Smoldering multiple myeloma requiring treatment: time for a new

Review Article

Smoldering multiple myeloma requiring treatment: time fora new definition?Angela Dispenzieri,1 A. Keith Stewart,2 Asher Chanan-Khan,3 S. Vincent Rajkumar,1 Robert A. Kyle,1 Rafael Fonseca,2

Prashant Kapoor,1 P. Leif Bergsagel,2 Arleigh McCurdy,1 Morie A. Gertz,1 Martha Q. Lacy,1 John A. Lust,1

Stephen J. Russell,1 Steven R. Zeldenrust,1 Craig Reeder,2 Vivek Roy,3 Francis Buadi,1 David Dingli,1 Suzanne R. Hayman,1

Nelson Leung,1 Yi Lin,1 Joseph Mikhael,2 and Shaji K. Kumar1

1Division of Hematology, Mayo Clinic, Rochester, MN; 2Division of Hematology/Oncology, Mayo Clinic, Arizona, Scottsdale, AZ; and 3Divisions 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-

nol 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

whoshould 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 inthe 1980s.1 It bridged the gap between monoclonal gammopathy ofundetermined significance (MGUS; a mostly premalignant disorder)and active multiple myeloma (MM). The classification of SMM isbased on levels of circulating monoclonal immunoglobulin, bonemarrow plasmacytosis, and end-organ damage. Until the Interna-tional Myeloma Working Group (IMWG) classification system wasdeveloped (Table 1), definitions had varied.2 The minimum andmaximum thresholds for immunoglobulin, bone marrow plasma-cytosis, presence of bone lesions, and degree of anemia have variedby the study.1,3 The common theme across these studies was theuniversal recognition that there were asymptomatic patients whoexceeded the limits of the definition of MGUS, who could remainwithout end-organ damage for years, and who outsurvived MMpatients with higher tumor burden and/or end-organ damage. Studiesperformed in the 1980s assessing the role of observation vs earlyintervention in these patients revealed no prolongation of survival withtreatment.4-6 Studies performed over the next 2 decades assessingbisphosphonate and/or thalidomide usage also did not show any clearadvantage to instituting therapy in these asymptomatic patients otherthan fewer skeletal-related events (SREs).7-14However, a recent reportfrom the PETHEMA-GEM (Programa Español de Tratamientos enHematologica) group described both fewer calcium increased, renaldysfunction, anemia, and bone lesions (CRAB) events as well asbetter overall survival (OS) among high-risk SMM patients treatedwith lenalidomide and dexamethasone.15

This article will try to address the following 3 questions. First,should the definition of SMM be reconsidered such that those

patients who are considered to have the highest-risk SMM are addedinto the active MM category in order to preserve the doctrine thatSMM is an entity that can be observed without therapy? Second, hasthe time come when not treating is more dangerous than treating?Third, alternatively, could unintended medical harm result fromoverzealous intervention?

Definitions of SMM

Approximately 8% to 20% of patients with MM are recognized bychance without significant symptoms. Kyle and Greipp first used theterm “smoldering myeloma” in 1980 (Table 1).1 This expressionreferred to those patients who satisfied the following criteria: (1) Mprotein $30 g/L, (2) bone marrow plasmacytosis $ 10%, (3) noend-organ damage, and (4) no progression of disease at 5 years.At the same time, Alexanian et al explored the use of the term“indolent”myeloma (IMM),16 an entity that allowed for up to 3 lyticbone lesions, a minimum bone marrow plasmacytosis of 15%, anddistinct minimum and maximum thresholds for immunoglobulin G(IgG) and IgA. Over time, Alexanian et al also separated the SMM(or asymptomaticMM) from the IMM, assigning amaximum value ofM-spike of 45 g/L for the former category.3 Subsequent to the SMMand the IMM classifications came that of evolving MM, which wasdefined as an M protein that abruptly increases when symptomaticMM develops.17 There was considerable overlap between Durie-Salmon stage (DSS) IA18,19 and SMM. It was not until 2003, when

Submitted August 14, 2013; accepted October 7, 2013. Prepublished online as

Blood First Edition paper, October 21, 2013; DOI 10.1182/blood-2013-08-

520890.

© 2013 by The American Society of Hematology

4172 BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26

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there was international consensus about the definitions of plasma celldisorders, that the criteria for SMM were established.2 Mostsubsequent publications have used this more uniform definition.

Defining risk in SMM

As shown in Table 2, many investigators have evaluated the riskof progression among patients with SMM. In most of the earlierstudies, “high-risk” patients had annual progression rates as high as25% to 40%, depending on the risk criteria applied, and had survivalrates comparable to patients with active myeloma.20 Several of theserisk factors, especially those that related to tumor mass, may beuseful to identify patients with the most “advanced” disease ratherthan those with the most aggressive biology.

