Smoldering multiple myeloma requiring treatment time for a new definition
online October 21, 2013
originally published doi:10.1182/blood-2013-08-5208902013 122: 4172-4181
Buadi, David Dingli, Suzanne R. Hayman, Nelson Leung, Yi Lin, Joseph Mikhael and Shaji K. Kumar
Lacy, John A. Lust, Stephen J. Russell, Steven R. Zeldenrust, Craig Reeder, Vivek Roy, Francis Rafael Fonseca, Prashant Kapoor, P. Leif Bergsagel, Arleigh McCurdy, Morie A. Gertz, Martha Q. Angela Dispenzieri, A. Keith Stewart, Asher Chanan-Khan, S. Vincent Rajkumar, Robert A. Kyle,
definition?
Smoldering multiple myeloma requiring treatment: time for a new
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Review Article
Smoldering multiple myeloma requiring treatment:time for
a new de?nition?
Angela Dispenzieri,1A.Keith Stewart,2Asher Chanan-Khan,3S.Vincent Rajkumar,1Robert A.Kyle,1Rafael Fonseca,2 Prashant Kapoor,1P.Leif Bergsagel,2Arleigh McCurdy,1Morie A.Gertz,1Martha https://www.wendangku.net/doc/0c303349.html,cy,1John A.Lust,1
Stephen J.Russell,1Steven R.Zeldenrust,1Craig Reeder,2Vivek Roy,3Francis Buadi,1David Dingli,1Suzanne R.Hayman,1 Nelson Leung,1Yi Lin,1Joseph Mikhael,2and Shaji K.Kumar1
1Division of Hematology,Mayo Clinic,Rochester,MN;2Division of Hematology/Oncology,Mayo Clinic,Arizona,Scottsdale,AZ;and3Divisions of Hematology and Oncology,Mayo Clinic,Florida,Jacksonville,FL
Smoldering multiple myeloma(SMM) bridges the gap between monoclonal gammopathy of undetermined signifi-cance(a mostly premalignant disorder) and active multiple myeloma(MM).Un-til recently,no interventional study in patients with SMM showed improved overall survival(OS)with therapy as compared with observation.A report from the PETHEMA-GEM(Programa Espa-n?ol de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among
patients with high-risk SMM who were
treated with lenalidomide and dexameth-
asone.This unique study prompted us to
review current knowledge about SMM and
address the following questions:(1)Are
there patients currently defined as SMM
who should be treated routinely?(2)Should
the definitions of SMM and MM be recon-
sidered?(3)Has the time come when not
treating is more dangerous than treating?
(4)Could unintended medical harm result
from overzealous intervention?Our con-
clusion is that those patients with the
highest-risk SMM(extreme bone marrow
plasmacytosis,extremely abnormal serum
immunoglobulin free light chain ratio,and
multiple bone lesions detected only by
modern imaging)should be reclassified
as active MM so that they can receive
MM-appropriate therapy and the para-
digm of careful observation for patients
with SMM can be preserved.(Blood.2013;
122(26):4172-4181)
Introduction
Smoldering multiple myeloma(SMM)was initially recognized in the1980s.1It bridged the gap between monoclonal gammopathy of undetermined signi?cance(MGUS;a mostly premalignant disorder) and active multiple myeloma(MM).The classi?cation of SMM is based on levels of circulating monoclonal immunoglobulin,bone marrow plasmacytosis,and end-organ damage.Until the Interna-tional Myeloma Working Group(IMWG)classi?cation system was developed(Table1),de?nitions had varied.2The minimum and maximum thresholds for immunoglobulin,bone marrow plasma-cytosis,presence of bone lesions,and degree of anemia have varied by the study.1,3The common theme across these studies was the universal recognition that there were asymptomatic patients who exceeded the limits of the de?nition of MGUS,who could remain without end-organ damage for years,and who outsurvived MM patients with higher tumor burden and/or end-organ damage.Studies performed in the1980s assessing the role of observation vs early intervention in these patients revealed no prolongation of survival with treatment.4-6Studies performed over the next2decades assessing bisphosphonate and/or thalidomide usage also did not show any clear advantage to instituting therapy in these asymptomatic patients other than fewer skeletal-related events(SREs).7-14However,a recent report from the PETHEMA-GEM(Programa Espa?ol de Tratamientos en Hematologica)group described both fewer calcium increased,renal dysfunction,anemia,and bone lesions(CRAB)events as well as better overall survival(OS)among high-risk SMM patients treated with lenalidomide and dexamethasone.15
This article will try to address the following3questions.First, should the de?nition of SMM be reconsidered such that those patients who are considered to have the highest-risk SMM are added into the active MM category in order to preserve the doctrine that SMM is an entity that can be observed without therapy?Second,has the time come when not treating is more dangerous than treating? Third,alternatively,could unintended medical harm result from overzealous intervention?
