Evolving therapeutic paradigms for multiple myeloma: back to the future

451

Leukemia & Lymphoma, March 2013; 54(3): 451–463

© 2013 Informa UK, Ltd.

ISSN: 1042-8194 print / 1029-2403 online

DOI: 10.3109/10428194.2012.717277

Correspondence: Dr. Ola Landgren, Multiple Myeloma Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville

Pike, Bldg 10/Room 13N240, Bethesda, MD 20892, USA. Tel: � 1-301-496-0670. Fax: � 1-301-496-9956. E-mail: [email protected]

Received 29 May 2012 ; revised 9 July 2012 ; accepted 27 July 2012

REVIEW

Evolving therapeutic paradigms for multiple myeloma: back to the future

Benjamin M. Cherry , Neha Korde , Mary Kwok , Mark Roschewski & Ola Landgren

Multiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Introduction

Multiple myeloma (MM), a malignant disorder of bone mar-

row plasma cells, has existed in humans for millennia. Pale-

ontological evidence of MM in humans has been documented

in mummifi ed Egyptian remains dating back to 1500 bc [1]

(Figure 1). In the United States, MM is second only to non-

Hodgkin lymphoma as the most prevalent hematologic

malignancy [2], and has an annual incidence of 20 000 [3]. Th e

disease is characterized by clonal proliferation of bone marrow

plasma cells leading to microenvironmental disturbances and

high levels of circulating monoclonal-M-immunoglobulin

( “ M-protein ” ). Th e clinical manifestations of MM include hyper-

calcemia, renal dysfunction, anemia and bone lytic lesions.

MM consistently evolves from a precursor state (mono-

clonal gammopathy of undetermined signifi cance, MGUS;

and smoldering myeloma, smoldering MM) characterized

by the presence of abnormal plasma cells in the bone mar-

row and presence of an M-protein but without the aforemen-

tioned MM clinical manifestations [4]. Based on small patient

sample studies, the average annual risk of transformation to

MM from MGUS and smoldering MM is 1% and 10% per year,

respectively [5]. Unlike malignancies that can be defi nitively

treated when identifi ed in their earliest stages, e.g. malignant

melanoma, no proven therapy currently exists for patients

with MM precursor disease. Successive generations of induc-

tion therapies have prolonged both progression-free survival

(PFS) and overall survival (OS), but the need for maintenance

therapies – those that can be continuously given following

primary treatment response to suppress disease and further

improve survival – has remained a critical area of research in

this largely incurable disease.

Early approaches to treatment and the advent of extended dosing

Th e fi rst well-documented case of MM was reported as “ mol-

lities ossium ” by Samuel Solly in 1844, and in 1847 Henry

Bence Jones asserted the diagnostic signifi cance of the urinary

protein which now bears his name [6]. Th ere was no eff ective

therapy for MM, and the outlook was dismal, with a median

survival of 7 – 10 months from the time of diagnosis [7]. By the

1940s, strategies to treat MM included radioactive phospho-

rous, stilbamidine and other diamidines, nitrogen mustards,

urethane and radiotherapy ( “ roentgen-ray therapy ” ) [8].

Although radiotherapy showed some utility in decreasing

pain and eff ecting recalcifi cation in local disease [9], these

therapies were largely ineff ective and highly toxic [10].

Th e earliest successful specifi c agent for the treatment of

myeloma was sarcolysin, a phenylalanine mustard alkylating

agent synthesized for use as a chemotherapeutic by Bergel

and Stock in 1953 [11] (Figure 2). In 1956, Soviet scientists

Abstract

Multiple myeloma (MM) is an ancient disease, but until the

alkylating agent melphalan was found to have anti-myeloma

properties in the 1950s there was virtually no eff ective therapy. By

the late 1960s, extended dosing with melphalan and prednisone

tripled survival from diagnosis and became the standard of care

for newly diagnosed MM. “ Maintenance therapy ” to prolong

survival through sustained disease control following induction

chemotherapy was sought by 1970, but early strategies were

ineff ective and toxic. Subsequent applications of high-dose

therapy (HDT)/autologous stem cell transplant (ASCT) changed

the treatment paradigm for MM from extended dosing to an

intensive strategy designed to eradicate the malignant cells in

a single course of treatment. Although HDT-ASCT resulted in

prolonged duration of remission and improved survival, the

vast majority of patients still relapsed. Interferon (IFN) and

glucocorticoid maintenance therapies demonstrated marginal

improvements in outcomes but signifi cant adverse eff ects. Novel

agents introduced over the last decade have prolonged survival

when given for maintenance following HDT-ASCT, but have also

challenged the HDT-ASCT paradigm by achieving comparable

remission rates when used alone as extended frontline therapy.

This article reviews the evolution of therapeutic strategies for

MM and discusses future questions facing MM investigators.

Keywords: Multiple myeloma , maintenance , extended dosing ,

lenalidomide , thalidomide

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452 B. M. Cherry et al.

Blokhin et al . empirically administered sarcolysin to patients

with diverse solid and hematologic malignancies and found

that the drug possessed signifi cant anti-myeloma properties

[12]. Over the next decade, sarcolysin was largely replaced

in clinical use by its l -isomer melphalan [13]. An early

dosing strategy was to give bursts of moderate to high

doses (0.7 – 1.2 mg/kg over 4 days) of melphalan repeated at

6 – 8-week intervals [14,15]. Th is regimen tripled median

survival to more than 36 months from the time of diagno-

sis for the approximately 50% of patients who responded

to therapy, but was associated with an 18% mortality rate

in non-responders [14]. Subsequently, investigators dem-

onstrated that an extended dosing approach with low-dose

(up to 4 mg/day) daily melphalan achieved equal response

and survival with less treatment-related toxicity and a 4%

treatment-related mortality rate [7].

In 1969, Alexanian and colleagues reported the superiority

of extended dosing with melphalan plus the glucocorticoid

prednisone (MP) versus melphalan alone [16]. Th is study

randomized 183 patients with MM to 30 months of con-

tinuous therapy in one of four treatment groups: daily mel-

phalan, intermittent (every 4 – 6 weeks) melphalan, intermit-

tent melphalan plus alternate-day prednisone, or melphalan

plus prednisone given together at 4 – 6-week intervals. MP

prolonged median survival from initiation of therapy by 33%

versus the groups receiving melphalan alone. Most patients

receiving alternate-day prednisone developed Cushingoid

symptoms that were eff ectively managed with dose reduc-

tion, and other toxicities in the MP groups were comparable

to the melphalan-only groups. Subsequent studies confi rmed

the survival benefi t for MP versus melphalan alone [17], and

extended dosing with MP became the standard strategy to

induce remission in patients with MM.