The most commonly identified risk factor for progression to activemyeloma in the era before the 2003 IMWG criteria was the number ofbone lesions.2,3,18-20 The realization that patients with lytic lesionswere among those with the shortest time to requiring systemic therapycontributed to the decision of excluding those patients with lytic bonelesions from the modern SMM definition (Table 2). The size of the Mspike and the degree of plasmacytosis were also consistent risk factors(Figure 1A-B).21 The IgA isotype,22,23 the presence of protein-uria,23,24 an abnormal serum immunoglobulin free light chain (FLC)ratio (Figure 1B-C),25-27 circulating plasma cells by slide-basedimmunofluorescence,28,29 a high proliferative rate of bone marrowplasma cells (BMPCs),30 immunoparesis,31 a high percentage ofBMPCs with aberrant flow cytometry (Figure 1D),27,31 and an

abnormal magnetic resonance imaging (MRI) (Figure 1E)27,32-34

have also been recognized as risk factors for progression. Bonemarrow plasmacytosis as a risk factor is a relatively complexparameter given the variability of estimation, depending on thesource of the sample.35 Computed tomography and MRI revealspecific lesions in 40% of DSS I myeloma patients.36 Amongasymptomatic MM patients with normal radiographs, 50% havetumor-related abnormalities on MRI of the lower spine.37

Two groups have recently reported the impact of interphase flu-orescence in situ hybridization (FISH) on risk of progression (Table 2and Figure 1F-G).38,39 Both found that the presence of deletion 17p ort(4;14) is associated with the shortest time to progression (TTP) andthat trisomies were a risk factor for progression from SMM to MM.The Mayo paper addressed this peculiar finding of trisomies beinga SMM risk factor—but a well-accepted favorable prognostic factor inactiveMM—by assessing OS in the SMM cohort.38 OS from the timeof SMM diagnosis for the trisomy SMM patients was comparable tothat of patients with either normal FISH or with standard riskabnormalities such as t(11;14) and deletion 13/13q. This was in starkcontrast to outcomes for the deletion 17p and t(4;14) patients, who hadinferior OS both from the time of SMM diagnosis and from activeMM diagnosis (Figure 2). The Heidelberg group also found that gainsof 1q21 were a risk factor for progression among patients with SMM.These authors made an effort to relate FISH abnormalities with otherreported risk factors, most notably tumor burden, and found that riskof the high-risk FISH was independent of tumor burden onmultivariate analysis, with the greatest impact among those patientswith lower tumor burden.39

Table 1. 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 at 5 y

Alexanian et al, 19883 35 $10, (and . 20 but , 45 g/L), [hemoglobin .

10.5 g/dL]

Asymptomatic lytic bone lesions (n 5 10), M

protein . 30 g/L

TTP all: 19 mo; TTP no bone: 25 mo; OS all:

105 mo; OS no bone: 125 mo

IMWG, 20032 $10, (or $ 30 g/L), [absence of: high calcium,

hemoglobin 2 g/dL below normal or , 10 g/

dL, lytic bone lesions or osteoporosis with

compression fracture, symptomatic

hyperviscosity, amyloidosis, or . 2

bacterial infections/12 mo]

Not available

DSS IA18,19 Not stated, (IgG , 50 g/L, IgA , 30 g/L, or

urine M component , 4 g/24 h),

[hemoglobin . 10 g/dL, calcium , 12 mg/

dL, no more than solitary bone lesion]

Not available OS: 69 mo76

DSS IIA18,19 Not stated, (immunoglobulins higher than

stage I), [hemoglobin . 8.5 but , 10 g/dL,

calcium , 12 mg/dL, more than a solitary

bone lesion, but not advanced bone

disease]

Not available OS: 58 mo76

Alexanian et al,

19801620 “Indolent MM”: $ 15%, (and IgG . 25 g/L or

IgA . 10 g/L), [Hb .10.0 g/dL; , 3 lytic

bone lesions; no painful compression

fracture]

Not available TTP: 28 mo; OS from IMM: 64 mo; OS from

treatment: 36 mo

Alexanian et al, 19883 16 Indolent MM $ 10 (and $ 45 g/dL), [or Hb ,

10.5]

Not available 8 mo

Rosinol et al, 200317 53 Evolving MM $ 10, (and $ 30 g/L or light

chain excretion 1 g/24 h), [hemoglobin

. 10 g/dL, no bone lesions, renal, or

hypercalcemia]