Definitions of SMM
Approximately8%to20%of patients with MM are recognized by chance without signi?cant symptoms.Kyle and Greipp?rst used the term“smoldering myeloma”in1980(Table1).1This expression referred to those patients who satis?ed the following criteria:(1)M protein$30g/L,(2)bone marrow plasmacytosis$10%,(3)no end-organ damage,and(4)no progression of disease at5years. At the same time,Alexanian et al explored the use of the term “indolent”myeloma(IMM),16an entity that allowed for up to3lytic bone lesions,a minimum bone marrow plasmacytosis of15%,and distinct minimum and maximum thresholds for immunoglobulin G (IgG)and IgA.Over time,Alexanian et al also separated the SMM (or asymptomatic MM)from the IMM,assigning a maximum value of M-spike of45g/L for the former category.3Subsequent to the SMM and the IMM classi?cations came that of evolving MM,which was de?ned as an M protein that abruptly increases when symptomatic MM develops.17There was considerable overlap between Durie-Salmon stage(DSS)IA18,19and SMM.It was not until2003,when
Submitted August14,2013;accepted October7,2013.Prepublished online as
Blood First Edition paper,October21,2013;DOI10.1182/blood-2013-08-
520890.
?2013by The American Society of Hematology
4172BLOOD,19DECEMBER2013x VOLUME122,NUMBER26
there was international consensus about the de?nitions of plasma cell disorders,that the criteria for SMM were established.2Most subsequent publications have used this more uniform de?nition. Defining risk in SMM
As shown in Table2,many investigators have evaluated the risk of progression among patients with SMM.In most of the earlier studies,“high-risk”patients had annual progression rates as high as 25%to40%,depending on the risk criteria applied,and had survival rates comparable to patients with active myeloma.20Several of these risk factors,especially those that related to tumor mass,may be useful to identify patients with the most“advanced”disease rather than those with the most aggressive biology.
The most commonly identi?ed risk factor for progression to active myeloma in the era before the2003IMWG criteria was the number of bone lesions.2,3,18-20The realization that patients with lytic lesions were among those with the shortest time to requiring systemic therapy contributed to the decision of excluding those patients with lytic bone lesions from the modern SMM de?nition(Table2).The size of the M spike and the degree of plasmacytosis were also consistent risk factors (Figure1A-B).21The IgA isotype,22,23the presence of protein-uria,23,24an abnormal serum immunoglobulin free light chain(FLC) ratio(Figure1B-C),25-27circulating plasma cells by slide-based immuno?uorescence,28,29a high proliferative rate of bone marrow plasma cells(BMPCs),30immunoparesis,31a high percentage of BMPCs with aberrant?ow cytometry(Figure1D),27,31and an abnormal magnetic resonance imaging(MRI)(Figure1E)27,32-34 have also been recognized as risk factors for progression.Bone marrow plasmacytosis as a risk factor is a relatively complex parameter given the variability of estimation,depending on the source of the sample.35Computed tomography and MRI reveal speci?c lesions in40%of DSS I myeloma patients.36Among asymptomatic MM patients with normal radiographs,50%have tumor-related abnormalities on MRI of the lower spine.37 Two groups have recently reported the impact of interphase?u-orescence in situ hybridization(FISH)on risk of progression(Table2 and Figure1F-G).38,39Both found that the presence of deletion17p or t(4;14)is associated with the shortest time to progression(TTP)and that trisomies were a risk factor for progression from SMM to MM. The Mayo paper addressed this peculiar?nding of trisomies being a SMM risk factor—but a well-accepted favorable prognostic factor in active MM—by assessing OS in the SMM cohort.38OS from the time of SMM diagnosis for the trisomy SMM patients was comparable to that of patients with either normal FISH or with standard risk abnormalities such as t(11;14)and deletion13/13q.This was in stark contrast to outcomes for the deletion17p and t(4;14)patients,who had inferior OS both from the time of SMM diagnosis and from active MM diagnosis(Figure2).The Heidelberg group also found that gains of1q21were a risk factor for progression among patients with SMM. These authors made an effort to relate FISH abnormalities with other reported risk factors,most notably tumor burden,and found that risk of the high-risk FISH was independent of tumor burden on multivariate analysis,with the greatest impact among those patients with lower tumor burden.39
Table1.Definitions of SMM(asymptomatic)/IMM/evolving MM
Reference n%BMPCs,(M protein,g/L),[other criteria]Risk factors Median TTP and OS
Kyle and Greipp, 198016$10,(and$30),[no anemia,hypercalcemia,
or renal insufficiency]
Not available Selected for no progression at5y
Alexanian et al,1988335$10,(and.20but,45g/L),[hemoglobin.