A shift from extended dosing to maintenance

Despite the survival benefi t achieved with extended MP, 25%

of patients failed to respond to this therapy and all inevitably

Figure 1. Osteolysis of vertebral body recovered from the necropolis of Th ebes-West. Th e lesion revealed almost no osseous reaction, suggestive of plasmacytoma (multiple myeloma). Reprinted from Nerlich et al . [1], with permission.

Figure 2. Timeline of therapeutic advances in MM. MM, multiple myeloma; RRMM, relapse and/or refractory multiple myeloma.

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Evolving myeloma treatment paradigms 453

relapsed [16]. Th ere was a distinct need for further therapy to

prolong treatment response. Unlike salvage therapies given

at relapse, maintenance therapies are administered during

periods of remission or stable disease to prolong survival

through continuous disease suppression. Early maintenance

eff orts with conventional chemotherapeutics yielded signifi -

cant toxicity and no survival benefi t. Th e Southwest Oncology

Group (SWOG) randomized 96 patients who had responded

to 12 months of MP induction therapy to continued treat-

ment with MP, combination prednisone and carmustine, or

no treatment, but found no diff erences between duration of

remission or overall survival [18].

Interferon Th e interferon (IFN) cytokines were among the fi rst drugs

to show promise for MM maintenance therapy. Th ese mol-

ecules are soluble glycoproteins produced by human cells

that act by binding to receptors on target cells to induce

gene transcription, resulting in varied downstream eff ects

[19,20]. Th ey have been shown in vitro to aff ect tumor cell

survival and immune response through the Janus kinase-

signal transducer and activator of transcription (JAK-STAT)

and nuclear factor- κ B (NF- κ B) signaling pathways [21,22],

and act as potent inhibitors of the cell cycle, leading to an

accumulation of cells in the G0 phase [23].

IFNs have been used to treat both hematologic and non-

hematologic malignancies [24], and have been studied as

therapy for MM since 1979, when Mellstedt and colleagues

demonstrated a partial response to single agent IFN- α in four

chemotherapy resistant MM patients [25]. Th e fi rst random-

ized, controlled trial using high-dose IFN for single agent

induction therapy showed it to be inferior to melphalan/

prednisone and revealed signifi cant central nervous system

and gastrointestinal toxicities [26]. Subsequent studies of

IFN as a co-induction agent have yielded confl icting results

[27], and these agents are not routinely included in current

induction strategies.

In 1985, Mandelli et al . initiated a randomized trial of IFN

as maintenance therapy in MM and found that in patients

who had responded to conventional chemotherapy, IFN

maintenance signifi cantly prolonged treatment response (26

vs. 14 months, p � 0.0002) but did not result in extended OS

[28]. Th ree subsequent studies also found that IFN mainte-

nance extended the plateau phase – defi ned as 3 – 6 months

of clinical stability, stable M-protein levels regardless of the

percentage decrement of M-protein, and transfusion inde-

pendence [29] – following chemotherapy, but twice as many

found no benefi t to IFN maintenance versus observation

(Table I). None of these studies demonstrated a signifi cant

prolongation of OS.

By contrast, two large meta-analyses of randomized tri-

als detected a statistically signifi cant survival benefi t for

IFN maintenance therapy. Fritz et al . analyzed 13 trials of

IFN maintenance therapy versus observation and found a

PFS benefi t of 4.4 months ( p � 0.01) and an OS benefi t of 7

months ( p � 0.01) [30]. Th e Myeloma Trialists ’ Collaborative

Group performed a meta-analysis of individual patient data

from 12 trials of IFN maintenance, and at 3 years of follow-up

found superiority of IFN versus observation for PFS (33%

vs. 24%, p � 0.00001) and OS (53% vs. 49%, p � 0.01), with

a median survival benefi t of approximately 4 months [31].

Interpretation of these results is complicated by the fact that

many of the trials included in these analyses were published

only in abstract form, and some studies used IFN both as a

co-induction agent and in maintenance.

Th ese maintenance studies also confi rmed the signifi cant

adverse eff ects associated with IFN therapy, including a fl u-

like syndrome of fever, chills, tachycardia, malaise, myalgias

and headaches aff ecting nearly 100% of patients on their

fi rst exposure to IFN [32]. Other signifi cant toxicities of IFN

therapy include central nervous system (CNS) disturbances

such as depression and cognitive changes [33], cardiovascu-

lar eff ects including arrhythmias, especially in patients with

pre-existing cardiac disease [34], and abnormalities in liver

Table I. Trials evaluating interferon- α versus observation as maintenance therapy for multiple myeloma. Adapted from Khoo et al . [27].

Author, study Year n Impact on progression-free survival Impact on overall survival

Mandelli, Pulsoni, Italian group study

1990, 1998 101 IFN superior to observation in sustaining induction response, 24 months vs. 13 months ( p � 0.0016)

Trend toward OS benefi t in IFN arm at 9 years ’ follow-up, 50 vs. 39 months ( p � 0.07)

Salmon et al ., SWOG 1994 193 No statistically signifi cant diff erence in PFS No statistically signifi cant diff erence in OS

Westin et al ., Swedish and Italian group study

1994 125 IFN superior to observation in sustaining plateau phase, 13.9 months vs. 5.7 months ( p � 0.0001)

No statistically signifi cant diff erence in OS

Harousseau et al ., French study

1995 110 No statistically signifi cant diff erence in PFS No statistically signifi cant diff erence in OS

Joshua et al ., ALLG II 1997 113 No statistically signifi cant diff erence in PFS No statistically signifi cant diff erence in OS

Blade et al ., PETHEMA 1998 92 IFN superior to observation in sustaining plateau phase, 13 months vs. 7.7 months ( p � 0.042)


Drayson et al ., MRC 1998 284 No statistically signifi cant diff erence in PFS No statistically signifi cant diff erence in OS

Cunningham et al ., British study


Wada et al ., Japanese study


Schaar et al ., HOVON 2005 90 IFN superior to observation in sustaining plateau phase, 27.3 months vs. 20 months ( p � 0.04)


Barlogie et al ., US intergroup trial


IFN, interferon; PFS, progression-free survival; OS, overall survival.

