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Page 1: SIE, SIES, GITMO evidence-based guidelines on novel agents ... · ORIGINAL ARTICLE SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide)

ORIGINAL ARTICLE

SIE, SIES, GITMO evidence-based guidelines on novelagents (thalidomide, bortezomib, and lenalidomide)in the treatment of multiple myeloma

Giovanni Barosi & Giampaolo Merlini & Atto Billio &

Mario Boccadoro & Paolo Corradini & Monia Marchetti &Massimo Massaia & Patrizia Tosi & Antonio Palumbo &

Michele Cavo & Sante Tura

Received: 11 January 2012 /Accepted: 1 March 2012 /Published online: 4 April 2012# Springer-Verlag 2012

Abstract In this project, we produced drug-specific recom-mendations targeting the use of new agents for multiplemyeloma (MM). We used the GRADE (Grades of Rec-ommendation, Assessment, Development, and Evalua-tion) system which separates the judgments on qualityof evidence from the judgment about strength of recom-mendations. We recommended thalidomide and bortezo-mib in MM patients candidates to autologous stem celltransplantation (ASCT) (weak positive). We did notrecommend novel agents as maintenance therapy afterASCT (weak negative). In patients not candidate to

ASCT, thalidomide or bortezomib (strong positive) as-sociated with melphalan and prednisone were recom-mended. In these patients, no specific course of actioncould be recommended as for maintenance therapy. Inpatients who are refractory or relapsing after first-linetherapy, we recommended bortezomib and pegylatedliposomal doxorubicin, or lenalidomide and dexametha-sone combinations (weak positive).

Keywords Multiple myeloma . Bortezomib . Thalidomide .

Lenalidomide . Guideline . GRADE . Recommendations

G. BarosiLaboratory of Clinical Epidemiology and Center for the Studyof Myelofibrosis, Fondazione IRCCS Policlinico San Matteo,Pavia, Italy

G. MerliniAmyloidosis Research and Treatment Center andDepartment of Biochemistry, Fondazione IRCCS PoliclinicoSan Matteo and University of Pavia,Pavia, Italy

A. BillioDepartment of Ematology, Ospedale Centrale,Bolzano, Italy

M. Boccadoro :M. Massaia :A. PalumboDivisione di Ematologia dell’Università di Torino, AOU S.Giovanni Battista,Turin, Italy

P. CorradiniDivision of Hematology,Fondazione IRCCS Istituto Nazionale dei Tumori,Milan, Italy

M. MarchettiUnit of Hematology, Hospital “C. Massaia”,Asti, Italy

P. TosiUnit of Hematology, Ospedale Infermi Rimini,Rimini, Italy

M. CavoIstituto di Ematologia ed Oncologia Medica “Seragnoli”,Università di Bologna,Bologna, Italy

S. TuraUniversità di Bologna,Bologna, Italy

G. Barosi (*)Unità di Epidemiologia Clinica/Centro per lo Studio dellaMielofibrosi, Fondazione IRCCS Policlinico S. Matteo,Viale Golgi 19,27100 Pavia, Italye-mail: [email protected]

Ann Hematol (2012) 91:875–888DOI 10.1007/s00277-012-1445-y

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Introduction

The effort toward understanding the molecular pathogenesisof multiple myeloma (MM) has led to the rational develop-ment of novel therapeutic agents: thalidomide, bortezomiband lenalidomide. Their introduction in clinical practice hassignificantly changed the natural history of MM patients[1–3]. However, since the treatment of MM must be tailoredto the patient’s fitness and ability to tolerate more toxiccombination therapies, the use of the new agents requires ahigh degree of professional experience. This is a difficulttask due to the fact that the end-points and the population ofpatients of the trials may be not necessarily those that arerelevant in clinical practice. Thus, the clinical decision ofthe use of the new molecules leaves the potential for inap-propriate use.

In its mandate to promote the best hematological care, theItalian Society of Hematology (SIE) and the affiliate socie-ties, Società Italiana di Ematologia Sperimentale (SIES) andGruppo Italiano Trapianto di Midollo Osseo (GITMO), in2004 have produced guidelines for the therapy of MM [4].As recommended by the AGREE group [5], and due to thechanged therapeutic scenario of this disorder, in thisproject we revised the original guidelines, in particular,we set out to produce drug-specific recommendationstargeting open clinical questions for the use of newantimyeloma agents. We used the GRADE (Grades ofRecommendation, Assessment, Development, and Eval-uation) system [6], which is based on a sequentialassessment of the quality of evidence followed by ananalysis of the benefit–risk balance and subsequentjudgment about the strength of recommendations.

Methods

Guidelines development process

A three-member Advisory Council (AC) with expertise inclinical epidemiology, hematology and in critical appraisaland research synthesis oversaw the process. An expert panel

was selected according to the conceptual framework ele-ments of the NIH Consensus Development Program [7].The steps in the process are shown in Table 1.

Systematic review and grading evidence

The AC systematically retrieved literature. Indexed paperswere identified through computerized search of the availablebibliographic databases: PubMed, the Cochrane Register ofSystematic Reviews, the Cochrane Central Register of Con-trolled Trials, and ISI Web of Knowledge, EMBASE. A firstsearch was performed on December 2009 and limited toEnglish-language publications edited after 2005. Analysisof data published since that date up to 15 December 2011was performed before publication of the present paper. Newtrials or adjourn of trials published in abstract form wereconsidered in writing this paper. The following conferenceproceedings were manually retrieved: American Society ofHematology, 2009–2011; European Hematology Associa-tion, 2010, 2011; American Society of Clinical Oncology,2009–2011. Ongoing or finished but yet unpublished trialsregistered at the NCI web site and addressing patients withMM were selected and protocol description was down-loaded. The AC members prioritized data from randomizedclinical trials (RCTs), when available, and performed poolanalysis of the data when applicable.