10.5g/dL]Asymptomatic lytic bone lesions(n510),M
protein.30g/L
TTP all:19mo;TTP no bone:25mo;OS all:
105mo;OS no bone:125mo
IMWG,20032$10,(or$30g/L),[absence of:high calcium,
hemoglobin2g/dL below normal or,10g/
dL,lytic bone lesions or osteoporosis with
compression fracture,symptomatic
hyperviscosity,amyloidosis,or.2
bacterial infections/12mo]
Not available
DSS IA18,19Not stated,(IgG,50g/L,IgA,30g/L,or
urine M component,4g/24h),
[hemoglobin.10g/dL,calcium,12mg/
dL,no more than solitary bone lesion]
Not available OS:69mo76
DSS IIA18,19Not stated,(immunoglobulins higher than
stage I),[hemoglobin.8.5but,10g/dL,
calcium,12mg/dL,more than a solitary
bone lesion,but not advanced bone
disease]
Not available OS:58mo76
Alexanian et al, 19801620“Indolent MM”:$15%,(and IgG.25g/L or
IgA.10g/L),[Hb.10.0g/dL;,3lytic
bone lesions;no painful compression
fracture]
Not available TTP:28mo;OS from IMM:64mo;OS from
treatment:36mo
Alexanian et al,1988316Indolent MM$10(and$45g/dL),[or Hb,
10.5]
Not available8mo
Rosinol et al,20031753Evolving MM$10,(and$30g/L or light
chain excretion1g/24h),[hemoglobin
.10g/dL,no bone lesions,renal,or
hypercalcemia]Evolving(n522),nonevolving(n526);trend
toward hemoglobin,12g/dL and M
protein.35g/L were risk factors
TTP nonevolving:47mo;TTP evolving:16
mo;OS from dexamethasone:98mo;OS
from treatment:42mo
Cesana et al,2002771271-y stability required11%-19%,(or IgG35-69
g/L,IgA21-69g/L,Bence Jones proteinuria
1g/24h),[no bone lesions,anemia,
hypercalcemia,and renal insufficiency]BMPC.10%;IgA M protein;proteinuria Not given
BLOOD,19DECEMBER2013x VOLUME122,NUMBER26REDEFINING SMOLDERING MM4173
Table2.Prognostic factors for progression of SMM to active MM
Reference n%BMPC,(M protein,g/L),[other criteria]Risk factors Median TTP and OS
Wisloff et al,19912071$10,(*or IgA.15,IgG.30,Bence Jones
proteinuria.1g/24h)Lytic bone lesions;BMPCs.20%TTP26mo;OS45mo;no risk:TTP39mo;
either risk:TTP10mo
Dimopoulos et al,19932495.15,(*and serum M protein,45g/L),[any
lytic bone lesion was exclusionary;.
hemoglobin10.5g/dL]Protein risk:M protein.30g/L or proteinuria
.50mg/24h;low(n527):no factor;
intermediate(n543):either protein
characteristic;high(n525):lytic bone
lesions and/or both protein risk
characteristics
TTP:26mo;low:61mo;intermediate:25
mo;high:10mo;OS from SMM(from
treatment):low:89mo(35mo);
intermediate:92mo(31mo);high:57mo
(41mo)
Witzig et al,19942857.10,(not stated),[no CRAB]Circulating cells by PBLI(n514)TTP:circulating:9mo;no circulating:30mo
Facon et al,19952291.15%,(*and DSS I)Hemoglobin,12g/dL;BMPC.20%;
M protein.30g/L(IgG)or.25g/L(IgA);
0factor(n538);1factor(n535);.1
factor(n518)TTP:48mo:0:.50mo;1:26mo;.1factor: 6mo;OS from SMM(from treatment):
0:.70m(33mo);1:50mo(31mo); .1:38mo(32mo)
Moulopolous et al, 19953338.10,(or M-spike.25-45g/L or Bence
Jones.150mg/d),[hemoglobin.10.5
g/dL;no lytic bone lesions]
Abnormal MRI TTP:normal MRI:43mo;abnormal MRI:16
mo;variegated:22mo;diffuse:16mo;
focal:6mo
Weber et al,199723101See Moupolous et al,1995M protein.30g/L;IgA M protein;proteinuria
.50mg/24h;low(n516):0;
intermediate(n565):1;high(n520):2
or more TTP:low:95mo;intermediate:39mo;high: 17mo;OS from dexamethasone(from
treatment):low:89mo(26mo);
intermediate:87mo(34mo);high:51mo (32mo)
Kyle et al,200721276IMWG M protein$30;BMPC$10%;group A:M
protein only(n527);group B:BMPC only
(n5143);group C:both(n5106)2-y TTP(5-y TTP):A:6%(15%);B:22% (43%);C:45%(69%)
Perez-Persona et al, 200731IMWG95%aberrant BMPC(absence of CD19and/
or CD45expression,overexpression of
CD56,or weak expression of CD38);
immunoparesis of the uninvolved
immunoglobulins:neither(n528),either
(n539),both(n539)
Median TTP(5-y TTP):neither:NR(4%);
either:73mo(46%);both:23mo(72%)
Dispenzieri et al,200825273IMWG M protein$30;BMPC$10%;involved FLC/
uninvolved;FLC$8;1high(n581);2
high(n5114);3high(n578)2-y TTP(5-y TTP):1:12%(25%);2:27% (51%);3:52%(76%)
Hillengass et al,201034149IMWG Whole-body MRI:low(n5126):no or1focal
lesion;high(n523):.1focal lesion Median(2-y TTP):low:not reached(20%);