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alone and found a PFS benefi t in the IFN plus prednisone

arm, 19 months vs. 9 months ( p � 0.008) [44]. No OS benefi t

was observed. In a subsequent study comparing single-agent

maintenance with dexamethasone versus IFN, Alexanian

et al . showed a similar duration of remission between the two

arms, but demonstrated that patients in the dexamethasone

maintenance arm were half as likely to respond to a steroid-

containing regimen at relapse versus patients in the IFN arm

[45]. Th e National Cancer Institute of Canada (NCIC) CTG

MY.7 study compared dexamethasone to observation and

found an increase in PFS of 2.8 years vs. 2.1 years ( p � 0.0002),

but again showed no OS benefi t.

Published in 2002, SWOG 9210 is the only random-

ized trial to demonstrate an OS benefi t with glucocorticoid

maintenance therapy for MM [46]. Th is trial randomized 125

patients who had responded to induction with vincristine,

doxorubicin, dexamethasone and prednisone (VAD-P) or

VAD-P plus quinine (VAD-P/Q) to receive either predni-

sone 50 mg or prednisone 10 mg on an alternate-day dosing

schedule until disease progression. At a median follow-up

of 53 months, both PFS and OS were found to be prolonged

in the 50 mg arm versus the 10 mg arm: 14 months vs.

5 months ( p � 0.003) and 37 months vs. 26 months ( p � 0.05),

respectively. Th e authors noted that while prednisone main-

tenance was generally well-tolerated, 23% of patients in the

study experienced grade 3 adverse events or higher, includ-

ing infection, edema, weight gain, change in mood, muscle

weakness and myalgia, and Cushingoid appearance. No

subsequent randomized study has been conducted to

confi rm the survival benefi t of single-agent glucocorticoid

maintenance reported in SWOG 9210.

A paradigm shift: the age of intensive therapy

With the above-mentioned maintenance therapies show-

ing only marginal improvements on conventional therapies,

clinicians sought treatment options that could produce

radical tumor debulking with the hope that this outcome

would lead to longer remissions or cure. High-dose therapy

(HDT) for MM was fi rst explored in 1981, when physicians

at Royal Marsden Hospital in the United Kingdom used high

doses (100 – 140 mg/m 2 ) of intravenous melphalan in eight

patients with MM, half of whom had received previous che-

motherapy [47]. Four of these patients, including one who

function tests [35]. Hematologic side eff ects of anemia, leu-

kopenia and thrombocytopenia appear to be dose-related

and are most common in patients receiving � 10 MU per

day [36], but treatment cessation rates of 20% due to IFN-

associated toxicity have been reported even at doses as low

as 3 MU, three times per week [37]. Th e severity of toxic side

eff ects is linked in part to patient age [24], and studies of older

patients with MM have reported toxicity-related cessation of

treatment in as many as 37% of patients receiving IFN [38].

Glucocorticoids Glucocorticoids were discovered to inhibit cells of lympho-

cytic origin in the 1940s [39], and have since become crucial

agents for the treatment of hematological malignancies,

including leukemias, lymphomas and MM [39 – 41]. Given

prednisone ’ s success in extending survival when used as part

of initial therapy, this class was among the fi rst to be explored

for maintenance therapy in MM, along with IFNs. As mainte-

nance agents, they represented an appealing alternative to

IFN therapy due to their more favorable toxicity profi le.

Th ese adrenocortical steroid hormones modulate

immune processes, metabolism, cell growth and prolifera-

tion, development and reproduction; they have been used

for therapeutic immunosuppression, to treat infl ammation

and to induce cytotoxicity [42]. Th e exact mechanism by

which these agents exert their anti-MM eff ect is unknown,

but in vitro studies have shown that the cytolytic eff ects of

glucocorticoids are mediated via the glucocorticoid receptor,

a ligand-dependent transcription factor that is ubiquitously

expressed in human cells [43]. Th e glucocorticoid receptor

resides in the cytoplasm as part of an oligomeric complex,

and upon ligand binding translocates to the nucleus where it

aff ects gene transcription through interaction with the basal

transcription machinery and other transcription factors

including activator protein 1 (AP-1) and NF- κ B [43].

Although glucocorticoids are an integral component of

induction regimens for MM, results from studies evaluat-

ing their use as maintenance agents have been generally

disappointing (Table II). Th eir long-term use is limited by

the development of adrenal suppression that may cause

secondary adrenal insuffi ciency; abrupt withdrawal in this

context leads to acute adrenal crisis. Th e earliest published

randomized trial of glucocorticoid maintenance therapy for

MM, SWOG 9028, compared IFN plus prednisone to IFN

Table II. Trials evaluating glucocorticoids as maintenance therapy for multiple myeloma.

Author, study Year n Comparison Impact on progression-free survival Impact on overall survival

Salmon et al ., SWOG 9028

1998 89 IFN � prednisone, IFN IFN � prednisone superior to IFN alone, 19 months vs. 9 months ( p � 0.008)


Alexanian et al . 2000 84 Dexamesthasone, IFN Similar duration to fi rst remission between study arms; dexamethasone inferior to IFN in duration to melphalan-resistant relapse, 19 months vs. 32 months ( p � 0.01)


Berenson et al ., SWOG 9210

2001 125 Prednisone 50 mg, prednisone 10 mg

Prednisone 50 mg superior to prednisone 10 mg, 14 months vs. 5 months ( p � 0.003)

Prednisone 50 mg superior to prednisone 10 mg, 37 months vs. 26 months, p � 0.05

Shustik et al ., NCIC CTG MY.7

2006 292 Dexamethasone, observation

Dexamethasone superior to observation, 2.8 years vs. 2.1 years ( p � 0.0002)


IFN, interferon; PFS, progression-free survival; OS, overall survival.

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had received previous treatment, achieved complete remis-

sion (CR) defi ned as disappearance of detectable M-protein

and absence of abnormal plasma cells within the bone mar-

row. Subsequent studies by the same group confi rmed a

dose – response eff ect of high-dose therapy, but also observed

profound myelosuppression resulting from this treatment:

approximately 20% of patients died within 2 months of HDT,

mainly due to sepsis or hemorrhage [48].

Research on disseminated skin cancer (malignant mela-

noma) had shown as early as 1959 that autologous bone

marrow transplant could support patient survival following

high systemic doses of cytotoxic agents including nitrogen

mustards [49] and melphalan [50]. Building on these fi nd-

ings, Barlogie and colleagues carried out the fi rst phase II

trials of HDT followed by autologous stem cell transplant

(ASCT) for MM in patients with relapsed and refractory dis-

ease [51,52]. Without bone marrow (BM) support, Barlogie

et al . reported 31% mortality associated with melphalan HDT

[52], but demonstrated that the HDT-ASCT technique could

induce a durable CR in a subset of patients [53]. Further ran-

domized trials demonstrated the superiority of HDT-ASCT

therapy over conventional chemotherapeutic approaches

in terms of both PFS and OS [54,55], and in the early 1990s

HDT-ASCT was adopted as the standard of care for younger

patients with newly diagnosed disease.

