complica-tions that result in pain and a reduced quality of life. Bispho-sphonates continue to be the mainstay of treatment, as they havedemonstrated a reduction in skeletal-related events composedof pathological vertebral fractures, spinal cord compression,hypercalcemia and/or pain requiring surgery, radiotherapy oropioid analgesics.75 Intravenous zoledronate has been comparedwith oral clodronate in a large cohort of myeloma patients andwas found to supersede clodronate in terms of skeletal-relatedevents and, importantly, also in OS.76 Pamidronate is anotheraminobisphosphonate that has been extensively tested inmyeloma patients. The usually administered dose is 90 mg every4 weeks, but a lower dose (30 mg) has been found to be equallyeffective and better tolerated.77 The optimal duration ofbisphosphonate therapy requires further investigation in trials.Bisphosphonates should be discontinued after 2 years in patientsachieving complete response and may be continued in those withactive disease or restarted if the patient meets disease progressioncriteria.78 Interestingly, the MRC IX trial showed that treatment

with bisphosphonates for 2 or more years was associated with asignificant improvement in OS compared with clodronate,suggesting that treatment beyond the generally recommendedduration of 2 years may be associated with substantial benefits.79

However, further data are needed. Whether denosumab, amonoclonal antibody against RANKL, will become a therapeuticoption in MM depends on the outcome of a currently ongoinglarge randomized trial evaluating denosumab in comparison withzoledronate.

In addition, patients with bone disease should be monitored forcalcium and vitamin D levels and receive calcium and vitamin Dsupplementation if one of these parameters is low. Localradiotherapy (20-40 Gy) usually results in the rapid improvementof bone pain, and concerns about harming normal bone marrowfunction are unfounded, provided radiotherapy is focused onlocalized myeloma lesions only.80 In patients with a limitednumber of painful vertebral compression fractures, balloonkyphoplasty or vertebroplasty usually result in immediate painrelief.81,82 Osteosynthesis or other surgical management offractures of long bones or of other complications may berequired in individual cases. The positive results obtained inpatients without overt bone disease at baseline, who were treatedwith zoledronate, indicate that bisphosphonate therapy should beoffered to all patients in need of anti-myeloma chemotherapy.The recommendations for DEXA scanning are those issued for thegeneral population and relate particularly to postmenopausalwomen.

Prevention of infectionsInfections are frequent, and often serious complications in MMthat significantly increase morbidity and mortality and shouldtherefore be managed proactively and aggressively.83–85

Importantly, the risk of infections is highest during the firstcycles of therapy and subsequently during episodes of activedisease. Because of frequent substantial humoral and cellularimmunosuppression, patients are at a higher risk of developinginfections involving encapsulated pathogens, such aspneumococci and haemophilus influenzae, as well as viralinfections. Although the response to vaccination is frequentlyimpaired in patients with MM,86 prophylactic vaccination isrecommended for influenza A and B virus, pneumococci andhaemophilus influenzae. Care givers and patient relatives should

Parameters

Patient specific Disease specific Treatment specific

AgeConsider ASCT in ‘younger patients’

Good prognosis

Retreatment with effective and well tolerated first line regimen feasible

Significant response to previous treatment, long PFS, well tolerated

Consider retreatment

Neuropathy

Avoid bortezomib and thalidomide if feasible, if not, use weekly and subcutaneous bortezomib

Symptomatic and rapidly progressive

Switch drug class, incorporate novel agents

Insufficient response to previous treatment

Switch drug class and change regimen

Light chain-induced nephropathy

Use preferentially bortezomib combinations, adaptation of dose of lenalidomide according to GFR mandatory

High risk cytogenetics

Consider bortezomib combinations ± bendamustine

All common regimens exploited

Consider DCEP, DT-PACE, enrollment in clinical trials

Figure 1. Parameters relevant for treatment selection in patients with relapsed/refractory multiple myeloma.


6


also be vaccinated against influenza, but scientific data supportingthis recommendation are scarce. Live vaccines should be avoidedbecause of the risk for vaccine-induced infection due to thecompromised immune response in many patients.