high:13mo(70%)
Rajkumar et al,201162655IMWG BMPCs$60%(n521)*Median TTP(2-y TTP):BMPC$60%:7mo
(95%)
Larsen et al,201326586IMWG Involved FLC/uninvolved FLC,100(n5
496);involved FLC/uninvolved FLC$100
(n590)Median(2-y TTP;5-y TTP);low:NR(28%;
53);high:15mo(79%;94%)
Bianchi et al,20132991IMWG High:slide based.53106/L or.5%PC/
100cIg MNC;low(n577);high(n514)Median(2-y TTP):low:57mo(24%);high: 12mo(71%);OS from SMM(from
treatment):low:148mo(66mo);high:49 mo(31mo)
Rago et al,201359397IMWG Hemoglobin#12.5;M protein$2.5;BMPC
$60(2.5%of patients)10-y TTP:45%;BMPC$60%had35.6risk of progression
Madan et al,201030175IMWG PCLI,1%;PCLI$1%2-y TTP(5-y TTP):low:40%(60%);high:
60%(68%)
Rajkumar et al,201338351IMWG FISH:low:(n553),normal or insufficient;
standard:(n5106),t(11;14),maf
translocations,other/unknown
translocations,or deletion13/13q;
intermediate:(n5148),trisomies alone;
high:(n544),t(4;14)or deletion17p TTP:low:not reached;standard:54mo;
intermediate:34mo;high:24mo;OS
from SMM(from treatment):low,135mo (60mo);standard,147mo(77mo);
intermediate,135mo(86mo);high risk, 105mo(60mo)
Kastritis et al,20132796IMWG Risk factors:involved FLC/uninvolved FLC$
100;BM$60%Median TTP:no risk factor:73mo;1risk factor:18mo;both risk factors8mo
Neben et al,201239246IMWG High-risk FISHs:t(4:14),deletion17p or1
1q21;high tumor burden:M protein$20
g/L;FISH and tumor burden:both low risk
(n581);FISH high risk,tumor low risk
(n544);FISH low risk,tumor high risk
(n576);both high risk(n544)3-y TTP:both low risk:8%;FISH high risk only:30%;tumor high risk only:40%;both high risk:59%
cIg,cytoplasmic immunoglobulin;MNC,mononuclear cells;NR,no response;PBLI,peripheral blood labeling index;PC,plasma cells;and PCLI,plasma cell labeling index.
*The estimate of bone marrow plasmacytosis was according to the methods of Rajkumar et al35(ie,using the highest estimate of plasma cells from the aspirate or the bone marrow).
4174DISPENZIERI et al BLOOD,19DECEMBER2013x VOLUME122,NUMBER26
There are fewer data about the risk of abnormal metaphase cytogenetics in SMM,40in part because they are normal in 70%of patients with newly diagnosed MM;however,abnormal meta-phase cytogenetics are a re ?ection of proliferative myeloma 41and are also a risk factor for progression.42
Results of interventional therapeutic trials
As mentioned,the purpose of the SMM construct was to bridge the gray zone between MGUS and MM (Figure 3).The separation was useful for management because SMM patients had a risk of pro-gression many times greater than MGUS patients and hence needed more frequent follow-up than MGUS patients.Similarly,SMM pa-tients were distinguished from MM because they could be observed without therapy until evidence of disease progression.This strategy was aimed at avoiding unnecessary side effects and cumulative ex-posure of alkylating drugs,which were found to be associated with myelodysplastic syndrome and acute leukemia.43-46Patients with DSS I disease,who also meet the criteria for smoldering or asymptomatic myeloma,could be managed expectantly.Median progression-free survival (PFS)in asymptomatic DSS I patients,observed without any therapy,ranged from 12months to .48months.4,5,22,47
Melphalan
Two small randomized clinical trials were reported in the 1990s comparing immediate institution of melphalan and prednisone to initiation only once patients progressed from SMM to symptomatic MM (Table 3).Neither of these trials demonstrated a survival advantage,although they were not adequately powered to make de ?nitive conclusions.4-6
Bisphosphonates
The next class of drug evaluated in SMM patients in prospective clinical trials (1small pilot study 7and 2randomized controlled
trials)was single-agent bisphosphonate (Table 3).8-10Neither of the randomized trials demonstrated improved TTP or OS,but both demonstrated fewer SREs with bisphosphonate use.Patients using bisphosphonate also had higher rates of symptomatic hypocalce-mia,fever,and osteonecrosis of the jaw.