Th e success of intensive induction with HDT-ASCT led

investigators to explore variations on this therapy. Early

approaches sought to extend the dose – response eff ect of mel-

phalan with dual sequential (tandem) transplants, and early

tandem ASCT trials confi rmed improvements in response

and survival outcomes [56,57]. Transplant with allogeneic

hematopoietic stem cells after myeloablative conditioning

was developed with the goal to establish a graft-versus-

myeloma eff ect, but early experiences with this therapy

revealed frequent graft-versus-host disease and transplant-

related mortality approaching 50% [58]. Studies of reduced-

intensity conditioning (non-myeloablative) matched sibling

donor allogeneic transplant following ASCT have reported

superior survival and decreased relapse versus single ASCT

[59], but a recent multicenter trial including 710 patients at

37 transplant centers across the United States found that

non-myeloablative allogeneic stem cell transplant follow-

ing ASCT was not superior to tandem ASCT for patients with

standard-risk myeloma [60].

Despite signifi cant improvements in overall survival

achieved by intensive induction with HDT-ASCT relative

to conventional chemotherapeutics, this approach did not

lead to a defi nitive cure. Attal and colleagues reported that

60 months after diagnosis, 61% of patients who had under-

gone HDT-ASCT had disease progression [54]. Moreover,

they found no signifi cant increase in median survival follow-

ing relapse versus patients who had received conventional

chemotherapy. In order to capitalize on the HDT-ASCT

approach and improve survival, there was a clear need to

inhibit proliferation and induce apoptosis of residual malig-

nant cells; maintenance therapy was the logical choice for

this [61]. Th e treatment paradigm for MM had come full

circle, and the search for an eff ective maintenance therapy

began anew.

Novel agents and the return to maintenance

Thalidomide A major advance in MM maintenance therapy arrived with

the introduction of immunomodulatory drugs thalidomide

and lenalidomide and the proteasome inhibitor bortezomib.

Th e best studied of these is thalidomide, which was syn-

thesized in Germany in 1954 for use as a sedative and anti-

emetic in early pregnancy [62]. Th e drug gained considerable

notoriety, and was banned in the early 1960s when it was

found to cause severe congenital malformations. Interest in

thalidomide was renewed in 1965 when the drug proved effi -

cacious for treating the cutaneous infl ammatory lesions of

erythema nodosum leprosum [62], and subsequent research

demonstrated that thalidomide possessed considerable anti-

angiogenic and immunomodulatory properties [63,64]. In

1999, Singhal and colleagues reported a signifi cant response

to thalidomide in patients with relapsed and refractory MM

[65], and in 2002 Rajkumar et al . demonstrated the effi cacy

of thalidomide and dexamethasone as front-line therapy for

newly diagnosed MM [66]. In 2006, thalidomide received

Food and Drug Administration (FDA) approval for primary

treatment of MM in combination with dexamethasone [67],

and the drug is currently employed in induction and main-

tenance regimens for both transplant-eligible and -ineligible

patients with MM (Tables III and IV).

Th e fi rst study of thalidomide maintenance after HDT-

ASCT was the French IFM-99, which randomized patients

after tandem transplant to maintenance with thalidomide – -

pamidronate, pamidronate alone, or no therapy [61]. Th is

study reported improvements in both event-free survival

(EFS) and OS in the thalidomide – pamidronate arm, but the

benefi t was limited to patients who had not yet achieved

a very good partial response (VGPR) following induc-

tion therapy. Notably, thalidomide ’ s benefi cial eff ect was

evident across disease parameters including patient age,

β 2 -microglobulin level, lactate dehydrogenase (LDH) level

and Durie – Salmon stage, although patients with deletion of

chromosome 13 did not benefi t. Another important fi nding

of this study was the consolidation role of thalidomide to

improve depth of response: 16 of the 200 patients random-

ized to receive thalidomide – pamidronate maintenance who

had achieved a partial response (PR) or less with induction

therapy improved to CR or VGPR following randomization.

Subsequent trials of thalidomide maintenance following

HDT-ASCT confi rmed the consolidation role of thalidomide

in this setting [68 – 70]. A trend toward improved OS across tri-

als was also seen, and although this trend reached statistical

signifi cance in only three [61,70,71], a recent meta-analysis

of fi ve of the six studies confi rmed a signifi cant improve-

ment in both PFS (hazard ratio [HR] 0.64, 95% confi dence

interval [CI] 0.56 – 0.73, p � 0.001) and in OS (HR 0.70, 95% CI

0.55 – 0.89, p � 0.004) [72].

Th e role of thalidomide maintenance for patients con-

sidered ineligible for HDT-ASCT is less clear. Five random-

ized trials have evaluated thalidomide maintenance after

induction with standard therapies [73 – 76]. Four of these

assigned patients to MP induction followed by observation

or MP plus thalidomide induction followed by thalidomide

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Total Th erapy 2 study at 30 months [71], increasing to nearly

80% at 80 months [80].

To further evaluate these toxicities, Stewart and col-

leagues studied maintenance therapy with thalidomide

(either 200 mg or 400 mg per day) plus prednisone (50 mg

on alternate days) following HDT-ASCT, with a primary

outcome measure of discontinuation or dose reduction due

to toxicity within 6 months of beginning maintenance [81].

Th e investigators defi ned “ a tolerable maintenance therapy ”

as no dose reduction or discontinuation due to toxicity in at

least 65% of patients; the 200 mg arm met and the 400 mg

arm failed to meet this defi nition, with overall rates of dose

reduction or discontinuation of 31% and 64%, respectively. In

2010, this group included specifi c quality of life endpoints in

their evaluation of thalidomide and prednisone (TP) main-

tenance following HDT-ASCT [82]. Th ey reported a non-

signifi cant increase in survival for TP maintenance compared

to observation alone (not reached [NR] vs. 5 years, p � 0.18).

Although the TP group experienced superior PFS versus

observation (28 months vs. 17 months, p � 0.0001), there was

also a signifi cantly higher incidence of serious (grade 3 and 4)

toxicities (grade 3: 92% vs. 49%; grade 4: 16% vs. 7%), as well

maintenance (MPT-T), and showed that MPT-T was associ-

ated with signifi cant improvement in overall response rates.