In patients receiving bortezomib-containing regimens, theroutine use of acyclovir prophylaxis is recommended to preventherpes zoster infection, which was seen in 13% of patients withoutprophylaxis in the APEX trial.87 With acyclovir, the risk canmarkedly be reduced.88 Differing results have been published onthe efficacy of prophylactic antibiotics.89,90 The risk of bacterialinfections depends on various factors, such as the state of thedisease, the type and intensity of therapy and patient-specificimmune factors. Patients with a high risk of developing aninfection likely benefit from quinolone or trimethoprim-sulfamethoxazole prophylaxis, whereas in other patientsprophylaxis may not be helpful. The administration ofintravenous immunoglobulins reduced the incidence ofinfections in patients in the plateau phase, and the effect wasmost pronounced in those with an impaired response topneumovax.91 However, these data were based on a smallstudy. Routine use of fluconazole prophylaxis is notrecommended, but there may be exceptions in patients treatedwith high doses of glucocorticosteroids and in those at a higherrisk of mucocutaneous candidiasis. Pneumocystis prophylaxis withtrimethoprim–sulfamethoxazole may be considered in patientsundergoing stem cell transplantation.

Active infections should be diagnosed immediately, and empirictreatment should be installed as fast as possible, with appropriatetreatment adaptions being made when results of blood culturesand other tests become available. It is appropriate that patientskeep an emergency supply of ciprofloxacin or amoxicillin andclavulanic acid at home so that they can start antibiotics ifinstructed on the telephone

Renal failureRenal failure is a serious complication associated with an increasedrisk of infections and a shorter survival.92 It is important todistinguish between non-paraprotein-related causes andpathogenic light-chain-induced renal impairment in order toimplement effective interventions. Non-paraprotein-related causesof renal failure include infection, nephrotoxic drugs, hypercalcemia,dehydration, hyperviscosity, myeloma cell infiltration of kidneys andother possible renal pathologies.93 Renal failure due to pathogeniclight chains can manifest itself as cast nephropathy, amyloidosis,light-chain deposit disease or Fanconi syndrome. The promptmanagement of renal failure with the aim of restoring function isparamount to increase the likelihood of response to treatment andto improve survival.94

Once pathogenic light chains have been identified as the causeof renal failure, the following interventions should be initiatedimmediately: discontinuation of any nephrotoxic medication,adequate hydration and fluid balance. In addition, alkalinizationshould be considered. Furthermore, an effective myeloma therapyregimen should be chosen to reduce the amount of toxic lightchains. Recommended myeloma therapies include thalidomide,lenalidomide and bortezomib, all of which have been shown to beeffective in patients with renal impairment; improvements in renalfunction have been seen with all of these therapies,94,95 butbortezomib-based regimens seem to be most active.96 In addition,the use of high-dose dexamethasone97 during the first treatmentcycle is recommended. For thalidomide-based therapy, doseadjustments according to glomerular filtration rate are notrequired. However, increased episodes of hyperkalemia havebeen reported and, furthermore, thalidomide-specific toxicitieshave been observed more frequently in patients with creatininelevels 43.0 mg/dl. With bortezomib-based regimens, doseadjustments according to glomerular filtration rate are not

required. It is recommended to use bortezomib at full dose toachieve a rapid response. Recent data show that clearance ofcarfilzomib is independent of renal function and may also safelybe used in patients with renal impairment.98 With anylenalidomide-based treatment, dose adjustments according toglomerular filtration rate are essential. With regard to mechanicaldevices for the removal of light chains, the benefit forplasmapheresis has so far not been proven. In addition, the useof special dialysis membranes and long-term dialysis for theremoval of serum free light-chains is not yet established. Specialcare should be taken to prevent infections or, in case of thedevelopment of acute infections, to immediately install adequatetreatment.

AnemiaAnemia is a frequent complication of myeloma and, depending onthe definition of anemia, treatment intensity and patient age, maybe found in 40–100% of patients.99 The pathogenesis of anemia inMM is usually multifactorial, with chronic anemia of cancer andcancer therapy being frequent causes. The consequences ofanemia are frequently pronounced in the typically elderly patientswith myeloma. Treatment with ESAs should be considered inpatients receiving chemotherapy who have hemoglobin levelso10 g/dl. Therapy with either erythropoetin (10 000 U TIW or40 000 U once weekly) or darbepoetin (150 mg once weekly, or450mg q 3 weeks) is recommended. Treatment should bediscontinued in case of no response (defined as an increase inHb of 1.0 g/dl or less) after 6 weeks of treatment. In addition,treatment should be discontinued in case Hb levels increasebeyond 12 g/dl. Of note, ASH/ASCO guidelines recommend thediscontinuation of treatment already at an Hb level of 10 g/dl.100