Evolving (n 5 22), nonevolving (n 5 26); trend

toward hemoglobin , 12 g/dL and M

protein . 35 g/L were risk factors

TTP nonevolving: 47 mo; TTP evolving: 16

mo; OS from dexamethasone: 98 mo; OS

from treatment: 42 mo

Cesana et al, 200277 127 1-y stability required 11%-19%, (or IgG 35-69

g/L, IgA 21-69 g/L, Bence Jones proteinuria

1 g/24 h), [no bone lesions, anemia,

hypercalcemia, and renal insufficiency]

BMPC . 10%; IgA M protein; proteinuria Not given

BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26 REDEFINING SMOLDERING MM 4173




Table 2. 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, 199120 71 $10, (*or IgA . 15, IgG . 30, Bence Jones

proteinuria . 1 g/24 h)

Lytic bone lesions; BMPCs . 20% TTP 26 mo; OS 45 mo; no risk: TTP 39 mo;

either risk: TTP 10 mo

Dimopoulos et al, 199324 95 .15, (*and serum M protein , 45 g/L), [any

lytic bone lesion was exclusionary; .

hemoglobin 10.5 g/dL]

Protein risk: M protein. 30 g/L or proteinuria

. 50 mg/24 h; low (n 5 27): no factor;

intermediate (n 5 43): either protein

characteristic; high (n 5 25): lytic bone

lesions and/or both protein risk

characteristics

TTP: 26 mo; low: 61 mo; intermediate: 25

mo; high: 10 mo; OS from SMM (from

treatment): low: 89 mo (35 mo);

intermediate: 92 mo (31 mo); high: 57 mo

(41 mo)

Witzig et al, 199428 57 .10, (not stated), [no CRAB] Circulating cells by PBLI (n 5 14) TTP: circulating: 9 mo; no circulating: 30 mo

Facon et al, 199522 91 .15%, (*and DSS I) Hemoglobin , 12 g/dL; BMPC . 20%;

M protein . 30 g/L (IgG) or . 25 g/L (IgA);

0 factor (n 5 38); 1 factor (n 5 35); .1

factor (n 5 18)

TTP: 48 mo: 0:. 50 mo; 1: 26 mo;.1 factor:

6 mo; OS from SMM (from treatment):

0: . 70 m (33 mo); 1: 50 mo (31 mo);

.1: 38 mo (32 mo)

Moulopolous et al,

19953338 .10, (or M-spike . 25-45 g/L or Bence

Jones . 150 mg/d), [hemoglobin . 10.5

g/dL; no lytic bone lesions]

Abnormal MRI TTP: normal MRI: 43 mo; abnormal MRI: 16

mo; variegated: 22 mo; diffuse: 16 mo;

focal: 6 mo

Weber et al, 199723 101 See Moupolous et al, 1995 M protein. 30 g/L; IgA M protein; proteinuria

. 50 mg/24 h; low (n 5 16): 0;

intermediate (n 5 65): 1; high (n 5 20): 2

or more

TTP: low: 95 mo; intermediate: 39 mo; high:

17 mo; OS from dexamethasone (from

treatment): low: 89 mo (26 mo);

intermediate: 87 mo (34 mo); high: 51 mo

(32 mo)

Kyle et al, 200721 276 IMWG M protein $ 30; BMPC $ 10%; group A: M

protein only (n5 27); group B: BMPC only

(n 5 143); group C: both (n 5 106)

2-y TTP (5-y TTP): A: 6% (15%); B: 22%

(43%); C: 45% (69%)

Perez-Persona et al,

200731IMWG 95% aberrant BMPC (absence of CD19 and/

or CD45 expression, overexpression of

CD56, or weak expression of CD38);

immunoparesis of the uninvolved

immunoglobulins: neither (n 5 28), either

(n 5 39), both (n 5 39)

Median TTP (5-y TTP): neither: NR (4%);

either: 73 mo (46%); both: 23 mo (72%)

Dispenzieri et al, 200825 273 IMWG M protein$ 30; BMPC$ 10%; involved FLC/

uninvolved; FLC $ 8; 1 high (n 5 81); 2

high (n 5 114); 3 high (n 5 78)

2-y TTP (5-y TTP): 1: 12% (25%); 2: 27%

(51%); 3: 52% (76%)

Hillengass et al, 201034 149 IMWG Whole-body MRI: low (n5 126): no or 1 focal

lesion; high (n 5 23): . 1 focal lesion

Median (2-y TTP): low: not reached (20%);

high: 13 mo (70%)

Rajkumar et al, 201162 655 IMWG BMPCs $ 60% (n 5 21)* Median TTP (2-y TTP): BMPC $ 60%: 7 mo