Th e Dutch – Belgian Hemato-Oncology Cooperative Group

(HOVON) study reported a statistically signifi cant survival

benefi t for MPT-T versus MP, 40 months vs. 31 months

( p � 0.05) [76]. Although encouraging, these results are at

odds with similar studies, which found no survival benefi t to

MPT-T versus MP [73,75,77]. Furthermore, the inclusion of

thalidomide in induction makes it impossible to evaluate the

role of thalidomide maintenance in the HOVON observed

survival increase.

Th e benefi t of thalidomide also comes at the cost of

signifi cant toxicities, which manifest in both a dose- and

time-dependent manner [78]. Important side eff ects of

thalidomide therapy include somnolence, constipation,

peripheral neuropathy and venous thromboembolism [79].

Th e incidence of these toxicities varies between studies,

but leads to treatment discontinuation in an unaccept-

ably large number of patients. A 30% discontinuation rate

was observed in the Australian transplant study [70], 58%

discontinuation or dose reduction in the HOVON-50 trans-

plant study [69] and 43% discontinuation in the Arkansas

Table IV. Trials evaluating thalidomide as maintenance therapy following conventional chemotherapy induction for MM.

Author, study Year n Induction and maintenance

regimensImpact on progression-free

survival Impact on overall survival

Beksac, Turkish myeloma study group

2011 115 MPT (100/day), MP MPT vs. MP, 21 vs. 14 months ( p � 0.342)

MPT vs. MP, 26 vs. 28 months ( p � 0.655)

Palumbo, GIMEMA 2006 331 MPT (100/day), MP MPT superior to MP, 21.8 vs. 14.5 months ( p � 0.001)

No diff erence in MPT vs. MP, 45.0 vs. 47.6 months ( p � 0.79)

Waage, Nordic myeloma study group

2010 357 MPT (200/400/200), MP No diff erence in MPT vs. MP, 15 vs. 14 months ( p � 0.84)

No diff erence in MPT vs. MP, 29 vs. 32 months ( p � 0.16)

Wijermans, HOVON 49 2008 333 MPT (200/day), MP MPT superior to MP, 13 vs. 9 months ( p � 0 .001)

MPT superior to MP, 40 vs. 31 months ( p � 0.05)

Ludwig, CEMSG 2010 128 TD or MP induction, then either: IFN 3 MU TIW � thal 200 mg/day, IFN 3 MU TIW

Superiority of IFN � thal vs. IFN alone, 27.7 vs. 13.2 months ( p � 0.0068)

No diff erence in IFN � thal vs. IFN alone, 52.6 vs. 51.4 months ( p � 0.81)

MM, multiple myeloma; IFN, interferon; PFS, progression-free survival; OS, overall survival; MPT, melphalan, prednisone and thalidomide; MP, melphalan and prednisone; TD, thalidomide and dexamethasone; thal, thalidomide.

Table III. Trials evaluating thalidomide as maintenance therapy following HDT-ASCT for MM.

Author, study Year n Maintenance regimen Impact on progression-free survival Impact on overall survival

Attal, IFM-99 2006 597 Pamidronate � thalidomide, pamidronate, no maintenance

Pamidronate � thalidomide superior to pamidronate alone and no maintenance for 3-year EFS, 52% vs. 37% and 36%, respectively ( p � 0.009)

Pamidronate � thalidomide superior to pamidronate alone and no maintenance for 4-year OS, 87% vs. 74% and 77%, respectively ( p � 0.04)

Morgan, MRC IX

2011 818 Th alidomide, observation alone Th alidomide superior to observation for PFS among all patients, 23 vs. 15 months ( p � 0.001); no PFS diff erence for patients with adverse cytogenetics

Th alidomide associated with a worse outcome for patients with adverse cytogenetic profi les ( p � 0.009)

Spencer, ALLG MM6

2009 243 Th alidomide � prednisone, prednisone

Superiority of thalidomide vs. prednisone for 3-year PFS, 42% vs. 23% ( p � 0.001)

Superiority of thalidomide vs. prednisone for 3-year OS, 86% vs. 75% ( p � 0.004)

Barlogie, Total Th erapy 2

2006 668 All received induction, tandem ASCT, chemo consolidation and IFN maintenance; comparison of thalidomide in all phases of treatment vs. no thalidomide

Superiority of thalidomide vs. no-thalidomide for 5-year PFS, 57% vs. 44% ( p � 0.0005)

Superiority of thalidomide vs. no-thalidomide for 5-year OS, 68% vs. 65% ( p � 0.04)

Lokhorst, HOVON 50

2010 536 IFN (after VAD � ASCT), thalidomide (after TAD � ASCT)

Superiority of thalidomide vs. IFN, 34 vs. 25 months ( p � 0.001)

No diff erence in thalidomide vs. IFN, 73 vs. 60 months ( p � 0.77)

Stewart, NCIC CTG MY.10

2010 332 Th alidomide 200/day � prednisone 50/2 days, observation alone

Superiority of thalidomide vs. observation, 28 vs. 17 months ( p � 0.0001)

No diff erence in thalidomide vs. observation for 4-year OS, 68% vs. 60% ( p � 0.18)

HDT-ASCT, high-dose therapy – autologous stem cell transplant; MM, multiple myeloma; IFN, interferon; PFS, progression-free survival; OS, overall survival; VAD, vincristine, doxorubicin and dexamethasone; TAD, thalidomide, doxorubicin and dexamethasone.

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bortezomib and thalidomide salvage did not impact survival

in patients who had received MPT induction [77], and Lok-

horst et al . reported reduced survival after relapse in patients

who had received thalidomide, doxorubicin and dexametha-

sone (TAD) � thalidomide maintenance versus VAD � IFN- α

maintenance (20 months vs. 31 months, p � 0.009) [87].

Lenalidomide Th e limiting nature of thalidomide ’ s side eff ects prompted

the search for an agent with similar or improved effi cacy but

less toxicity. Th is led to the development of maintenance

strategies employing lenalidomide (Revlimid ® ; Celgene)

[88]. Lenalidomide is a thalidomide analog that possesses

diverse tumoricidal and immunomodulatory properties,

and received FDA approval after two parallel studies dem-

onstrated response rates of 61% for lenalidomide plus dex-

amethasone versus 22% for dexamethasone alone in patients

with relapsed/refractory MM [89].