Finally, iv iron supplementation should be considered in case ofabsolute (TSAT o20%, ferritin o30 mg/L) or functional (TSATo20%) iron deficiency. It is acknowledged that ESAs are notavailable in all countries, and concerns regarding increased risk forthromboembolic complications and for mortality when used innonapproved indications led to restrictive use. Red blood celltransfusions should be used in patients with Hb o8 g/dl who donot respond to erythropoetins or are not candidates forerythropoietin therapy because of their possible risks. Red bloodcell transfusions, however, are clearly indicated in patients whoare severely symptomatic because of anemia and in need forimmediate improvement. Besides the well-known possiblecomplications of RBC transfusions, recent data indicatedpreviously unidentified risks such as higher rate of infections,thromboembolic complications and recurrence of cancer.101

Venous thrombolic events (VTEs)Patients with MM have an increased risk for VTEs,102 which isfurther exacerbated by certain patient-specific risk factors and bysome of the available myeloma therapies, in particular bythalidomide and lenalidomide treatment. The occurrence ofVTEs is associated with shorter survival, and an important goalin the management of patients with MM is therefore theprevention of VTEs.103

In an individual patient, possible risk factors, such as obesity,previous VTE, cardiovascular complications or a pacemaker,associated disease (cardiac disease, chronic renal disease, diabetesmellitus, acute infection and immobilization) and surgery (generalsurgery, any anesthesia and trauma) should be assessed.In addition, the use of IMiDs and of erythropoietin and the presenceof blood clotting disorders have to be considered. In the presenceof p1 risk factor, prophylaxis should consist of 81–325 mg aspirin,whereas in the presence of X2 risk factors LMWH or full-dosewarfarin should be administered. For warfarin, the target INR is 2–3.Aside from patient-specific risk factors, full-dose warfarin or LMWHshould be considered if thalidomide or lenalidomide are used in


7


combination with high-dose dexamethasone, or doxorubicin aspart of multi-agent chemotherapy.104,105

PolyneuropathyPolyneuropathy (PNP) can be a dose- or treatment-limitingcomplication in MM. About 15% of patients present with PNP106

related to causes other than myeloma therapy, such as diabetes,

excessive alcohol consumption, vitamin B12 deficiency ormyeloma-related factors and unknown causes. Most frequently,PNP evolves as an untoward side effect of thalidomide and/orbortezomib therapy. Thalidomide primarily induces dorsal rootganglion and axonal damage, whereas dorsal root ganglia andsmall fibers are predominantly affected by bortezomib therapy.107

The clinical symptoms also vary. Thalidomide typically induces adose-dependent sensory, rather than motor, neuropathy, with

Table 4. Recommendations for dose adaptations in patients with thalidomide- or bortezomib-induced neuropathy

Thalidomide-induced polyneuropathy Bortezomib-induced polyneuropathy

Grade Intervention Grade Intervention

1 Reduce thalidomide dose by

50%

1 If patient is on twice-weekly schedulea: reduce current bortezomib dose by one levelb or prolong dosing interval to once-weekly

If patient is on once-weekly schedule: reduce bortezomib dose by one levelb

2 Discontinue thalidomideIf neuropathy resolves to grade

1 or better, treatment may be restarted at 50% dose reduction

1 with

pain or 2

Same as above, but if patient is already on a once weekly schedule: consider temporary discontinuation or reduction of bortezomib dose by one levelb

If neuropathy resolves to grade 1 without pain or better, once-weekly bortezomib at reduced dose may be restarted

3 and

4

Discontinue thalidomide 2 with

pain or 3

or 4

Discontinue bortezomib

aPatients X75 years may be immediately started on once-weekly regimen when initiating bortezomib. bBortezomib dose reductions: standard dose, 1.3mg/m2;dose reduced by 1 level, 1.0mg/m2; dose reduced by 2 levels, 0.7mg/m2.

Table 5. Recommended supportive care strategies for myeloma-associated complications

Abbreviation: LMWH, low-molecular-weight heparin. aSee text for risk factor assessment. bSee Table 4.