Producing and grading recommendations

The AC prepared for each relevant outcome "evidencetables," with short comments on all the predefined dimen-sions of quality (i.e., study design, quality, consistency, anddirectness); quantitative summaries of effect for each out-come were also provided. The AC was also in charge ofproducing "summaries of findings tables" providing data onabsolute and relative risk reduction on the outcomes previ-ously identified as critical for the decision. The AC alsorated the quality of evidence (for each item separately, andthen across all items), and the balance between benefits andrisks.

Table 1 Definition of project's objectives

Presentation to panel members of the GRADE system

Definition of the clinical questions

Discussion of all the relevant outcomes and individual rating of the importance (relevance) of each outcome

Systematic literature search and preparation of the evidence and summary of findings tables for each relevant outcome

Individual rating of the quality of evidence for each relevant outcome and overall

Individual rating of the balance of benefits and harms for each relevant outcome and overall

Drafting of recommendations by individual panel’s members, and individual rating of the strength of the recommendations

Meetings to reach the final version of the recommendations by group discussion

876 Ann Hematol (2012) 91:875–888

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The panel members received the material by mail,and they were asked to individually drafting recommen-dation by agreeing on benefit/risk ratio profile for eachintervention. Using a modified Delphi process [8], thelist of produced statements was circulated electronicallyto all participants through two iterations. Participantsvoted on which statements they felt warranted discus-sion at the meeting, and provided comments on thewording of the statements which were progressivelyfinalized. Final adjudication of the recommendation(s)was made through three face-to-face meetings held inBologna, Italy. The nominal group technique [9] wasused to solve any residual disagreement on the selecteditems. Recommendations were both classified into fourmutually exclusive categories — do it, probably do it,probably don’t do it, don’t do it — according toGRADE suggestions, and were provided in more de-tailed form with suggestions and comments derivedfrom consensus of the panel.

Recommendation Statements

The assessments described herein led to the recommenda-tions reported in Table 2.

Question 1 In patients with newly diagnosed MM whoare candidates to a strategy that includes autologousstem cell transplantation, are regimens including one ofthe new agents (thalidomide, bortezomib, lenalidomide)recommended?

In 2004, the SIE–SIES–GITMO group recommendedhigh dose melphalan as the standard treatment for thesepatients [4]. We searched for evidence addressing the ques-tion whether the introduction of individual new agent shouldbe better than standard induction regimens, including singleagent dexamethasone, or combination vincristine, doxoru-bicin, dexamethasone (VAD). The Panel agreed that in thissetting, results of trials should be evaluated according thecritical outcomes of progression-free survival (PFS) or over-all survival (OS). Responses were considered of less valuethan survival.

Thalidomide One meta-analysis of nine RCTs [10], and oneRCT published after the meta-analysis [11] compared theoutcomes of thalidomide with those of conventional chemo-therapy. The meta-analysis showed that higher rates of com-plete response (CR) were achieved in patients treated withthalidomide compared to non thalidomide [10]. The impactin OS and PFS was not assessable. The frequency of adverseevents (AEs) was increased in the thalidomide arm in allassessable trials.

VAD and TAD (thalidomide, adriamycin, dexamethasone)induction therapy were compared in newly diagnosed MMpatients (HOVON 50 trial) [11]. Thalidomide significantlyimproved event-free survival (EFS), PFS, and OS. However,the difference in OS was not significant. Neurotoxicity grades2–4 developed in 31% of patients treated with thalidomide.

The quality of overall evidence was graded as weak sincethe meta-analysis assessed the value of thalidomide-combinedtherapy against standard treatment in both transplant eligibleand non eligible patients (low directness), and the value of

Table 2 Clinical questions andstrength and direction of therecommendations formulated bythe panel using GRADE system

Clinical question Recommendation

1. In patients with newly diagnosed MM who arecandidates to a strategy that includes autologousstem cell transplantation, are regimens includingnew agents (thalidomide, bortezomib, lenalidomide)recommended?

Use it, weak positive, for thalidomideand bortezomib. No recommendationfor lenalidomide.

2. In patients with newly diagnosed MM and candidatesto a strategy that includes autologous stem celltransplantation, is a regimen including two or threenew agents better than a regimen including a single agent?

Use it, weak positive, for bortezomibplus thalidomide.

3. In patients who have received autologous stem celltransplant first line therapy, is the use of novel agentsrecommended as a consolidation and maintenance therapy?

Probably don’t use it, weak negative.

4. In patients aged more than 65 years, candidates tomelphalan and prednisone, is the association with anovel agent (thalidomide, lenalidomide or bortezomib)recommended?

Use it, strong positive for thalidomide andbortezomib in combination with melphalanand prednisone.

5. In patients aged more than 65 years, candidates tomelphalan and prednisone is thalidomide plus bortezomibrecommended?

No recommendation.

6. In patients aged more than 65 years, is post-inductionmaintenance therapy with a new agent recommended I

No recommendation.

7. Is the use of new agents recommended in patientsrefractory to or relapsing after first line therapy?

Use it, weak positive for bortezomib/pegylated liposomal doxorubicincombination and lenalidomide/dexcombination.

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therapy could be judged only on response and not on survival.On this regard, the therapy after the induction phase (trans-plant or not transplant), and the consolidation and mainte-nance of consolidation therapy were confounding factors inthe design of trials and in the interpretation of results. How-ever, based on the available evidence, the Panel judged thebenefits of using thalidomide in the induction phase of MMpatients candidates to autologous stem-cell transplantation(ASCT) to overcome the risks (weak positive).

Bortezomib One phase III multicenter trial (IFM 2005-01)randomized patients to receive VAD induction plus no con-solidation, VAD plus dexamethasone, cyclophosphamide,etoposide and cis-platinum consolidation, bortezomib anddexamethasone plus no consolidation, or bortezomib anddexamethasone plus dexamethasone, cyclophosphamide,etoposide and cis-platinum consolidation [12]. After a me-dian follow-up of 32 months, no significant gain in PFS andOS were demonstrated. The two groups of patients experi-enced similar AEs rates.