Lenalidomide exerts its tumoricidal eff ects by decreasing

production of cytokines and growth factors leading to disrup-

tion of stromal support, inducing tumor suppressor genes,

and activating caspases triggering tumor cell apoptosis. Like

thalidomide, lenalidomide has shown a signifi cant consoli-

dation eff ect when used following HDT-ASCT [90,91]. Its abil-

ity to provide sustained disease control is believed to be due

to enhancement of antigen-specifi c CD8 � T-cell cytolysis,

up-regulation of Fc- γ receptor signaling leading to increased

natural killer (NK)-cell activity, and activation of NKT cells

leading to greater secretion of IFN- γ , which is associated with

greater NKT cell anti-tumor activity [92]. Lopez-Girona et al .

showed that lenalidomide decreased both in vitro and in

vivo levels of interferon regulatory factor-4 (IRF4) [93], which

have been associated with a poor prognosis in MM [94].

Additionally, several small studies suggest that lenalidomide

signifi cantly increases circulating immune cell populations

[95,96], but the relationship between these observations and

a clinical benefi t is still under investigation.

Recently, three large phase III trials comparing lenali-

domide maintenance to placebo found PFS benefi ts for

both ASCT-eligible [97,98] and -ineligible [99] patients

(Table V). Palumbo and colleagues studied 459 newly diag-

nosed patients with MM aged 65 years or older and not eli-

gible for ASCT [99]. Th e patients were randomized into three

groups that received MP and lenalidomide induction followed

by lenalidomide maintenance (MPR-R), MPR induction

as more venous thromboembolic events in the absence of

prophylaxis (7% vs. 0%). Patients receiving TP showed clear

trends toward worse quality of life (QoL) on various mea-

sures including physical ( p � 0.07), role ( p � 0.08), cognitive

( p � 0.01) and global ( p � 0.06) domains. Patients receiving

TP also experienced signifi cantly worse symptoms includ-

ing dyspnea ( p � 0.0007), constipation ( p � 0.0001), thirst

( p � 0.003), leg swelling ( p � 0.03), numbness ( p � 0.02), dry

mouth ( p � 0.0001) and balance problems ( p � 0.0001). All

QoL measures were worse in the TP group with the exception

of appetite and sleep. Th is decreased quality of life without a

clear survival benefi t should give clinicians cause to consider

the true cost of PFS.

Th e signifi cant side eff ects of prolonged thalidomide

administration may be attenuated by dose reduction and

time-limited therapeutic regimens [70,83], but the largest trial

of thalidomide maintenance therapy has not shown a survival

benefi t with low-dose (100 mg/day) therapy after a median

follow-up of 38 months from randomization [84]. Moreover,

there are data to suggest that thalidomide maintenance is

ineff ective and potentially harmful in patients with higher-

risk disease associated with cytogenetic abnormalities (CA).

Th e British Medical Reesearch Council (MRC) IX study eval-

uated 818 patients randomized to thalidomide maintenance

or observation after an intensive or non-intensive induction

regimen [84]. Th is study found no signifi cant PFS benefi t in

patients with CA detected by interphase fl uorescence in situ

hybridization (FISH); in fact these patients had worse OS

relative to standard-risk patients when receiving thalido-

mide maintenance therapy ( p � 0.009). Similar results were

reported by Stewart et al . in a study including 332 patients

[82]. In a study of elderly patients randomized to thalidomide – -

interferon maintenance or interferon maintenance alone fol-

lowing MP or thalidomide – dexamethasone (TD) induction,

patients with CA by FISH had a median overall survival of

39.6 months vs. 72.3 months for patients with standard-risk

disease (HR 1.94, CI 0.91 – 4.13, p � 0.082) [85]. In patients

with CA detected by gene expression profi ling, however, the

Arkansas study showed thalidomide maintenance to be an

independent favorable prognostic variable versus control

[71], and long-term follow-up showed increased survival in

the thalidomide arm among all patients [86]. Finally, survival

after relapse tends to be shorter in patients receiving tha-

lidomide maintenance when those patients have previously

received thalidomide induction. Palumbo et al . found that

Table V. Trials evaluating lenalidomide as maintenance therapy for multiple myeloma.

Author, study Year n Comparison Impact on TTP/PFS Impact on overall survival

Attal et al ., IFM 2005-02

2012 614 Lenalidomide, placebo

Lenalidomide showed longer PFS vs. placebo, 41 months vs. 23 months, HR 0.5 ( p � 0.001)


McCarthy et al ., CALGB 100104

2012 460 Lenalidomide, placebo

Lenalidomide showed TTP benefi t vs. placebo, 46 months vs. 27 months ( p � 0.001)

Lenalidomide showed OS benefi t vs. placebo, at 34 months of follow-up, 85% vs. 77% ( p � 0.03)

Palumbo et al ., MM-015

2012 459 MPR-R, MPR-placebo, MP-placebo

MPR-R superior to MPR-p and MP-p for PFS, 31 months vs. 14 months vs. 13 months, HR 0.398 ( p � 0.0000001 for MPR-R vs. MP-p)


TTP, time to progression; PFS, progression-free survival; OS, overall survival; MP, melphalan and prednisone; MPR-R, MP and lenalidomide induction followed by lenalidomide maintenance; HR, hazard ratio; MP-p, MP induction with placebo maintenance; MPR-p, MPR induction with placebo maintenance.

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activity. In 1999, Adams and colleagues reported that bort-

ezomib (then known as PS-341) was an eff ective inhibitor

of the proteasome, a novel biochemical target [102]. Pro-

teasomes are enzyme complexes responsible for the degra-

dation and clearance of misfolded, unfolded and cytotoxic

intracellular proteins, including mediators of cell-cycle pro-

gression and apoptosis [103]. Bortezomib blocks the tumor

necrosis α (TNF- α )-induced up-regulation of NF- κ B, result-

ing in decreased binding of MM cells to bone marrow stem

cells (BMSCs) [104], and reversibly inhibits the chymotryptic

activity of the proteasome 20S subunit, leading to MM cell

apoptosis [105]. Th is activity is observed even in cell lines

resistant to conventional anti-MM therapies [106].

Bortezomib received FDA approval in 2003 [107], after

showing signifi cant activity in relapsed and refractory MM

[108]. Studies of bortezomib maintenance have shown it

to improve response rate and prolong survival (Table VI).

Mateos and colleagues compared MP to bortezomib in com-

bination with MP (VMP) for primary induction in elderly

patients with myeloma [109]. VMP demonstrated an 89%

induction response, including 32% immunofi xation-negative

CRs, in contrast to a historical response to MP induction of

42% [110]. At 16 months of follow-up, patients in the VMP

arm experienced superior PFS versus MP alone (91% vs.