8


numbness, paresthesias and pain. It often develops as a stingingsensation or numbness in the toes or sometimes in the fingers andthen spreads along the legs and arms. Genetic variations in certaingenes predispose individuals for this drug-associated toxicity.108

Because nerve electrophysiological studies do not reliably predictPNP,109 patients need to be assessed carefully and patient self-reporting instruments may be preferable. There is no causativedefinitive treatment, and therapy of symptoms is only marginallyeffective. The most important action relies on the earlyrecognition of evolving PNP and dose reduction or treatmentdiscontinuation, as there is only little improvement in symptomswhen PNP is established.110

Bortezomib therapy frequently results in a distal sensoryPNP, which may be painful, particularly at higher grades.110

Newer studies suggest an important role for the patient-specificgenetic background in conferring increased susceptibility tobortezomib-induced PNP (BiPNP).110,111 Recommendations fordose reductions in patients experiencing neuropathic toxicityduring thalidomide or bortezomib therapy are shown in Table 4.The suggestions for BiPNP have been developed for theintravenous administration of bortezomib. At the current time,they should also be applied to patients receiving bortezomib viasubcutaneous injection, which is less frequently associated withBiPN.112 After the discontinuation of bortezomib, BiPN usuallyimproves in most patients, although complete resolution is seen inonly a minority.

PainThe first step in the management of pain should be to ascertain itsorigin, its quality and intensity to enable the initiation of effectiverelief aimed at the particular cause, character and grade.Recommended treatments for pain include local radiotherapy orsurgical interventions in addition to analgesics, which should beadministered on the basis of the three-step pain ladder developedby the WHO (http://www.who.int/cancer/palliative/painladder/en/).Nonsteroidal anti-inflammatory drugs are quite effective atameliorating the pain due to myeloma-induced bone disease,but should be administered with care, as one of their possible sideeffects is the reduction in glomerular perfusion, which mightaggravate or lead to renal impairment. Whenever possible, theoral or transcutaneous route should be chosen preferentially overthe parenteral route. It can be helpful to use visual analog orcategorical scales for the patient self-assessment of pain. It isimportant to be prepared to manage breakthrough painpreferably by administering fentanyl via mucosal absorption orby iv injection.113 Concerning neuropathic pain, antidepressantsand anticonvulsants (gabapentin, pregabalin) have a specific role.Finally, appropriate co-medication, such as laxatives, anti-emeticsat the start of opioid therapy, corticosteroids and anti-depressantsfor depression should form part of the pain management strategy.Recommended supportive care strategies for myeloma-associatedcomplications are summarized in Table 5.

CONCLUSIONSEstablishing the diagnosis of MM, the assessment of stage,the initiation of the appropriate treatment and the monitoringof its effects, as well as the management of the side effects oftherapy and the symptoms of the disease, require professionalcompetence, experience and commitment to optimal patientcare. This overview provides the theoretical backbone for themanifold considerations and decisions that are required tocover the medical needs of patients affected by MM andto select the best possible strategy given the variations inavailability of novel procedures and drugs. It is hoped that it willsupport interested readers in optimizing their clinical care ofpatients with MM.

CONFLICT OF INTERESTHeinz Ludwig received honoraria and research funding from Celgene, Janssen-Cilagand Mundipharma; Jesus San Miguel received honoraria from Celgene, Millenium andJanssen-Cilag; Meltios Dimopoulos received honoraria from Celgene and Novartis;Antonio Palumbo received honoraria from Celgene, Janssen-Cilag and Millenium;Ramon Garcia Sanz received honoraria from Ortho-Biotech and Celgene; SuzanneLentsch received honoraria and research funding from Celgene; Jian Hou receivedhonoraria from Novartis and is member of the steering committee of Novartis; RomanHajek received honoraria from Merck and Celgene; Evangelos Terpos receivedhonoraria from Celgene; Kazuyuki Shimizu received honoraria from Celgene; DouglasJoshua received honoraria from Celgene and Janssen-Cilag for speakers forum andadvisory board functions; Elena Zamagni received honoraria from Janssen-Cilag andCelgene; and Brian Durie received research funding and honoraria from Celgene,Merck, Millenium and Novartis. Raymond Powles, Wen Ming Chen, Artur Jurczynszyn,Kenneth Romeril, Vania Hungria, Angelina Rodrigues Morales, Dina Ben-Yehuda andPia Sondergeld did not declare any conflict of interest.

ACKNOWLEDGEMENTSWe wish to acknowledg the secretarial assistance of Raphaela Oswald and thesupport by the International Myeloma Foundation and Austrian Forum againstCancer.

AUTHOR CONTRIBUTIONSAll authors participated actively in the IMWG summit in Amsterdam andcontributed to the workshop on global myeloma care. The outcome of themeeting was summarized in an initial draft, which was circulated, modifiedand/or commented by all authors. All authors contributed to the manuscript.Heinz Ludwig and Pia Sondergeld served as writers.