(95%)

Larsen et al, 201326 586 IMWG Involved FLC/uninvolved FLC , 100 (n 5

496); involved FLC/uninvolved FLC $ 100

(n 5 90)

Median (2-y TTP; 5-y TTP); low: NR (28%;

53); high: 15 mo (79%; 94%)

Bianchi et al, 2013 29 91 IMWG High: slide based . 5 3 106/L or . 5% PC/

100 cIg MNC; low (n 5 77); high (n 5 14)

Median (2-y TTP): low: 57 mo (24%); high:

12 mo (71%); OS from SMM (from

treatment): low: 148 mo (66 mo); high: 49

mo (31 mo)

Rago et al, 201359 397 IMWG Hemoglobin # 12.5; M protein $ 2.5; BMPC

$ 60 (2.5% of patients)

10-y TTP: 45%; BMPC $ 60% had3 5.6 risk

of progression

Madan et al, 201030 175 IMWG PCLI , 1%; PCLI $ 1% 2-y TTP (5-y TTP): low: 40% (60%); high:

60% (68%)

Rajkumar et al, 201338 351 IMWG FISH: low: (n 5 53), normal or insufficient;

standard: (n 5 106), t(11;14), maf

translocations, other/unknown

translocations, or deletion 13/13q;

intermediate: (n 5 148), trisomies alone;

high: (n 5 44), t(4;14) or deletion 17p

TTP: low: not reached; standard: 54 mo;

intermediate: 34 mo; high: 24 mo; OS

from SMM (from treatment): low, 135 mo

(60 mo); standard, 147 mo (77 mo);

intermediate, 135 mo (86 mo); high risk,

105 mo (60 mo)

Kastritis et al, 201327 96 IMWG Risk factors: involved FLC/uninvolved FLC $

100; BM $ 60%

Median TTP: no risk factor: 73 mo; 1 risk

factor: 18 mo; both risk factors 8 mo

Neben et al, 201239 246 IMWG High-risk FISHs: t(4:14), deletion 17p or 1

1q21; high tumor burden: M protein $ 20

g/L; FISH and tumor burden: both low risk

(n 5 81); FISH high risk, tumor low risk

(n 5 44); FISH low risk, tumor high risk

(n 5 76); both high risk (n 5 44)

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).

4174 DISPENZIERI et al BLOOD, 19 DECEMBER 2013 x VOLUME 122, NUMBER 26




There are fewer data about the risk of abnormal metaphasecytogenetics in SMM,40 in part because they are normal in 70%of patients with newly diagnosed MM; however, abnormal meta-phase cytogenetics are a reflection of proliferative myeloma41

and are also a risk factor for progression.42

Results of interventional therapeutic trials

As mentioned, the purpose of the SMM construct was to bridge thegray zone between MGUS and MM (Figure 3). The separation wasuseful for management because SMM patients had a risk of pro-gression many times greater than MGUS patients and hence neededmore frequent follow-up than MGUS patients. Similarly, SMM pa-tients were distinguished from MM because they could be observedwithout therapy until evidence of disease progression. This strategywas aimed at avoiding unnecessary side effects and cumulative ex-posure of alkylating drugs, which were found to be associated withmyelodysplastic syndrome and acute leukemia.43-46 PatientswithDSSI disease, who also meet the criteria for smoldering or asymptomaticmyeloma, could be managed expectantly. Median progression-freesurvival (PFS) in asymptomatic DSS I patients, observed without anytherapy, ranged from 12 months to .48 months.4,5,22,47

Melphalan

Two small randomized clinical trials were reported in the 1990scomparing immediate institution of melphalan and prednisone toinitiation only once patients progressed from SMM to symptomaticMM (Table 3). Neither of these trials demonstrated a survivaladvantage, although they were not adequately powered to makedefinitive conclusions.4-6

Bisphosphonates

The next class of drug evaluated in SMM patients in prospectiveclinical trials (1 small pilot study7 and 2 randomized controlled

trials) was single-agent bisphosphonate (Table 3).8-10 Neither ofthe randomized trials demonstrated improved TTP or OS, but bothdemonstrated fewer SREs with bisphosphonate use. Patients usingbisphosphonate also had higher rates of symptomatic hypocalce-mia, fever, and osteonecrosis of the jaw.