The efficacy on PFS of bortezomib during induction inpatients candidates for high-dose therapy was measured in atrial (HOVON-65/GMMG-HD4) reported in abstract formin which patients were randomly assigned to standard VAD(arm A) or PAD (bortezomib, doxorubicin and dexametha-sone) (arm B) before high-dose melphalan with ASCT.Patients treated with bortezomib had a better OS (hazardratio [HR]00.74). Polyneuropathy WHO grade 3 plus 4occurred in 7% (arm A) and 16% (arm B) [13].

The quality of overall evidence was graded as weak dueto inconsistent results. However, the Panel deemed the ben-efits of using bortezomib in the induction phase of MMpatients who are candidates to ASCT to overcome the risks(weak positive).

Lenalidomide No trial compared lenalidomide with stan-dard therapy in patients who are candidate to ASCT. TheEastern Cooperative Oncology Group reported a random-ized trial comparing lenalidomide plus high-dose dexameth-asone with lenalidomide plus low-dose dexamethasone inpatients with newly diagnosed MM [14]. The panel judgedthe evidence resulting from this trial of low quality forunfair directness.

The Panel deemed that no recommendation could bedone for the use of front-line lenalidomide in patients whoare candidates to ASCT.

Recommendations

In patients with newly diagnosed MM, and candidates toASCT, regimens including thalidomide or bortezomib arerecommended in the induction therapy before ASCT.

Question 2 In patients with newly diagnosed MM andcandidates to a strategy that includes autologous stem celltransplantation, is a regimen including two new agentsbetter than a regimen including a single agent?

The AC reviewed trials in which any combination of thenew agents were compared with a single agent in patientscandidates to ASCT. OS and PFS were established as theoutcomes of interest for this question.

In a phase III, open label study, 480 patients were rand-omised to bortezomib–thalidomide–dexamethasone (VTD)or thalidomide–dexamethasone (TD) [15]. Patients receivedthe same regimens for consolidation therapy after transplant.The estimated 3-year rate of PFS was 68% in the VTD armas compared to 56% in TD. Grade 3 peripheral neuropathyand skin rash were reported more frequently with VTDinduction therapy than with TD. In a recent analysis, thespecific impact of VTD consolidation on clinical outcomeswas analyzed [16]. At the landmark analysis, the PFS wassignificantly longer for patients receiving VTD consolida-tion than for those treated with TD (3-year estimates: 62%vs. 46%). However, no improved OS was evidenced be-tween the two groups. The frequency of treatment-emergentgrades 3–4 adverse events was comparable in the twogroups.

A phase III trial addressed the question if the combina-tion of reduced-dose bortezomib plus thalidomide and dexa-methasone (vTD) was superior and better tolerated thanbortezomib plus dexamethasone (VD) [17]. vTD performedbetter in terms of response after induction phase. Despite theaddition of thalidomide, the incidence of severe peripheralneuropathy in vTD arm was only 3%.

The Spanish Myeloma Group (PETHEMA/GEM) ac-tivated a randomized phase III trial comparing TD ver-sus VTD versus VBMCP/VBAD/Bortezomib [18]. Theestimated OS at 4 years was 76% with no significantdifferences among the three arms. After a medianfollow-up of 27 months, the median PFS was notreached with VTD, while it was 27 and 38 months withTD and VBMCP/VBAD/B, respectively. The frequencyof grade ≥3 peripheral neuropathy was 12% with VTDcompared to 1% in both the TD and the VBMCP/VBAD/B arms.

The quality of summary evidence in favour of usingthe combination of bortezomib plus thalidomide insteadof thalidomide single agent as first line therapy intransplant-eligible patients was graded as of low direct-ness and consistency. The Panel judged the benefit ofusing the drugs combination to overcome the risks(weak positive). The quality of evidence in favour ofusing consolidation therapy after transplant was gradedas weak due to lack of documented effect on OS and tolow consistency.

878 Ann Hematol (2012) 91:875–888

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Recommendations

In newly diagnosed patients with MM and who are candi-dates to ASCT, regimens including bortezomib and thalido-mide are recommended instead of a regimen includingthalidomide alone. The value of consolidation therapy aftertransplant should be further tested in order to document theimpact on the estimate of overall survival.

Question 3 In patients who have received autologous stemcell transplant first-line therapy, is the use of novel agentsrecommended as a maintenance therapy?

The recent literature on maintenance after ASCT wasrevised according to the preliminary decision that the out-come critical for the question should be primarily OS. PFSor EFS were outcomes considered in the analysis but of lessvalue than OS. Moreover, the panel deemed that in order tojudge the quality of evidence on maintenance therapy, thetype of upfront induction therapy patients received wasrelevant for the strength of the recommendations.

Thalidomide Five open label RCTs addressed the issue ofthalidomide maintenance after ASCT [11, 19–22], whileanother randomized trial evaluated thalidomide maintenanceafter either an intensive or non intensive treatment pathway[23]. Attal et al. [19] randomised patients treated with VADplus two ASCTs to no maintenance (arm A), maintenancewith pamidronate (arm B) or maintenance with pamidronateand thalidomide (arm C). With a median follow-up of40 months, the probability of OS 4 years after enrolmentwas 87% for the thalidomide arm versus 77% (arm A) and74% (arm B). Drug-related AEs led to discontinuation ofthalidomide in 39% of patients.

Barlogie et al. [20] randomized patients treated with twoASCTs to thalidomide maintenance versus IFN. In the ex-perimental arm, thalidomide was also part of the inductionregimen. Eight-year estimates of OS were not significantlybetter than the control arm. Thalidomide was discontinuedwithin 2 years after enrolment in 30% of patients and within4 years of enrolment in more than 60% of patients.

Spencer et al. [21] randomized post single ASCT patientsto thalidomide consolidation for 12 months plus indefinite50 mg alternate day prednisolone or to indefinite 50 mgalternate day prednisolone maintenance therapy (controlgroup). After a median follow-up of 3 years, OS rates were86% and 74%, favouring thalidomide maintenance. At12 months, 58% of patients remained on thalidomide.