Thalidomide
Thalidomide with or without bisphosphonate has been studied in patients with SMM in phase 2trials and in 1underpowered ran-domized controlled trial (Table 3).11-14,48Eligibility criteria varied among trials as did response rates,PFS,and OS.In the Mayo Clinic randomized controlled trial,4882%were DSS 1A,but 63%were high risk according to the Mayo Clinic SMM risk classi ?cation as de ?ned by Dispenzieri et al.25There was a signi ?cant improvement in PFS in the thalidomide/zoledronic acid arm compared with the zoledronic acid alone arm (29months vs 14months)but no dif-ference in PFS as de ?ned by CRAB events (49months vs 40months;P 5.18)or in OS (6-year OS .70%).48The overall response rate was 37%for the thalidomide-containing arm and none with the zoledronic acid group.Thalidomide was poorly tolerated,with 80%of the thalidomide group developing grade 1or 2periph-eral neuropathy and 74%with grade 1or 2fatigue in the thalidomide/zoledronic acid arm.The patients treated with zole-dronic acid alone also had adverse effects,including grade 1or 2fatigue in 52%and grade 1or 2peripheral neuropathy in 18%.The outcomes of this phase 3trial differed slightly from its phase 2predecessors in that TTP was shorter than that of Barlogie et al 11or Rajkumar et al 12,13(29months vs 4-year event-free survival 60%vs 35months,respectively).Part of the discrepancy may relate to the fact that the Barlogie et al study allowed for all-risk SMM patients and that the Rajkumar et al phase 3study allowed for patients with IMM to enter.Another discrepancy between these studies is that patients in the Barlogie et al study who achieved a partial response or better had a shorter TTP than the nonresponders,in contrast to the ?ndings of the 2Mayo-led trials.Indeed,Barlogie et al ’s study
was
Figure 1.Risk of SMM progression to active MM according to different prognostic systems as compared with risk of progression of MGUS to active MM.Gray shading includes 2-year time point.(A)SMM risk based on BMPCs $10%,M protein $30g/L.21Bold solid line,both above threshold;solid line,BMPCs $10%but M-protein ,30g/L;dashed line,BMPC ,10%but M-protein $30g/L.(B)SMM risk based on BMPC $10,M protein $30g/L,and involved FLC/uninvolved FLC $8.25Bold solid line,all 3factors above threshold;solid line,any 2factors above threshold;dashed line,any 1factor above threshold.(C)SMM risk based on involved FLC/uninvolved FLC $100.26Bold solid line,above threshold;solid line,below threshold.(D)SMM risk based on absence of CD19and/or CD45expression,overexpression of CD56,or weak expression of CD38and immunoparesis of either of the uninvolved immunoglobulins.31Bold solid line,both risk factors present;solid line,either risk factor present;dashed line,neither risk factor present.(E)SMM risk based on presence (bold solid)or absence (solid)of more than 1focal lesion on whole-body MRI.34(F)SMM risk based on FISH.38Bold solid line,del17p,or t(4;14);solid line,trisomies alone;dashed line,any other interphase FISH abnormality;dotted line,normal or insufficient interphase FISH.(G)SMM risk based on high-risk interphase FISH [del17p,t(4;14),11q21,or hyperdiploidy]and high tumor burden (M-protein $20g/L).39Bold solid line,both high-risk factors present;solid line,interphase FISH low risk and tumor high risk;dashed line,FISH high risk and tumor low risk;dotted line,both low risk.(H)MGUS risk of progression to MM based on M protein $30g/L,abnormal rFLC,and heavy chain IgA or IgM.60Bold solid line,all risk factors present;solid line,2risk factors present;dashed line,1risk factor present;dotted line,no risk factor present.
BLOOD,19DECEMBER 2013x VOLUME 122,NUMBER 26
REDEFINING SMOLDERING MM
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concerning in that it implied that treatment with thalidomide may actually select for more aggressive myeloma clones to emerge under the selective pressure of the drug.
Lenalidomide
The most provocative study for patients with SMM is that of the PETHEMA-GEM group.15These authors reported on 119patients with high-risk SMM managed in an open-label randomized con-trolled trial by either observation or lenalidomide and dexametha-sone.The lenalidomide and dexamethasone patients received 9months of induction (28-day cycles of lenalidomide 25mg/day days 1-21and dexamethasone 20mg days 1-4and 12-15)followed by 15months of single-agent lenalidomide (10mg days 1-21every month).The high-risk population was de ?ned by the presence of both BMPCs .10%and M protein .30g/L or,if only 1criterion was present,patients had a proportion of aberrant (de ?ned as absence of CD19and/or CD45expression,overexpression of CD56,or weak expression of CD38)plasma cells within the total BMPC compartment by immunophenotyping of $95%as well as immu-noparesis (reduction under the lower normal limit of either of the uninvolved immunoglobulins).
Patients in the abstention arm were more likely to develop symp-tomatic disease (76%vs 23%).The overall response rate during induction therapy was 79%,including 65%partial responses,11%very good partial responses,14%complete responses,and
7%
Figure 2.Distribution and outcomes based on FISH abnormalities among patients with SMM.(A)No interphase FISH abnormalities,white;standard risk:t(11;14),t(14;16),or t(14;20)or other/unknown IgH or del 13/13q,light gray;intermediate risk:trisomy without IgH translocation,dark gray;high risk:t(4;14)or del (17p),black.Solid bars,progression from SMM to MM;stippled bars,OS from SMM diagnosis.(B)Duration of time a patient lives with labels ranging from MGUS to SMM to active MM is in part related to interphase FISH.Although individuals harboring trisomies (ii)appear to progress more rapidly through their diagnosis of SMM than patients with normal FISH or non-t(4;14)trans-locations (i),they survive much longer than those with deletion 17p (iii)and about as long as patients with normal or non-t(4;14)translocations (i).Mo,
months.