Thalidomide

Thalidomide with or without bisphosphonate has been studied inpatients with SMM in phase 2 trials and in 1 underpowered ran-domized controlled trial (Table 3).11-14,48 Eligibility criteria variedamong trials as did response rates, PFS, and OS. In the Mayo Clinicrandomized controlled trial,48 82% were DSS 1A, but 63% werehigh risk according to the Mayo Clinic SMM risk classification asdefined by Dispenzieri et al.25 There was a significant improvementin PFS in the thalidomide/zoledronic acid arm compared with thezoledronic acid alone arm (29 months vs 14 months) but no dif-ference in PFS as defined by CRAB events (49 months vs 40months; P 5 .18) or in OS (6-year OS . 70%).48 The overallresponse rate was 37% for the thalidomide-containing arm and nonewith the zoledronic acid group. Thalidomide was poorly tolerated,with 80% of the thalidomide group developing grade 1 or 2 periph-eral neuropathy and 74% with grade 1 or 2 fatigue in thethalidomide/zoledronic acid arm. The patients treated with zole-dronic acid alone also had adverse effects, including grade 1 or 2fatigue in 52% and grade 1 or 2 peripheral neuropathy in 18%. Theoutcomes of this phase 3 trial differed slightly from its phase 2predecessors in that TTP was shorter than that of Barlogie et al11 orRajkumar et al12,13 (29 months vs 4-year event-free survival 60% vs35 months, respectively). Part of the discrepancy may relate to thefact that the Barlogie et al study allowed for all-risk SMM patientsand that the Rajkumar et al phase 3 study allowed for patients withIMM to enter. Another discrepancy between these studies is thatpatients in the Barlogie et al studywho achieved a partial response orbetter had a shorter TTP than the nonresponders, in contrast to thefindings of the 2 Mayo-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$ 30 g/L.21 Bold solid line, both above threshold; solid line, BMPCs$ 10% but M-protein, 30 g/L;

dashed line, BMPC, 10% but M-protein$ 30 g/L. (B) SMM risk based on BMPC$ 10, M protein$ 30 g/L, and involved FLC/uninvolved FLC$ 8.25 Bold solid line, all 3 factors above

threshold; solid line, any 2 factors above threshold; dashed line, any 1 factor above threshold. (C) SMM risk based on involved FLC/uninvolved FLC $ 100.26 Bold solid line, above

threshold; solid line, below threshold. (D) SMM risk based on absence of CD19 and/or CD45 expression, overexpression of CD56, or weak expression of CD38 and immunoparesis of

either of the uninvolved immunoglobulins.31 Bold 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 1 focal lesion on whole-body MRI.34 (F) SMM risk based on FISH.38 Bold 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$ 20 g/L).39 Bold 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$ 30 g/L, abnormal rFLC, and heavy chain IgA or IgM.60 Bold solid line, all risk

factors present; solid line, 2 risk factors present; dashed line, 1 risk factor present; dotted line, no risk factor present.





concerning in that it implied that treatment with thalidomide mayactually select for more aggressive myeloma clones to emerge underthe selective pressure of the drug.

Lenalidomide

The most provocative study for patients with SMM is that of thePETHEMA-GEM group.15 These authors reported on 119 patientswith 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 25 mg/day days1-21 and dexamethasone 20 mg days 1-4 and 12-15) followed by 15months of single-agent lenalidomide (10 mg days 1-21 everymonth). The high-risk population was defined by the presence ofboth BMPCs .10% and M protein .30 g/L or, if only 1 criterionwas present, patients had a proportion of aberrant (defined asabsence of CD19 and/or CD45 expression, overexpression of CD56,or weak expression of CD38) plasma cells within the total BMPCcompartment by immunophenotyping of $95% as well as immu-noparesis (reduction under the lower normal limit of either of theuninvolved immunoglobulins).

Patients in the abstention arm were more likely to develop symp-tomatic disease (76% vs 23%). The overall response rate duringinduction 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.





stringent complete responses. In the treatment group, there were nograde 4 adverse events, but there was 1 death due to pneumoniaand 12% of patients had serious adverse events as compared with3% in the observation arm. Most adverse events were grade 1 or 2.Rates of diarrhea or constipation were 37% (vs 5% in observationarm) and rash occurred in 32%. There were only 3 deep venousthromboses. Seventeen of 57 patients (30%) in the treatment armwithdrew due to toxicity or choice as compared with 3 (4.8%) inthe observation arm. A potential impact in quality of life needs tobe excluded.