In the HOVON 50 trial [11], at a median follow-up of52 months, OS in both arms was comparable. Neurotoxicitygrade 3 or 4 developed in 10% of patients. The results ofNCIC Clinical Trials Group MY.10 study comparing main-tenance with thalidomide and prednisone versus observation

alone following ASCT were recently reported in abstractform [22]. Thalidomide plus prednisone maintenance thera-py did not significantly prolong OS.

In the MRC Myeloma IX study [23], patients were firstrandomized to intensive or non intensive treatment and to twodifferent regimens of biphosphonates. At the end of the in-duction therapy, patients were further randomized to mainte-nance therapy with thalidomide or no maintenance. At theinterim analysis, the results indicated that thalidomide main-tenance had no beneficial effect on OS and the randomizationwas closed and treatment with thalidomide stopped.

In summary, the quality of evidence was graded as weakfor study limitations (absence of concealment), indirectness(different induction treatments in the different trials), andpoor consistency (only two out of six trials had benefit inOS) [20, 22] (Table 3). The panel judged that the benefits ofusing thalidomide in the maintenance therapy after ASCTdo not overcome the risks of the therapy (weak negative).These conclusions were not challenged after the outcomedata of phase III RCTs reporting the maintenance therapy ofthalidomide were pooled in a meta-analysis and published inabstract form [24]. A total of 3,194 patients were evaluated.The 3-yer OS and 3-year PFS were superior with mainte-nance therapy. However, both peripheral neuropathy andthrombo-embolic events were superior in the thalidomidearms (HR02.18 and 1.63, respectively), and toxicities wereincreased with thalidomide and steroid maintenance.

Lenalidomide Two RCTs were analyzed for the efficacy oflenalidomide as consolidation/maintenance after transplan-tation [25, 26]. Both studies were reported in abstract formand for this reason the quality of evidence was downgraded.In a phase III, placebo-controlled trial (IFM 2005-02),patients under 65 years of age were randomized to receiveconsolidation with lenalidomide followed by maintenancewith either placebo (arm A) or lenalidomide until relapse(arm B) [25]. At the final analysis, maintenance with lena-lidomide improved PFS. The 5-year post diagnosis OSremained similar in the two treatment groups. The definitiveinterruption rate for serious adverse events during mainte-nance was similar in both arms.

In the CALGB100104 trial [26], patients with stabledisease or better after ASCT were randomized to lenalido-mide or placebo. At an interim analysis, the estimated me-dian TTP was 42.3 months for the lenalidomide arm and21.8 months for the placebo arm. Results on OS were notreported. Comparing AEs, there were significantly moreepisodes of thrombocytopenia, neutropenia, anemia, andinfections with lenalidomide.

In summary, the quality of evidence was graded as weak.The panel judged that the benefits of using lenalidomide inthe maintenance therapy after ASCT do not overcome therisks of the therapy (weak negative).

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Bortezomib/thalidomide compared with thalidomideand alpha-2b interferon

In the PETHEMA/GEM randomized phase III trial compar-ing induction with TD versus VTD versus VBMCP/VBAD/bortezomib, a maintenance with thalidomide/bortezomib(TV) versus thalidomide (T) versus alpha 2b-interferon

(alpha-2b-IFN) was planned. RR and TTP were recentlyreported in abstract form [27]. After a median follow-up of24 months, the PFS was significantly longer with TV com-pared with T and alpha 2b-IFN. However, OS was notsignificantly different among the three arms. Grade 3 and4 hematological toxicities were similar, ranging from 16%to 22%. The quality of evidence was graded as weak.

Table 3 Evidence table for maintenance therapy (thalidomide)

Quality assessment Summary of findings

Trials Design Limitations Inconsistency Indirectness Imprecision No of patients Effect Quality

Thalidomide (Thal)maintenance

Control

Overall Survival

RCT

Attal, 2006 [19] Yes Yes No No 201 196 p<0.03 low

Barlogie, 2006 [20] Yes Yes No No 323 345 p=0.09 low

Spencer, 2009 [21] None Yes No No 114 129 HR, 0.41 (95%CI 0.22–0.76)

moderate

Lockhorst, 2010 [11] Yes No No No 90 156 HR, 0.96 (95%CI 0.74–1.25)

moderate

Stewart, 2010 [22] Yes NA No NA 332 HR, 0.77 (95%CI 0.53–1.13)

moderate

Morgan, 2012 [23] Yes Yes Yes NA 408 410 HR=0.78 (95%CI, 0.57–1.07)

low

Progression freesurvival

RCT

Attal, 2006 [19] NA NA NA NA NA NA NA NA

Barlogie, 2006 [20] NA NA NA NA NA NA NA NA

Spencer, 2009 [21] None No No No 114 129 HR, 0.5 (95%CI 0.22–0.76)

high

Lockhorst, 2010 [11] Yes No No 90 156 HR, 0.67 (95%CI 0.55–0.82)

moderate

Stewart, 2010 [22] HR, 0.56 (95%CI 0.43–0.73)

Event free survival

RCT

Attal, 2006 [19] Yes No No No 201 196 p<0.01 low

Barlogie, 2006 [20] Yes No No No 323 345 p=0.001 low

Spencer, 2009 [21] NA NA NA NA NA NA NA NA

Lockhorst, 2010 [11] No No No No 80 156 HR, 0.60 (95%CI 0.48–0.75)

high

Stewart, 2010 [22] NA NA NA NA NA NA NA NA

Compliance

RCT

Attal, 2006 [19] Yes No No No 201 196 Thal: 39% stoppedafter a median of15 months

low

Barlogie, 2006 [20] Yes No No No 323 345 Thal: 30% stopped at24 months

low

Spencer, 2009 [21] None No No No 114 129 Thal: 62% stopped high

Control 12% stopped(at 12 months)

Lockhorst, 2010 [11] Yes No No No 90 156 Thal: 53% stopped at24 months

Moderate

Thal: 70% stopped at36 months

Stewart, 2010 [22] NA NA NA NA NA NA NA NA

NA not available, RCT randomized controlled trial, HR hazard ratio

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Recommendations

The general use of thalidomide, lenalidomide or bortezomibin the post-transplant therapy (maintenance therapy) is notrecommended. The value of maintenance therapy with thenew drugs should be further tested in order to documentimpact on the estimate of overall survival.