Figure 3.Present,future,and ideal state for distribution of patients with MGUS,SMM,and MM.
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DISPENZIERI et al
BLOOD,19DECEMBER 2013x VOLUME 122,NUMBER 26
stringent complete responses.In the treatment group,there were no grade4adverse events,but there was1death due to pneumonia and12%of patients had serious adverse events as compared with 3%in the observation arm.Most adverse events were grade1or2. Rates of diarrhea or constipation were37%(vs5%in observation arm)and rash occurred in32%.There were only3deep venous thromboses.Seventeen of57patients(30%)in the treatment arm withdrew due to toxicity or choice as compared with3(4.8%)in the observation arm.A potential impact in quality of life needs to be excluded.
With a median follow-up of40months,the treated patients had a superior3-year survival without progression to symptomatic disease(77%vs30%;P,.001)and a superior3-year OS(94%vs 80%;P5.03)from the time of registration.A major limitation in interpreting this study was the difference in how asymptomatic biochemical progression was handled in the2groups.In the observation arm,full CRAB progression was required for patients to receive antimyeloma therapy,whereas in the treatment arm, asymptomatic biochemical progression(.25%increase of mono-clonal component)during maintenance lenalidomide was suf?cient to warrant salvage with dexamethasone(or reescalation of lenalido-mide).A total of42%(24/57)of patients in the intervention group, who developed asymptomatic biochemical progression,were not counted as events in the Kaplan-Meier curves;rather,18had dexa-methasone added,and an unspeci?ed fraction had their lenalidomide dose reescalated according to protocol.Finally,the cause for the large discrepancy of discontinuation due to“choice”between the inter-vention arm vs the abstention arm(23%vs5%)could be attributed at least in part to patients’or treating physicians’reluctance to tolerate asymptomatic biochemical progression in patients for whom therapy had already begun(ie,lenalidomide and dexamethasone).These questions and the design of the study do not allow us to clearly determine if a preemptive strategy may be equally bene?cial with less toxicity than a prophylactic strategy.
Moreover,this difference in managing asymptomatic biochemical progression events may explain the relatively high3-year mortality of 20%in the control arm.Historically,this rate of3-year mortality is seen in the elderly,49-52but3-year mortality for patients with newly diagnosed active myeloma who are transplant eligible is closer to10% to15%.53-55Another caveat is that lenalidomide-dexamethasone was not used consistently as salvage for the abstention group upon progression.
Questions that require clari?cation before this strategy can be adopted even for high-risk patients include(1)Could some of the excess mortality in the observation arm relate to the protocol re-quirement that CRAB be reached before instituting therapy?(2)Was there a difference in follow-up compliance and intensity/frequency of de facto testing between the intervention and observation arms? Providing these clari?cations will allow this very important study to shed light on questions that extend beyond its primary and secondary objectives.
Rethinking the definition of SMM and timing of therapy
Some have argued that SMM is not a unique biologic state,but rather a heterogeneous entity comprising some patients with biological pre-malignancy(MGUS)and some with true malignancy who have yet to declare clinical end-organ damage.56,57With the advent of multiple novel markers of disease(from MRI to positron emission tomography/ computed tomography[PET/CT]to?ow phenotype to FISH cyto-genetics)and of newer(and presumably safer)antimyeloma therapies, should the de?nition of SMM be reconsidered?We believe so. Patients who are considered to have the highest-risk SMM should be moved into the active MM category in order to preserve the doctrine that SMM is an entity that can be observed without therapy(Figure3).
Table3.Treatment trials for patients with SMM
Reference Study Therapy N TTP OS
Hjorth et al,19934RCT Initial vs delayed MP50SMM and
IMM
12mo No difference
Riccardi et al,1994and20005,6RCT Initial vs delayed MP145DSS I;12mo No difference64mo vs71
mo
Peest et al,199578Observational Delayed MP54DSS I2-y PFS75%Tumor-specific OS80%at
60mo
Martin et al,20027Pilot Pamidronate5SMM and7
IMM
2-y TTP25%
Musto et al,20038and D’Arena et al,20119RCT Pamidronate vs observation177SMM5-y PFS53%both arms;SRE74%
vs39%,P5.009
Median OS46mo and48
mo
Musto et al,200810RCT Zoledronate vs observation31y163SMM TTP:67mo vs59mo,P5NS SRE:
55%vs78%,P5.04
OS not different Barlogie et al,200811Phase2Thalidomide pamidronate76SMM4-y EFS60%4-y OS91%
Rajkumar et al,200112,13Phase2Thalidomide19SMM and
10IMM Median35mo OS:86mo OS from
treatment:49mo
Weber et al,200314Phase2Thalidomide28high-risk
SMM
NA NA
Witzig et al,201348RCT Thalidomide1ZA vs ZA68SMM29mo vs14mo6y.70%
Lust et al,200979Ph2Interleukin-1receptor antagonist6
dexamethasone 47SMM and
IMM
37mo
Golombick et al,200980Crossover Curcumin vs placebo17SMM
Mateos et al,201315RCT Lenalidomide1dexamethasone3
9mo→lenalidomide
maintenance315mo vs
observation 119SMM2-y PFS:92%vs50%,P,.0013-y OS:93%vs76%,
P5.04
EFS,event-free survival;MP,melphalan-prednisone;NA,not applicable;NS,not significant;RCT,randomized controlled trial;ZA,zoledronic acid.