With a median follow-up of 40 months, the treated patients hada superior 3-year survival without progression to symptomaticdisease (77% vs 30%; P, .001) and a superior 3-year OS (94% vs80%; P 5 .03) from the time of registration. A major limitation ininterpreting this study was the difference in how asymptomaticbiochemical progression was handled in the 2 groups. In theobservation arm, full CRAB progression was required for patientsto receive antimyeloma therapy, whereas in the treatment arm,asymptomatic biochemical progression (. 25% increase of mono-clonal component) during maintenance lenalidomide was sufficientto warrant salvage with dexamethasone (or reescalation of lenalido-mide). A total of 42% (24/57) of patients in the intervention group,who developed asymptomatic biochemical progression, were notcounted as events in the Kaplan-Meier curves; rather, 18 had dexa-methasone added, and an unspecified fraction had their lenalidomidedose reescalated according to protocol. Finally, the cause for the largediscrepancy of discontinuation due to “choice” between the inter-vention arm vs the abstention arm (23% vs 5%) could be attributed atleast in part to patients’ or treating physicians’ reluctance to tolerateasymptomatic biochemical progression in patients for whom therapyhad already begun (ie, lenalidomide and dexamethasone). Thesequestions and the design of the study do not allow us to clearlydetermine if a preemptive strategy may be equally beneficial withless toxicity than a prophylactic strategy.

Moreover, this difference inmanaging asymptomatic biochemicalprogression events may explain the relatively high 3-year mortality of20% in the control arm. Historically, this rate of 3-year mortality isseen in the elderly,49-52 but 3-year mortality for patients with newlydiagnosed activemyelomawho are transplant eligible is closer to 10%to 15%.53-55 Another caveat is that lenalidomide-dexamethasone wasnot used consistently as salvage for the abstention group uponprogression.

Questions that require clarification before this strategy can beadopted even for high-risk patients include (1) Could some of theexcess mortality in the observation arm relate to the protocol re-quirement that CRAB be reached before instituting therapy? (2)Wasthere a difference in follow-up compliance and intensity/frequencyof de facto testing between the intervention and observation arms?Providing these clarifications will allow this very important study toshed light on questions that extend beyond its primary and secondaryobjectives.

Rethinking the definition of SMM and timingof therapy

Some have argued that SMM is not a unique biologic state, but rathera heterogeneous entity comprising some patients with biological pre-malignancy (MGUS) and some with true malignancy who have yet todeclare clinical end-organ damage.56,57 With the advent of multiplenovelmarkers of disease (fromMRI to positron emission tomography/computed tomography [PET/CT] to flow phenotype to FISH cyto-genetics) and of newer (and presumably safer) antimyeloma therapies,should the definition of SMM be reconsidered? We believe so.Patients who are considered to have the highest-risk SMM should bemoved into the active MM category in order to preserve the doctrinethat SMM is an entity that can be observed without therapy (Figure 3).

Table 3. Treatment trials for patients with SMM

Reference Study Therapy N TTP OS

Hjorth et al, 19934 RCT Initial vs delayed MP 50 SMM and

IMM

12 mo No difference

Riccardi et al, 1994 and 20005,6 RCT Initial vs delayed MP 145 DSS I ;12 mo No difference 64 mo vs 71

mo

Peest et al, 199578 Observational Delayed MP 54 DSS I 2-y PFS 75% Tumor-specific OS 80% at

60 mo

Martin et al, 20027 Pilot Pamidronate 5 SMM and 7

IMM

2-y TTP 25%

Musto et al, 20038 and D’Arena

et al, 20119RCT Pamidronate vs observation 177 SMM 5-y PFS 53% both arms; SRE 74%

vs 39%, P 5 .009

Median OS 46 mo and 48

mo

Musto et al, 200810 RCT Zoledronate vs observation 3 1 y 163 SMM TTP: 67 mo vs 59 mo, P 5 NS SRE:

55% vs 78%, P 5 .04

OS not different

Barlogie et al, 200811 Phase 2 Thalidomide pamidronate 76 SMM 4-y EFS 60% 4-y OS 91%

Rajkumar et al, 200112,13 Phase 2 Thalidomide 19 SMM and

10 IMM

Median 35 mo OS: 86 mo OS from

treatment: 49 mo

Weber et al, 200314 Phase 2 Thalidomide 28 high-risk

SMM

NA NA

Witzig et al, 201348 RCT Thalidomide 1 ZA vs ZA 68 SMM 29 mo vs 14 mo 6 y . 70%

Lust et al, 200979 Ph 2 Interleukin-1 receptor antagonist 6

dexamethasone

47 SMM and

IMM

37 mo

Golombick et al, 200980 Crossover Curcumin vs placebo 17 SMM

Mateos et al, 201315 RCT Lenalidomide 1 dexamethasone 3

9 mo → lenalidomide

maintenance 3 15 mo vs

observation

119 SMM 2-y PFS: 92% vs 50%, P , .001 3-y OS: 93% vs 76%,

P 5 .04

EFS, event-free survival; MP, melphalan-prednisone; NA, not applicable; NS, not significant; RCT, randomized controlled trial; ZA, zoledronic acid.