Question 4 In patients aged more than 65 years, candidatesto melphalan and prednisone, is the association with a novelagent (thalidomide, bortezomib or lenalidomide)recommended?

The panel took the decision that in this setting the criticaloutcomes should be primarily OS. PFS or EFS were judgedof less value in grading the evidence.

Is melphalan–prednisone–thalidomide (MPT) better thanconventional therapy? Six randomized trials assigned a to-tal of 1,827 patients mostly older than 65 years and notcandidate to ASCT to either MPT or MP [28–34]. By pool-ing the reported results, the use of MPT increased medianOS by 9 months (95% confidence interval [CI], 8.8–9.5 months) and PFS by 8 months (95% CI, 7.8–8.2 months). Grade 3–4 neurotoxicity was higher in patientstreated with MPT (odds ratio, 13.4; 95% CI, 4–44] with anincreased risk of 7% (95% CI, 5–10%). The overall qualityof the studies was low to moderate because of the high drop-out rate and some inconsistencies among the studies. Mul-tivariate analysis did not confirm superior outcomes of MPTversus MP in patients with renal failure or moderate anemia,however, MPT significantly prolonged PFS in patients aged75 years or older and in all ISS risk classes [30]. Theanalysis of OS was confounded by the impact of the novelagents as rescue therapies. Indeed, only two [32, 33] of thesix trials showed an OS benefit with MPT.

The results of our pooled analysis were confirmed by ameta-analysis that considered data for 1,685 individualpatients from six randomized controlled trials, launched inor after 2000, comparing MP and MPT [35]. There was ahighly significant benefit to OS from adding thalidomide toMP (HR00.83; 95% CI, 0.73–0.94, p00.004), representingincreased median OS time of 6.6 months, from 32.7 months(MP) to 39.3 months (MPT). The thalidomide regimen wasalso associated with superior PFS (HR00.68; 95% CI, 0.61–0.76; p<0.0001) and better 1-year response rates (partialresponse or better was 59% on MPT and 37% on MP).The meta-analysis concluded that thalidomide added toMP improves OS and PFS in previously untreated elderlypatients with MM, extending the median survival time by onaverage 20%. The summary evidence was further analyzedby the Panel, which deemed that the benefit of using MPToutweighs the risks (strong positive).

Is thalidomide–dexamethasone (thal/dex) better than con-ventional therapy? Two trials tested the efficacy of thalido-mide plus dexamethasone in comparison to dexamethasonealone [36, 37]. The ECOG trial [36] showed a higher RR ofthal/dex, but did not properly assess OS, which seemedunchanged in the two treatment arms at 2 years. In aplacebo-controlled phase III clinical trial, thal/dex was com-pared with dexamethasone alone as initial therapy for newlydiagnosed MM [37]. TTP was significantly longer with thal/dex compared with placebo/dex (22.6 vs. 6.5 months).Grade 4 adverse events were more frequent with thal/dexthan with placebo/dex (30.3% vs. 22.8%).

Thal/dex versus MP was explored by only one fullypublished randomized trial [38]: higher rates of VGPR andPR were counterbalanced by higher toxicity and earlydeaths, therefore leading to a worse OS and not betterPFS. The trial was of moderate quality due to some limi-tations and imprecision. Moreover, the directness of theresults was partial, since maintenance therapy was applied(either thalidomide plus IFN or IFN)

The panel deemed that the benefit of using thalidomide–dexamethasone instead of conventional therapy in patientsnot candidates to ASCT does not overcome the risks.

Is cyclophosphamide, thalidomide, and dexamethasone(CTD) better than conventional therapy? As part of therandomized MRC Myeloma IX trial, an attenuated regimenof cyclophosphamide, thalidomide, and dexamethasone(CTDa) was compared with MP in patients with newlydiagnosed MM ineligible for ASCT [39]. The primary end-points were overall RR, PFS, and OS. The overall RR wassignificantly higher with CTDa than MP (63.8% vs. 32.6%),however, CTDa was not associated with improved survivaloutcomes. CTDa was associated with higher rates of throm-boembolic events, constipation, infection, and neuropathythan MP.

The panel deemed that the benefit of using CTD insteadof conventional therapy in patients not candidates to ASCTdoes not overcome the risks.

Is bortezomib, melphalan and prednisone (VMP) better thanconventional therapy? One randomized trial comparedstandard MP therapy with MP plus bortezomib (VMP) inpatients who were ineligible for high-dose therapy (VISTAtrial) [40]. VMP doubled RRs and significantly prolongedOS. Grade 3 adverse events occurred in a higher proportionof patients in the bortezomib group, but there were nodifferences in grade 4 events or treatment-related deaths.Updated analyses of OS documented that after a medianfollow-up of 36.7 [41] and 60.1 months [42], OS resultedprolonged with VMP versus MP (HR, 0.653 and 0.695,respectively) being VMP associated with a 35% and 31%reduced risk of death, respectively. Analyses of second

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primary malignancy risk showed no difference in incidencebetween arms and incidence rates on both arms were con-sistent with background incidence rate in the general popu-lation aged 65–74 years [42].

The benefits of using VMP were deemed to outweigh therisks (strong positive).

Is lenalidomide, melphalan and prednisone (MPR) betterthan conventional therapy? In a prospective, randomizedphase III trial (MM-015), MPR was compared with contin-uous lenalidomide treatment and fixed-duration regimens ofMP (MPR-R) in transplant-ineligible patients with newlydiagnosed MM [43]. Overall, MPR-R reduced the risk ofdisease progression by 58% compared with MP with ahigher 2-year PFS rate. Follow-up remains too short toidentify significant OS differences between the three groups.The evidence was downgraded for criticism on directnessand on the fact that results were in abstract form (weakevidence).