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60 Palumbo A, Bringhen S, Rossi D, Cavalli M, Ria R, Gentilini S et al. Overall survivalbenefit for bortezomib-melphalan-prednisone-thalidomide followed bymaintenance with bortezomib-thalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients.Blood 2012; 120: abstract 200.

61 Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J et al.Continuous lenalidomide treatment for newly diagnosed multiple myeloma.N Engl J Med 2012; 366: 1759–1769.

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63 Palumbo A, Cavallo F, Gay F, di Toritto T, Cavalli M, Ben Yehuda D et al.Melphalan/Prednisone/Lenalidomide (MPR) versus high-dose melphalan andautologous transplantation (MEL200) in newly diagnosed multiple myeloma(MM) patients. Haematologica 2013; 98(Suppl 1): S96 (abstract P222).

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65 Ludwig H, Durie BG, McCarthy P, Palumbo A, San Miguel J, Barlogie B et al. IMWGconsensus on maintenance therapy in multiple myeloma. Blood 2012; 119:3003–3015.

66 Mothy B, El-Cheikh J, Yakoub-Agha I, Avet-Loiseau H, Moreau P, Mothy M.Treatment strategies in relapsed and refractory multiple myeloma: a focus ondrug sequencing and ‘retreatment’ approaches in the era of novel agents.Leukemia 2011; 26: 73–85.

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70 Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michael J et al. Autologousstem cell transplantation: an effective salvage therapy in multiple myeloma. BiolBlood Marrow Transplant 2013; 19: 445–449.

71 Ludwig H, Avet-Loiseau H, Blade J, Boccadoro M, Cavenagh J, Cavo M et al.European perspective on multiple myeloma treatment strategies: updatefollowing recent congresses. The Oncologist 2012; 17: 592–606.

72 Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW et al. Aprospective, international phase 2 study of bortezomib retreatment in patientswith relapsed multiple myeloma. Br J Haematol 2013; 160: 649–659.

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75 Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A et al.Bisphosphonates in multiple myeloma: a network meta-analysis. CochraneDatabase Syst Rev 2012; 5: CD003188.

76 Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ et al. First-linetreatment with zoledronic acid as compared with clodronic acid in multiplemyeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010; 376:1989–1999.

77 Gimsing P, Carlson K, Turesson I, Fayers P, Waage A, Vangsted A et al. Effect ofpamidronate 30 mg versus 90 mg on physical function in patients with newlydiagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind,randomised controlled trial. Lancet Oncol 2010; 11: 973–982.

78 Garcia-Sanz R, Oriol A, de la Rubia J, Palomera L, Ribas P, Hernandez MT et al.Analysis of zoledronic acid therapy for patients with multiple myeloma withasymptomatic biochemical relapse. Blood 2012; 120: abstract 2967.

79 Morgan GJ, Davies FE, Gregory WM, Szubert AJ, Bell SE, Drayson MT et al. Effectsof induction and maintenance plus long-term bisphosphonates on bone diseasein patients with multiple myeloma: MRC Myeloma IX trial. Blood 2012; 119:5374–5383.

80 Balducci M, Chiesa S, Manfrida S, Rossi E, Za T, Frascino V et al. Impactof radiotherapy on pain relief and recalcification in plasma cell neoplasms:long-term experience. Strahlenther Onkol 2011; 187: 114–119.

81 Hussein MA, Vrionis FD, Allison R, Berenson J, Berven S, Erdem E et al. The role ofvertebral augmentation in multiple myeloma: International Myeloma WorkingGroup consensus statement. Leukemia 2008; 22: 1479–1484.

82 Berenson J, Pflugmacher R, Jarzem P, Zonder J, Schechtman K, Tillman JB et al.Balloon kyphoplasty versus nonsurgical fracture management for treatmentof painful vertebral body compression fractures in patients with cancer:a multicentre, randomised controlled trial. Lancet Oncol 2011; 12: 225–235.

83 Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res ClinHaematol 2007; 20: 817–835.

84 Terpos E, Cibeira MT, Blade J, Ludwig H. Management of complications inmultiple myeloma. Semin Hematol 2009; 46: 176–189.

85 Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era ofhigh-dose therapy and novel agents. Clin Infect Dis 2009; 49: 1211–1225.

86 Robertson JD, Nagesh K, Jowitt SN, Dougal M, Anderson H, Mutton K et al.Immunogenicity of vaccination against influenza, Streptococcus pneumoniae andHaemophilus influenzae type B in patients with multiple myeloma. Br J Cancer2000; 82: 1261–1265.