The time has comewhen not treating a subset of what has up until nowbeen considered high-risk SMM is more dangerous than treating. Ourgroup has previously shown that even among patients with MGUS,the transition toMMcan be unexpected and associatedwith end-organdamage in 40% of patients who do progress.58 In other studies amongpatients with SMM who are observed until CRAB, the rates of renalfailure were 11% to 13% and SREs 58% to 73%.9,20 In yet anotherstudy, 32% of the clinical progressions were severe as defined as theneed for red blood cell transfusion, dialysis, or treatment of apathological fracture.59

Also worthy of consideration is the question of whether some ofthe lowest-risk SMM patients should be shifted into the MGUScategory 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 to3% to 5% per year (Figure 1H). Although this is a significantreduction, these rates of progression are still slightly higher than thatof 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.61 Figure 1 illustrates2-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 4 exceptions are bone marrow plasmacytosis of.60%,27,62 serum immunoglobulin FLC ratio .100 (Figure 1C),26,27

circulating plasma cells by slide-based immunofluorescence,29 and.1 focal lesion on whole-body MRI (Figure 1E).34 Bone marrowplasmacytosis of 60% affects 2% to 8% of all SMM patients, yieldsa median TTP of 7 months to 15 months,27,62 and had a specificityof 95.5% for progression at 18 months.27 The involved FLC/uninvolved FLC of 100 or greater captures approximately 7% to15% of the SMM population and had a specificity of 98% forprogression at 18 months.27 With a median TTP of 13 to 15 months,a 2-year TTP of 79%, and a 5-year TTP of 94%,26,27 shifting thesepopulations into the active MM category would also be reasonable(Figure 4), though it would be of interest to know howmany of these“high-risk” SMMhad smoldering light chain myeloma.63 More than1 focal lesion on whole-body MRI, which affected 15% of SMMpatients in one study, had a high predictive value for progression to

active MM with a median TTP of 13 months and a 2-year TTP of70%.34 Diffuse marrow infiltration pattern was also significant onmultivariate analysis. Both of these MRI variables made M proteinconcentration of 40 g/L and bone marrow infiltration of $20%insignificant in the multivariate model. Figure 4 summarizes ourinterpretation of the changing definitions for SMM and active MM.

In terms of other appealing candidates to help redefine SMMand active MM, circulating plasma cells as detected by slide-basedimmunofluorescence captures 15% of SMM patients and yieldeda median TTP of 12 months,29 but this test is not readily available.We therefore await data on a more accessible circulating plasmacell risk system using flow cytometry. Patients with high-risk FISH[deletion 17p, t(4;14), and gain 1q21] might be considered as activemyeloma and be candidates for early treatment, but these groups aretoo heterogeneous for us to make that recommendation.

Consensus recommendations on treatment

Recent work from our institution shows that there has been stagemigration64 among those patients being treated as active myeloma,suggesting that patients are being treated at an earlier time pointduring their disease course. It is possible, but not proven, that someof the improved survival seen in epidemiologic studies65-67 may bein part a function of physicians being more willing to treat patientsearlier, which potentially exaggerates the beneficial impact of noveltherapies over the past 15 years. The question remains, however,whether treating sooner than later improves quality of life and/orOS. Observation as practiced in the PETHEMA-GEM study inpatients with “high-risk” SMMwas associated with an unacceptableearly mortality that was significantly decreased by early treatmentwith lenalidomide and dexamethasone. As mentioned earlier, someof the benefit (both survival and time to symptomatic disease)observed in this study may relate to the protocol design: treatingbiochemical progression and a 30% drop-out rate by “choice” in thetreatment arm and strict adherence fulfilling a CRAB criterion priorto instituting therapy in the observation arm.

There are additional caveats that limit the generalizability of thePETHEMA-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 1q21 gains as

active MM; this population could account for as many

as 30% of SMM patients. §Consider using more than

1 fluorodeoxyglucose-avid lesion on PET/CT in lieu

of MRI. iFLC, involved FLC; uFLC, uninvolved FLC;

WbMRI, whole-body MRI.





patients with SMM, but only to “high-risk” SMM patients as definedby the trial criteria. Forty percent of patients enrolled did so purelybased on the flow-based definition of plasma cell immunophenotype,a methodology that is not available in most institutions and thatrequires considerable expertise to interpret the results even if thetechnology were available. Second, the authors did not uselenalidomide-dexamethasone as universal salvage for the abstentiontrial universally. Third, reviewing Figure 1 and Table 2, one sees thatthis strategy may result in overtreatment of approximately 40% ofpatients at 3 years, 30% of patients at 4 years, and 20% of patients at5 years. Fourth, the costs of intervention also need to be considered.61