Is lenalidomide–dexamethasone (len/dex) better than con-ventional therapy? Len/dex was compared to high-dosedexamethasone plus placebo as treatment of newly diag-nosed MM patients who were transplantation-ineligible or-denying [44]. The 1-year PFS with len/dex was superiorthan with the control arm. At 3 years, PFS remained superiorfor len/dex: 52% versus 32%. However, OS was not differ-ent between arms. Grade 3 or 4 myelosupression wasreported by 21% of patients treated with len/dex comparedwith 5% of patients treated with high-dose dexamethasonealone.

A second phase III randomized study compared lenali-domide plus high-dose dexamethasone with lenalidomideplus low-dose dexamethasone in patients with newly diag-nosed MM [14]. Survival significantly favoured lenalido-mide plus low-dose dexamethasone. A lower rate of grade 3or 4 adverse events among patients who were randomized tolenalidomide plus low-dose dexamethasone was reported.

The quality of the trial was judged weak (prematurelystopped). The Panel deemed that the benefits of using lena-lidomide–dexamethasone instead of conventional therapy inelderly patients do not outweigh the risks.

Which of the bortezomib-based combinations is recommen-ded? In a PETHEMA trial [45], patients with untreatedMM, 65 years and older, were randomly assigned to receiveVMP or bortezomib plus thalidomide and prednisone (VTP)as induction therapy. No significant differences in PFS and3-year OS were evidenced. Treatment with VTP resulted inmore serious adverse events and discontinuations than didtreatment with VMP. The evidence in favour of the VTPcombination regimen was not conclusive being the power ofthe study calculated on the basis of response.

In a phase III study, the efficacy of the combination ofbortezomib–melphalan–prednisone–thalidomide followedby maintenance with bortezomib–thalidomide (VMPT-VT)was compared with VMP treatment alone in untreated MMpatients who are ineligible for ASCT [46]. VMPT-VT wassuperior to VMP in terms of CR and PFS, but a better OSwas not apparent. Grade 3 to 4 neutropenia, cardiologicevents, and thromboembolic events were more frequentamong patients assigned to the VMPT-VT group. To de-crease neurologic toxicities, the protocol was amended andpatients in both arms received once-weekly instead of theinitial twice-weekly bortezomib infusions [47]. Non hema-tologic grade 3/4 adverse events were reported in 35% ofonce-weekly patients and 51% of twice-weekly patients.However, the improvement in safety did not appear to affectefficacy as long-term outcomes, in particular OS, appearedsimilar.

A US community-based phase IIIb randomized, openlabel, multicenter trial compared the efficacy and safety ofthree bortezomib-based regimens, bortezomib–dexametha-sone (VcD), VTD and VMP, followed by weekly bortezo-mib maintenance in elderly, transplant ineligible, MMpatients (UPFRONT trial) [48]. The results have beenreported in abstract form. After a median follow-up of21.8 months, no significant difference in PFS and OS wasobserved between the treatment arms.

Recommendations

The combination of melphalan and prednisone with a novelagent (thalidomide or bortezomib) should be considered thetreatment of choice in patients aged more than 65 years andnot candidates to standard ASCT. The evidence does notallow the selection of the best treatment to use: melphalan,prednisone and thalidomide or melphalan, prednisone andbortezomib are the regimens which have provided the bestresults on survival.

Even in the absence of evidence, the Panel agreed thataccording to the drugs' safety profile, bortezomib should bepreferred in patients with high thrombotic risk and renalfailure. Bortezomib, should be also preferred in patientswith a need for rapid cytoreduction. Neither of the drugsshould be recommended in patients with polineuropathy.

Question 5 In patients aged more than 65 years, is post-induction maintenance therapy including a novel agentrecommended

The Panel claimed OS being the relevant clinical out-comes against which to evaluate the evidence of the use ofnovel agents in post-induction maintenance therapy in el-derly patients. In this setting, most of the studies employing

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frontline novel drugs included maintenance therapy withnovel drugs.

In the MM015 trial [43], a landmark analysis comparingMPR-R and MPR initiated at the beginning of cycle 10demonstrated that maintenance lenalidomide resulted in a69% reduced risk of progression compared with placebo(HR00.314). In addition, patients who received mainte-nance lenalidomide had longer PFS compared with placebo.Follow-up was too short to identify OS differences betweenthe three groups. In a recent interim analysis published inabstract form, a trend for extended OS with MPR-R versusMP has been reported [49]. The hematologic second prima-ry malignancies were unbalanced against treatment withMPR-R.

In the PETHEMA trial [45], the induction stage wasfollowed by randomization to maintenance therapy withbortezomib plus either thalidomide (VT) or prednisone(VP). No evidence of OS advantage was provided. In arecent report of the maintenance phase of the trialpublished in abstract form, the median PFS from initi-ation of treatment was 35 months and the median OS60 months [50]. From the randomization to maintenancetherapy, the median PFS was 30 months for patientsreceiving VT and 24 months for those receiving VP.The slight benefit of VT versus VP as maintenancewas independent from the type of induction therapy.VT arm was associated with a higher incidence rate ofnon hematological toxicity.

In the Italian trial comparing VMPT and VMP [46], thebenefit of maintenance after VMPT could not be assessedbecause of the absence of a second random assignment afterinduction and relatively short follow-up.

In a study, elderly patients who were randomized tothalidomide–dexamethasone or melphalan–prednisolone in-duction therapy were randomized to either thalidomide–interferon or interferon alone maintenance. Thalidomideplus interferon increased PFS but not OS and was associatedwith more toxicity than maintenance with interferon alone[51].

The Panel concluded that the evidence is not suffi-cient to recommend maintenance therapy in this setting.Continuous lenalidomide treatment with MPR-R signifi-cantly reduced disease progression risk compared withMP and MPR. However, the Panel deemed the evidenceon efficacy with respect OS being not mature and dataon second primary malignancies insufficient to performa risk/benefit analysis.

Recommendation

The evidence is not mature to recommend any consolida-tion/maintenance therapy after front-line therapy in elderlypatients.

Question 6 Is the use of new agents recommended inpatients refractory to or relapsing after first line therapy?