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The time has come when not treating a subset of what has up until now been considered high-risk SMM is more dangerous than treating.Our group has previously shown that even among patients with MGUS,the transition to MM can be unexpected and associated with end-organ damage in 40%of patients who do progress.58In other studies among patients with SMM who are observed until CRAB,the rates of renal failure were 11%to 13%and SREs 58%to 73%.9,20In yet another study,32%of the clinical progressions were severe as de ?ned as the need for red blood cell transfusion,dialysis,or treatment of a pathological fracture.59
Also worthy of consideration is the question of whether some of the lowest-risk SMM patients should be shifted into the MGUS category in order to reduce anxiety and intensity of follow-up,because the absence of risk factors predicts not only a longer TTP,but also a superior OS.To date,annual rates of progression in the “low-risk ”SMM are reduced from approximately 10%per year to 3%to 5%per year (Figure 1H).Although this is a signi ?cant reduction,these rates of progression are still slightly higher than that of high-risk MGUS.60
As the questions about treating groups of SMM patients are con-sidered,there must be agreement about acceptable rates of “over-treatment ”and “undertreatment ”of patients.61Figure 1illustrates 2-year progression rates for several recent SMM risk assessments.Most systems contain high-risk groups with 2-year TTP rates of ,60%(Table 2).The 4exceptions are bone marrow plasmacytosis of .60%,27,62serum immunoglobulin FLC ratio .100(Figure 1C),26,27circulating plasma cells by slide-based immuno ?uorescence,29and .1focal lesion on whole-body MRI (Figure 1E).34Bone marrow plasmacytosis of 60%affects 2%to 8%of all SMM patients,yields a median TTP of 7months to 15months,27,62and had a speci ?city of 95.5%for progression at 18months.27The involved FLC/uninvolved FLC of 100or greater captures approximately 7%to 15%of the SMM population and had a speci ?city of 98%for progression at 18months.27With a median TTP of 13to 15months,a 2-year TTP of 79%,and a 5-year TTP of 94%,26,27shifting these populations into the active MM category would also be reasonable (Figure 4),though it would be of interest to know how many of these “high-risk ”SMM had smoldering light chain myeloma.63More than 1focal lesion on whole-body MRI,which affected 15%of SMM patients in one study,had a high predictive value for progression to
active MM with a median TTP of 13months and a 2-year TTP of 70%.34Diffuse marrow in ?ltration pattern was also signi ?cant on multivariate analysis.Both of these MRI variables made M protein concentration of 40g/L and bone marrow in ?ltration of $20%insigni ?cant in the multivariate model.Figure 4summarizes our interpretation of the changing de ?nitions for SMM and active MM.In terms of other appealing candidates to help rede ?ne SMM and active MM,circulating plasma cells as detected by slide-based immuno ?uorescence captures 15%of SMM patients and yielded a median TTP of 12months,29but this test is not readily available.We therefore await data on a more accessible circulating plasma cell risk system using ?ow cytometry.Patients with high-risk FISH [deletion 17p,t(4;14),and gain 1q21]might be considered as active myeloma and be candidates for early treatment,but these groups are too heterogeneous for us to make that recommendation.
Consensus recommendations on treatment
Recent work from our institution shows that there has been stage migration 64among those patients being treated as active myeloma,suggesting that patients are being treated at an earlier time point during their disease course.It is possible,but not proven,that some of the improved survival seen in epidemiologic studies 65-67may be in part a function of physicians being more willing to treat patients earlier,which potentially exaggerates the bene ?cial impact of novel therapies over the past 15years.The question remains,however,whether treating sooner than later improves quality of life and/or OS.Observation as practiced in the PETHEMA-GEM study in patients with “high-risk ”SMM was associated with an unacceptable early mortality that was signi ?cantly decreased by early treatment with lenalidomide and dexamethasone.As mentioned earlier,some of the bene ?t (both survival and time to symptomatic disease)observed in this study may relate to the protocol design:treating biochemical progression and a 30%drop-out rate by “choice ”in the treatment arm and strict adherence ful ?lling a CRAB criterion prior to instituting therapy in the observation arm.