Although the “cost” of undertreatment is partially captured (morebone lesions and renal failure and now a suggestion of inferior OS),the “cost” of overtreatment is less clear. With the simplest ofregimens (ie, lenalidomide plus dexamethasone), the annual cost oftherapy is approximately $100 000 USD, not including the extramonitoring required for patients on active therapy and managementof adverse events.68,69 Part of the “cost” of overtreatment mayinclude increased side effects, which may translate into inferiorquality of life. Finally, long-term safety data for protractedlenalidomide use are limited. The potential of this last “cost”would be abrogated if physicians choose to treat according tothe method of the PETHEMA-GEM study (ie, only 2 years oflenalidomide followed by observation until progression), a practicegaining favor in light of concerns of the potential risk of cumulativerisk of secondary primary malignancy.70-72

After reviewing all of the data, taking into account the risks andbenefits of observation as well as the risks and benefits of inter-vention, our recommendations for themanagement of SMMpatientsare shown in Figure 4. Clearly, there is still room for finding betterpredictors, but for now we recommend changing the definition ofactive MM, in the absence of CRAB, to include (1) patients withbone marrow plasmacytosis $60%, (2) a ratio of involved touninvolved FLC of $100, or (3) whole-body MRI demonstrating.1 focal lesion. In these patients, the risk of progression in the first 2or 3 years is 80% or higher. Once defined as having active MM,these patients should receive therapy appropriate for any newlydiagnosed patient, and one such therapy now supported with phase 3evidence would be lenalidomide plus dexamethasone as used in thePETHEMA-GEM interventional arm, though the combination is notFood and Drug Administration approved as first-line therapy in theUnited States. The cost of performing whole-body MRI on allpatients with SMM with the intent of treating only those with .1focal lesion on MRI would be much less expensive than treating anSMM patient who did not require treatment of 2 years or more.Limitations to using whole-body MRI are that many institutions donot have an algorithm to perform or interpret the test and thatpayment for the test may not be reimbursed by insurance providers.

PET/CTmay be a nice alternative to whole-bodyMRI because PET/CT has a superior sensitivity to standard bone radiographs, is fasterand more comfortable for the patient, and can be used in patientswith implanted pacemakers and defibrillators.73-75 We recommendthat all other patients with SMM be observed without therapy every3 to 6 months and encouraged to participate in clinical trials.Although the PETHEMA-GEM trial shows that a subset of thesepatients (those with both BMPCs . 10% and M protein . 30 g/L)could benefit from therapy, we do not recommend intervention atthis point until further confirmatory evidence emerges, though it isimportant that these data be shared with patients. We recommendthat our recommendations be considered by the IMWG to arrive atan international consensus.

Acknowledgments

This work was supported in part by the JABBS foundation, thePredolin Foundation, and the Robert A. Kyle Hematologic Malig-nancies Fund.

Authorship

Contribution: All authors contributed to the design, writing, andreview of the manuscript.

Conflict-of-interest disclosure: A.D. received research dollarsfrom Celgene, Millenium, Pfizer, and Janssen. K.S. received Celgenehonoraria, Millenium clinical trial funding, and consulting fees fromOnyx. R.F. has received a patent for the prognostication ofMMbasedon genetic categorization of the disease, and he has receivedconsulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS,Lilly, Onyx, Binding Site, Millennium, and AMGEN; he also hassponsored research from Cylene and Onyx. P.L.B. is an Onyxconsultant. M.A.G. received honoraria from Celgene, Millennium,Onyx, and Binding Site. M.Q.L. received research dollars fromCelgene. C.R. received research funding fromMillennium, Celgene,and Novartis. J.M. received research funding from Celgene, Onyx,and Sanofi. S.K.K. received clinical trial support from Celgene,Millennium, Onyx, Novartis, Cephalon/Teva Oncology, and Abbottand is a consultant (no personal reimbursement) for Millennium,Celgene, and Onyx. The remaining authors declare no competingfinancial interests.

Correspondence: Angela Dispenzieri, 200 First St SW, Rochester,MN 55905; e-mail: [email protected].

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online October 21, 2013 originally publisheddoi:10.1182/blood-2013-08-520890

2013 122: 4172-4181

Buadi, David Dingli, Suzanne R. Hayman, Nelson Leung, Yi Lin, Joseph Mikhael and Shaji K. KumarLacy, John A. Lust, Stephen J. Russell, Steven R. Zeldenrust, Craig Reeder, Vivek Roy, FrancisRafael 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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Smoldering multiple myeloma requiring treatment: time for a new