In order to evaluate the appropriateness of the use of newagents in patients who are refractory or relapsing after firstline therapy, we reviewed randomized trials in which the useof the new agents was compared to regimens not includingthem or in which patients with prior resistance to a second-line agent were excluded. The panel agreed that the outcomeof interest in this comparison should be OS, and greatrelevance should be addressed to quality of life issues.Moreover, the evaluation of the quality of evidence forstudies in refractory or relapsing patients should take intoaccount the confounding of the type of prior therapy, inparticular whether high-dose therapy with ASCT was inthe prior treatment strategy. Thus, in the analysis of thetrials, directness was analyzed according to these concepts.

Thalidomide single agent Despite a large number of uncon-trolled trials, no randomized trial compared thalidomide tono treatment or standard therapy.

Bortezomib single agent In the APEX trial [52, 53], patientswith progressive disease after one to three previous treat-ments were randomized to bortezomib, or to oral dexameth-asone. Bortezomib arm was superior regarding TTP, OS,CR+nCR. One-year survival was superior with bortezomib.Bortezomib was associated with better global health status,and less dyspnoea and less sleep disturbance over timecompared to high dose dexamethasone [54]. Grade 3-4AEs were reported in 75% of patients treated with bortezo-mib and 60% of those treated with dexamethasone. Noanalysis of different types of previous treatments wasreported. Likely, no analysis was done of survival benefitin early and late relapsing patients. The quality of evidencewas judged weak for the low generalizability and weakdirectness of the results. The panel judged the benefit ofsingle agent bortezomib overcome the risk (weak positive).

Bortezomib–pegylated liposomal doxorubicin (PLD) com-bination therapy Orlowsky et al. randomized MM patientswith progressive disease after response to one or more linesof therapy or refractory to initial treatment to bortezomiband PLD or bortezomib monotherapy (DOXIL-MMY-3001)[55]. After a median follow-up of 7.2 months, patientstreated with bortezomib–PLD combination had a significantTTP prolongation, and the 15-month OS rate was in favourof the combination arm. An updated analysis confirmed theimprovement in TTP and OS and documented this occurreddespite prior thalidomide or lenalidomide exposure [56].Grade 3–4 AEs were more frequent in the combinationgroup. No measure of quality of life was reported. Subgroupanalyses showed that in the early relapse group, 1-year

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survival was significantly better with bortezomib/PLD thanwith bortezomib alone. The panel judged the benefit ofbortezomib/PLD combination therapy overcome the risks.The strength of the evidence was judged weak for poorgeneralizability of the results.

Lenalidomide–dexamethasone (len/dex) combination thera-py Len/dex was compared with high-dose dexamethasonein two RCTs of identical design but different locations[57–59]. Results showed a significant survival benefit oflen/dex. Recent data from an expanded access programshowed that among 1,488 patients who received len/dexfor refractory or relapsed MM, grade 3–4 toxicity washaematological [60]. The quality of evidence was judgedhigh. A recent analysis of the long-term outcomes and safetyof continuous len/dex treatment has been reported in ab-stract form [61]. Overall 18% of patients treated with len/dex achieved a PFS of >2years. No increase in secondprimary malignancy was observed with long term len/dextherapy.

Recommendations

The Panel claimed that from the evidence so far obtained,both bortezomib in combination with pegylated liposomaldoxorubicin and lenalidomide dexamethasone combinationshould be recommended in patients with refractory or re-lapsing MM. The decision on what is the best treatment inrefractory or relapsed patients according their previous ther-apy and time from end of therapy to progression cannot betaken on the basis of the available evidence.

The Panel consensually recommended that patients whohave a late relapse (relapsing after 12 months from the endof therapy) after a bortezomib-containing regimen should bere-challenged with bortezomib. Early relapsing or refractoryto bortezomib should receive lenalidomide withdexamethasone.

Discussion

We applied GRADE system to develop recommendationson the use of novel agents, i.e., thalidomide, bortezomib andlenalidomide, in the treatment of MM. Separation of thejudgments on quality of evidence and strength of recom-mendations is a critical feature of GRADE that had renderedthe system favourably evaluated and increasingly used byrespected organizations, including the World Health Orga-nization (WHO), and the UK National Institute of Healthand Clinical Excellence [62, 63].

In this project, we prioritized data from RCTs, thus alarge body of evidence on the efficacy of new agents derivedfrom phase II studies was neglected, as being not relevantfor the decisional process we intended. The result of such a

decisional enterprise was that we issued two strong and fourweak recommendations in favour and one weak recommen-dation against the index treatment. For two questions, nospecific course of action could be recommended.

A comparison with currently available evidence-basedguidelines is shown in Table 4. The induction therapy wasthe target of three guidelines systems, from CNNC,mSMART, and BCSH, respectively [64–66]. All guidelinesaccepted as appropriate for the decision of the frontlinetherapy the preliminary distinction based on patients trans-plant candidacy. A more subtle distinction between patientsat standard risk and those at high risk was proposed frommSMART [64], even though the existing evidence relies onclinical studies in which such a stratification is mostlyneglected. Thus, the recommendations issued according tothe risk class (i.e., lenalidomide or bortezomib in standardrisk patients and bortezomib-based regimen in high-riskpatients) are at variance from our recommendations inwhich lenalidomide is not included in the up-front therapydue to lack of evidence for its use. Our recommendations onthe use of regimens including bortezomib and thalidomidein patients who are candidates to transplant are also atvariance from those of the National Comprehensive CancerNetwork (NCCN) that include a list of agents or schedulesas alternative options [65]. These recommendations werebased considering preliminary evidence from phase II stud-ies that we have considered immature.

The recommendation on induction therapy in non-transplant candidates may be compared with four guidelinessystems, including the International Myeloma Workinggroup [67]. MPT or MPV are consistently recommendedby all guideline systems. NCCN extended the possible regi-mens in this setting also to lenalidomide plus dexametha-sone that we excluded since evidence was derived from atrial whose directness with respect to the question wasjudged poor.