There are additional caveats that limit the generalizability of the PETHEMA-GEM study.First,the trial results apply not to
all
Figure 4.Algorithm for reclassifying SMM and active MM.*Consider including patients with the following FISH:deletion 17p,t(4;14),and 1q21gains as active MM;this population could account for as many as 30%of SMM patients.§Consider using more than 1fluorodeoxyglucose-avid lesion on PET/CT in lieu of MRI.iFLC,involved FLC;uFLC,uninvolved FLC;WbMRI,whole-body MRI.
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patients with SMM,but only to“high-risk”SMM patients as de?ned by the trial criteria.Forty percent of patients enrolled did so purely based on the?ow-based de?nition of plasma cell immunophenotype, a methodology that is not available in most institutions and that requires considerable expertise to interpret the results even if the technology were available.Second,the authors did not use lenalidomide-dexamethasone as universal salvage for the abstention trial universally.Third,reviewing Figure1and Table2,one sees that this strategy may result in overtreatment of approximately40%of patients at3years,30%of patients at4years,and20%of patients at 5years.Fourth,the costs of intervention also need to be considered.61 Although the“cost”of undertreatment is partially captured(more bone lesions and renal failure and now a suggestion of inferior OS), the“cost”of overtreatment is less clear.With the simplest of regimens(ie,lenalidomide plus dexamethasone),the annual cost of therapy is approximately$100000USD,not including the extra monitoring required for patients on active therapy and management of adverse events.68,69Part of the“cost”of overtreatment may include increased side effects,which may translate into inferior quality of life.Finally,long-term safety data for protracted lenalidomide use are limited.The potential of this last“cost”would be abrogated if physicians choose to treat according to the method of the PETHEMA-GEM study(ie,only2years of lenalidomide followed by observation until progression),a practice gaining favor in light of concerns of the potential risk of cumulative risk of secondary primary malignancy.70-72
After reviewing all of the data,taking into account the risks and bene?ts of observation as well as the risks and bene?ts of inter-vention,our recommendations for the management of SMM patients are shown in Figure4.Clearly,there is still room for?nding better predictors,but for now we recommend changing the de?nition of active MM,in the absence of CRAB,to include(1)patients with bone marrow plasmacytosis$60%,(2)a ratio of involved to uninvolved FLC of$100,or(3)whole-body MRI demonstrating .1focal lesion.In these patients,the risk of progression in the?rst2 or3years is80%or higher.Once de?ned as having active MM, these patients should receive therapy appropriate for any newly diagnosed patient,and one such therapy now supported with phase3 evidence would be lenalidomide plus dexamethasone as used in the PETHEMA-GEM interventional arm,though the combination is not Food and Drug Administration approved as?rst-line therapy in the United States.The cost of performing whole-body MRI on all patients with SMM with the intent of treating only those with.1 focal lesion on MRI would be much less expensive than treating an SMM patient who did not require treatment of2years or more. Limitations to using whole-body MRI are that many institutions do not have an algorithm to perform or interpret the test and that payment for the test may not be reimbursed by insurance providers.PET/CT may be a nice alternative to whole-body MRI because PET/ CT has a superior sensitivity to standard bone radiographs,is faster and more comfortable for the patient,and can be used in patients with implanted pacemakers and de?brillators.73-75We recommend that all other patients with SMM be observed without therapy every 3to6months and encouraged to participate in clinical trials. Although the PETHEMA-GEM trial shows that a subset of these patients(those with both BMPCs.10%and M protein.30g/L) could bene?t from therapy,we do not recommend intervention at this point until further con?rmatory evidence emerges,though it is important that these data be shared with patients.We recommend that our recommendations be considered by the IMWG to arrive at an international consensus.
Acknowledgments
This work was supported in part by the JABBS foundation,the Predolin Foundation,and the Robert A.Kyle Hematologic Malig-nancies Fund.
Authorship
Contribution:All authors contributed to the design,writing,and review of the manuscript.
Con?ict-of-interest disclosure: A.D.received research dollars from Celgene,Millenium,P?zer,and Janssen.K.S.received Celgene honoraria,Millenium clinical trial funding,and consulting fees from Onyx.R.F.has received a patent for the prognostication of MM based on genetic categorization of the disease,and he has received consulting fees from Medtronic,Otsuka,Celgene,Genzyme,BMS, Lilly,Onyx,Binding Site,Millennium,and AMGEN;he also has sponsored research from Cylene and Onyx.P.L.B.is an Onyx consultant.M.A.G.received honoraria from Celgene,Millennium, Onyx,and Binding Site.M.Q.L.received research dollars from Celgene.C.R.received research funding from Millennium,Celgene, and Novartis.J.M.received research funding from Celgene,Onyx, and Sano?.S.K.K.received clinical trial support from Celgene, Millennium,Onyx,Novartis,Cephalon/Teva Oncology,and Abbott and is a consultant(no personal reimbursement)for Millennium, Celgene,and Onyx.The remaining authors declare no competing ?nancial interests.
Correspondence:Angela Dispenzieri,200First St SW,Rochester, MN55905;e-mail:dispenzieri.angela@https://www.wendangku.net/doc/0c303349.html,.
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