66%, p � 0.002), as well as increased survival (90% vs. 62%,

p � 0.001). Subsequent studies confi rmed this survival ben-

efi t [111], and showed increased activity of bortezomib com-

pared to dexamethasone when used as a single agent [112].

Th e Spanish PETHEMA (Programa de Estudio y

Tratamiento de las Hemopat í as Malignas) trial randomized

260 patients to bortezomib maintenance in combination

with prednisone (VP) or thalidomide (VT) after randomiza-

tion to induction with VTP or VMP [113]. Th e trial found

similar proportions of patients achieving CR after induction

with VTP or VMP (28% vs. 20%, p � 0.2), and showed that

maintenance therapy with bortezomib increased the overall

CR rate to 42%. A subset of patients developed signifi cant

peripheral neuropathy following induction (7% VTP; 9%

VMP) and maintenance (2% VP; 7% VT).

with placebo maintenance, or MP induction with placebo

maintenance. Patients who received MPR-R experienced a

longer median PFS than patients in the MPR and MP arms,

and this benefi t persisted when the arms were compared

across patient characteristics including age, International

Staging System (ISS) disease stage, renal function, level of β 2 -

microglobulin and Karnofsky performance score. Th is study

is still in follow-up. At the American Society of Hematology

meeting in December 2011, the group reported a trend toward

a survival benefi t in the lenalidomide maintenance arm for

patients aged 65 – 75 years, with a 4-year OS of 69% vs. 58% for

the non-lenalidomide arm (HR 0.71, p � 0.133). In the most

recent analysis including all patients (February 2012), no OS

benefi t was observed for lenalidomide maintenance [99].

Attal et al . enrolled 614 patients with non-progressive MM

within 6 months of fi rst-line HDT-ASCT [98]. All patients were

given lenalidomide consolidation therapy following ASCT,

and then randomized to lenalidomide or placebo mainte-

nance. Th is study found that patients randomized to lenali-

domide maintenance experienced signifi cantly longer PFS of

41 months vs. 21 months with placebo (HR 0.5, p � 0.001), but

did not detect any statistically signifi cant survival benefi t after

45 months from randomization. McCarthy et al . randomized

patients with stable disease or better following HDT-ASCT

to maintenance therapy with lenalidomide or placebo [97].

Patients receiving lenalidomide experienced a signifi cant

decrease in the risk of disease progression with an extended

time to progression (TTP) when compared to placebo, 46

months vs. 27 months ( p � 0.001). Th e authors reported that

at 34 months of follow-up, 85% of patients in the lenalidomide

arm were alive versus 77% in the placebo arm ( p � 0.03). Th is

is the fi rst randomized, controlled trial for lenalidomide

maintenance to show a signifi cant survival benefi t.

Notably, all three of these studies reported more frequent

hematologic and non-hematologic malignancies in the groups

receiving lenalidomide at a rate of 7 – 8% [97,99]. Th e excess

of myeloid tumors and myelodysplastic diseases seems most

pronounced. Given that the Cancer and Leukemia Group B

(CALGB) study has reported a survival benefi t with lenalido-

mide maintenance, the signifi cance of these fi ndings is not

entirely clear. Th e FDA has encouraged physicians to weigh

the benefi ts of lenalidomide therapy against the risk of second

primary malignancies, and to continue to monitor patients for

this risk [73]. At present, it seems that the benefi ts do outweigh

the risks: the increased risk of death without treatment is sub-

stantially higher than the risk of death from a second malig-

nancy. A recent evaluation of 33 229 patients diagnosed with

MM and treated in the United States between 1973 and 2008

showed that the risk of second malignancies following MM was

substantially lower than the risk of dying from all other causes

(Figure 3) [100]. Until we have a better understanding of the

synergy of host-, treatment- and tumor-related factors, physi-

cians should address these questions with their patients and

discuss the risks and benefi ts of their planned treatment [101].

Bortezomib Developed in parallel with the novel immunomodulatory

agents was bortezomib (Velcade; Millenium Pharmaceu-

ticals), a fi rst-in-class agent with signifi cant antineoplastic

Figure 3. Cumulative incidence of developing a second cancer and cumulative probability of death because of competing causes, after multiple myeloma. Data based on 33 229 patients who received a diagnosis of multiple myeloma between 1973 and 2008 in the United States, maintained by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Reprinted from Landgren et al . [100], with permission.

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Th ough a cure remains elusive, our success in achieving

long-term disease suppression through continuous therapy

is transforming MM into a chronic disease. As we seek to

develop optimal strategies for the management of this dis-

ease, we must consider multiple complicated questions.

One prominent uncertainty is what role aggressive treat-

ment should play in the initial therapy of MM. While upfront

HDT-ASCT has led to signifi cant improvements in disease

response and PFS, it has shown no impact on OS when com-

pared to a stepwise treatment approach [116]. Th e results of

recent trials indicate that even by combining most available

chemotherapies in combination with novel drugs, only a

small number of patients with MM experience remissions

consistent with a cure [117].

An appealing alternative to using most drugs in most

patients is to develop agents that target the specifi c biology of

MM. At this time, several rationally designed small molecules

and antibodies against defi ned targets are being evaluated in

clinical trials for MM. Given current therapies, however, the

question remains: would patients who respond well to HDT-

ASCT as upfront therapy achieve similar survival if given

substantially less intensive and less toxic initial therapy with

newer agents alone? No randomized scientifi c data are yet

available to answer this critical question; however, newer

agents are demonstrating considerable effi cacy (responses

and PFS) when used upfront in the absence of HDT-ASCT

[74,111,118,119]. Proponents of both intensive and conserva-

tive approaches agree that there is a pressing need for better

risk-adapted treatment algorithms [120], which could guide

the choice of initial therapy based on individual patient char-

acteristics and minimize avoidable toxicities.

Th e question of toxicity in MM therapy is not a trivial one,

as both historical and recent experiences have shown. As

MM evolves to a chronic disease model, we should be par-

ticularly attentive to the recognized side eff ects of extended

therapy (Table VII) and to those that may emerge upon fur-

ther investigation. Relatively few studies of MM therapy have

included specifi c quality of life endpoints, and we believe

that future studies need to include such measures in parallel

with measures of clinical eff ect and survival outcomes. Cost

of therapy, too, will be an important issue in the future as we

consider indefi nite administration of maintenance agents.

For example, the estimated cost for 1 year of lenalidomide

therapy is approximately $ 160 000, and this number does not

include the cost of laboratory monitoring, physician visits or

management of treatment side eff ects [121].