87 Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, HarousseauJL et al. Analysis of herpes zoster events among bortezomib-treated patients inthe phase III APEX study. J Clin Oncol 2008; 26: 4784–4790.

88 Swaika A, Paulus A, Miller KC, Sher T, Almyroudis NG, Ball D et al. Acyclovirprophylaxis against varicella zoster virus reactivation in multiple myelomapatients treated with bortezomib-based therapies: a retrospective analysis of100 patients. J Support Oncol 2012; 10: 155–159.

89 Vesole DH, Oken MM, Heckler C, Greipp PR, Katz MS, Jacobus S et al. Oralantibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOGrandomized phase III study. Leukemia 2012; 26: 2517–2520.

90 Offidani M, Corvatta L, Polloni C, Gentili S, Brioni A, Visani G et al. Infectiouscomplications in patients with multiple myeloma treated with new drug com-binations containing thalidomide. Leuk Lymphoma 2011; 52: 776–785.

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93 Dimopoulos MA, Kastritis E, Rosinol L, Blade J, Ludwig H. Pathogenesis andtreatment of renal failure in multiple myeloma. Leukemia 2008; 22: 1485–1493.

94 Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S et al.Renal impairment in patients with multiple myeloma: a consensus statementon behalf of the International Myeloma Working Group. J Clin Oncol 2010; 28:4976–4984.

95 Ludwig H, Adam Z, Hajek R, Greil R, Tothova E, Keil F et al. Light-chain-induced acuterenal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multi-ple myeloma: results of a phase II study. J Clin Oncol 2010; 28: 4635–4641.


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97 Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasonetreatment of multiple myeloma. Blood 1992; 80: 887–890.

98 Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z et al. Carfilzomib inmultiple myeloma patients with renal impairment: pharmacokinetics and safety.Leukemia 2013; 27: 1707–1714.

99 Birgegård G, Gascon P, Ludwig H. Evaluation of anaemia in patients withmultiple myeloma and lymphoma: findings of the European Cancer AnaemiaSurvey. Eur J Haematol 2006; 77: 378–386.

100 Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL et al.Use of epoetin and darbepoetin in patients with cancer: 2007 American Societyof Clinical Oncology/American Society of Hematology clinical practice guidelineupdate. J Clin Oncol 2008; 26: 132–149.

101 Schrijvers D. Management of anemia in cancer patients: transfusions.The Oncologist 2011; 16(Suppl 3): 12–18.

102 Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein MA.Monoclonal gammopathy of undetermined significance and multiple myelomaare associated with an increased incidence of venothromboembolic disease.Cancer 2004; 101: 558–566.

103 Kristinsson SY, Pfeiffer RM, Bjorkholm M, Schulman S, Landgren O. Thrombosis isassociated with inferior survival in multiple myeloma. Haematologica 2012; 97:1603–1607.

104 Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, BarlogieB et al. Prevention of thalidomide- and lenalidomide-associated thrombosis inmyeloma. Leukemia 2008; 22: 414–423.

105 Kristinsson SY. Thrombosis in multiple myeloma. Hematology Am Soc HematolEduc Program 2010; 2010: 437–444.

106 Richardson PG, Xie W, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H et al.Single-agent bortezomib in previously untreated multiple myeloma: efficacy,characterization of peripheral neuropathy and molecular correlations withresponse and neuropathy. J Clin Oncol 2009; 27: 3518–3525.

107 Delforge M, Blade J, Dimopoulos MA, Facon T, Kropff M, Ludwig H et al.Treatment-related peripheral neuropathy in multiple myeloma: the challengecontinues. Lancet Oncol 2010; 11: 1086–1095.

108 Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ et al.Genetic factors underlying the risk of thalidomide-related neuropathy in patientswith multiple myeloma. J Clin Oncol 2011; 29: 797–804.

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110 Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O et al.Management of treatment-emergent peripheral neuropathy in multiplemyeloma. Leukemia 2012; 26: 595–608.

111 Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y et al.Mechanisms of peripheral neuropathy associated with bortezomib and vincris-tine in patients with newly diagnosed multiple myeloma: a prospective analysisof data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 2010; 11: 1057–1065.

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International Myeloma Working Group recommendations … · International Myeloma Working Group recommendations for global myeloma care H Ludwig1, JS Miguel2, ... Giessen, Germany;