Palumbo et al . randomized 511 patients to receive either

VMPT induction followed by continuous VT maintenance

(VMPT-VT) or VMP induction with no maintenance [114].

Th is study reported greater PFS at 3 years for VMPT-VT versus

VMP (56% vs. 41%, p � 0.008), even though a greater propor-

tion of patients receiving VMPT-VT had discontinued therapy

(72% vs. 60%, p � 0.007). Th e CR rate was signifi cantly higher

in the VMPT-VT arm (38% vs. 24%, p � 0.001), but survival at

3 years did not diff er signifi cantly between the study groups

(89% vs. 87%, p � 0.77).

Th e joint HOVON-65/German Speaking Myeloma Multi-

center Group (GMMG)-HD4 trial compared bortezomib to

conventional chemotherapy for induction in newly diagnosed

patients with MM [115]. Patients then underwent single or

double ASCT and were randomized to maintenance with

bortezomib or thalidomide. After a median follow-up of 40

months, the bortezomib arm showed a superior rate of VGPR

or better (75% vs. 61%), PFS (HR 0.81, p � 0.047 and p � 0.056

when adjusted for ISS stage) and OS (HR 0.74, p � 0.048).

Signifi cantly fewer patients discontinued bortezomib main-

tenance versus thalidomide due to toxicity (9% vs. 31%),

although rates of progression were similar (29% vs. 31%).

Summary and future directions

Strategies to achieve and maintain remission in MM have

continually evolved since the disease was described in the

mid-19th century. Th e last 50 years have witnessed substan-

tial advances in MM therapy as well as distinct changes in the

prevailing treatment paradigms for this currently incurable

disease. Early strategies sought to prolong survival through

control of post-response residual disease with extended

dosing of standard chemotherapeutics and with steroid

and interferon maintenance therapies. Th ese approaches

showed little to no benefi t in the face of undeniable side

eff ects and were not widely adopted. Th e introduction of

HDT-ASCT represented an aggressive shift in the intensity of

treatment for MM toward a curative approach, but this strat-

egy failed to induce durable remissions in the overwhelming

majority of patients. More recently introduced drugs such as

thalidomide, lenalidomide and bortezomib have revived the

prospect of eff ective long-term maintenance when given in

an extended dosing fashion alongside conventional chemo-

therapeutics and HDT-ASCT. Th is union of the “ cure ” and

“ control ” approaches represents our current best off ering for

patients with MM.

Table VI. Trials evaluating bortezomib as maintenance therapy for multiple myeloma.

Author, study Year n Maintenance regimen Findings

Mateos, PETHEMA

2010 260 VP (after VMP or VTP), VT (after VMP or VTP)

Consolidation role of bortezomib seen in both VP and VT maintenance, 39% and 44% achieved CR, respectively

Palumbo, GIMEMA

2010 511 VMPT induction, VT, observation alone

Superiority of VMPT-VT vs. VMPT-observation for CR rate, 38% vs. 24% ( p � 0.001), superiority of VMPT-VT vs. VMPT-observation for 3-year PFS, 56% vs. 41% ( p � 0.008), no diff erence in 3-year OS for VMPT-VT vs. VMPT-observation, 89% vs. 87% ( p � 0.77)

Sonneveld, HOVON-65/GMMG-HD4

2010 827 Induction � single or double ASCT, thalidomide 50 mg/day, bortezomib 1.3 mg/m 2 2 � /week

Superiority of bortezomib vs. thalidomide for 3-year PFS, 46% vs. 42% ( p � 0.047), superiority of bortezomib vs. thalidomide for 3-year OS, HR 0.74 (p � 0.048)

VP, bortezomib and prednisone; VT, bortezomib and thalidomide; VMP, bortezomib, melphalan and prednisone; VTP, bortezomib, thalidomide and prednisone; ASCT, autologous stem cell transplant; CR, complete remission; PFS, progression-free survival; OS, overall survival; HR, hazard ratio.

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A further important need is for better measures to monitor

treatment response and disease status. Rather than treating

all patients with a fi xed number of chemotherapy cycles and

relying on endpoints such as CR defi ned by elimination of

the M-spike, we anticipate that emerging tests will combine

both high sensitivity and specifi city (through molecular and

functional imaging-based methods) to rule out evidence of

minimal residual disease (MRD). If used in combination with

highly eff ective and less toxic drugs, these MRD tests may

help to determine the need for therapy and type of therapy

on an individual basis to maximize treatment effi cacy and

minimize toxicity.

In closing, the treatment paradigm for MM has shifted

back toward maintenance but continues to evolve. An

emerging and important area of exploration is the develop-

ment of treatment strategies for patients with lower disease

burden ( “ early myeloma ” ). Currently, a few clinical trials

are evaluating treatment for high-risk smoldering MM and

are showing signs of success in delaying progression to MM.

Defi nitive data are not yet available, and no drugs have been

approved for the treatment of smoldering MM. At present, all

treatment studies for high-risk smoldering MM have been

built on the platform of “ chronic disease control, ” e.g. lenali-

domide and dexamethasone for a fi xed number of cycles, fol-

lowed by a lower dose of lenalidomide maintenance therapy

[122]. With increased access to eff ective but less toxic drugs

and full integration of careful monitoring (including molec-

ular and imaging-based MRD tests), it is likely that we will

see the development of more targeted and less toxic treat-

ment studies for high-risk smoldering MM. Such studies will

revisit similar goals to those established at the conception of

HDT-ASCT, testing the hypothesis that it is possible to cure

or achieve long-term remissions in MM by approaching the

disease more eff ectively in an earlier time window. Th ese

and other important questions face MM investigators as we

look to the future.

Potential confl ict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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Perez-Persona E , Vidriales MB , Mateo G , et al . New criteria [3] to identify risk of progression in monoclonal gammopathy of uncertain signifi cance and smoldering multiple myeloma based on multiparameter fl ow cytometry analysis of bone marrow plasma cells . Blood 2007 ; 110 : 2586 – 2592 .

Landgren O , Kyle RA , Pfeiff er RM , et al . Monoclonal gammopathy [4] of undetermined signifi cance (MGUS) consistently precedes multiple myeloma: a prospective study . Blood 2009 ; 113 : 5412 – 5417 .

Kyle RA , Durie BG , Rajkumar SV , et al . Monoclonal gammopathy of [5] undetermined signifi cance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management . Leukemia 2010 ; 24 : 1121 – 1127 .

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Evolving therapeutic paradigms for multiple myeloma: back to the future

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