Maintenance therapy after ASCT is a point of disagree-ment among the guidelines [64–68]. Even though five trialsexplored this issue by the use of thalidomide and most ofthem reported increased RR and OS with the maintenance,we did not recommend the drug since the appraisal of theliterature did not provide consistency on the benefit in termof OS, and the outcome we established would be critical.Moreover, a critical analysis of adverse events with themaintenance therapy produced a negative recommendation.All other published guideline systems, instead, consideredthalidomide as an appropriate maintenance therapy [65–68].Substantial agreement among guidelines was reported onrelapsing or resistant patients.

The effort we did on using the GRADE methodology forguidelines production for new antimyeloma agents has con-firmed that new drugs are often recommended with limitedevidence available [69]. The transparency of the process for

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Tab

le4

Pub

lishedevidence-based

guidelines

inmultip

lemyeloma

Guidelin

esNCCN

mSMART,

2009

[64]

ASH,2009[68]

InternationalMyeloma

Working

Group,2009

[67]

NCCN,2011

[65]

BCSH

andUK

Myeloma

Forum

,2011

[66]

SIE,SIES,GITMO

(present

guidelines)

Primaryinduction

therapyfor

transplant

candidates

Standard-risk

patients:

lenalid

omideor

bortezom

ib-

containing

regimen.

Highrisk

patients:

bortezom

ibcontaining

regimens(bortezomib-dex

with

cyclophosphamide,

thal,or

lenalid

omide).

NA

NA

Category1.

Bortezomib/

dexamethasone

Bortezomib/

doxorubicin/

dexamethasone

Bortezomib/

thalidom

ide/

dexamethasone

Lenalidom

ide/dexamethasone

Inductionregimensshould

containat

leastone

novelagent

Regim

ensincluding

thalidom

ideor

bortezom

ib.Regim

ens

includingbortezom

ibandthalidom

ideare

recommendedinstead

ofaregimen

including

thalidom

idealone.

Primaryinduction

therapyfornon-

transplant

candidates

Standardrisk

patients:

melphalan,prednisone

andthalidom

ide

(MPT).Highrisk

patients:

melphalan,prednisone,

bortezom

ib(M

PV)

NA

MPTisconsidered

astandard

ofcare

for

patients>65

years.

VMPisanotherstandard

ofcare

forelderlypatients.

Category1.

Lenalidom

ide,

low-dosedexamethasone.

Melpahalanprednisone,

bortezmoib.

Melpahaln,

prednisone,thalidom

ide

melphalan

Athalidom

idecontaining

regimen

incombinatio

nwith

analkylatin

gagentandsteroidsuch

asMPTor

CTDa,or

bortezom

ibin

combinatio

nwith

melphalan

and

prednisolone

Melphalan,prednisone,

thalidom

ideor

bortezom

ib

Maintenance

treatm

entafter

autologous

stem

celltransplantation

Thalid

omidemaintenance

orconsolidationtherapyin

those

who

failto

achieveaVGPRwith

firstcourse

ofHDM

(for

those

who

have

notoptedfora

tandem

SCT).Standardrisk

patients:melphalan,prednisone

andthalidom

ide(M

PT).High

risk

patients:melphalan,

Prednisolone:

recommended

butnotused

widely

becauseof

toxicity

concerns.Thalid

omide:

recommendedbut

notused

widelybecause

oftoxicity

concerns.

Lenalidom

ide:

not

recommendeduntil

data

matures

andresults

are

available.Bortezomib:not

widelyused

until

data

from

ongoingstudiesareavailable

prednisone,bortezom

ib(M

PV)V

Maintenance

thalidom

ide

forpatientswho

arenot

incompleteremission

afterinductiontherapy.

Melphalan,prednisone,

thalidom

ideor

bortezom

ib

Category1.

Thalid

omide

plus/m

inus

prednisone

(category2B

)

Maintenance

with

single

agentthalidom

idetherapymay

improveEFSandOSin

patientswho

didnotachieve

VGPRposthigh-dose

therapyandin

thissetting

maintenance

therapycouldbe

considered.Patientswith

deletio

n13qmay

notbenefit.

Thalid

omideisnot

recommendedoptedfora

tandem

SCT)Maintenance

thalidom

ide

Post-inductionmaintenance

therapyforpatients

aged

more

than

65years

Nomaintenance

therapyafter

MPTor

MPVin

thispatient

group,

except

inthecontext

ofaclinical

trial.

NA

There

isinsufficient

evidence

regarding

theuseof

maintenance

therapyin

elderlypatients.

NA

Atpresent,thereisno

evidence

ofbenefitfortheuseof

thalidom

idemaintenance

inelderlypatientswho

did

notundergoautologous

transplantation.

Norecommendatio

n

Relapse

NA

NA

Bortezomib

with

orwith

out

dexamethasone

orin

combinatio

nwith

liposom

aldoxorubicinis

recommendedin

relapsed/refractory

patients.Lenalidom

idein

combinatio

nwith

dexamethasone

isrecommendedin

relapsed/refractory

patients.

Repeatprim

aryinduction

therapy(ifrelapse

at>6months).Category1.

Bortezomib/liposomal

doxorubicin,

Lenalidom

ide/

dexamethasone

For

patientsintolerant

ofthalidom

ide,or

refractory

tofirst-lin

etherapy,a

bortezom

ib-based

salvage

regimen

isrecommended.

Patientswith

≥grade2

peripheral

neuropathy

should

receivea

lenalid

omide-basedregimen

Bortezomib

andpegylated

liposom

aldoxorubicin.

Lenalidom

ideand

dexamethasone.

NAno

ravailable,MPTmelph

alan,prednisone,thalidom

ide,MPVmelph

alan,prednisone,bo

rtezom

ib

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producing recommendations will allow us to have a basisfor putting into consideration new evidence from new trialsin the field. In fact, it is believed that the therapeutic recom-mendations issued in these guidelines could be greatly in-fluenced by the clinical trials that will be concluded in 2012.The present guidelines should be therefore replaced by theend of 2013.

Acknowledgements Funding of the project was provided by SIE,SIES, and GITMO societies and from at-arm’s-length contributionfrom Celgene, Janssen Cilag and Novartis (Italy) provided to theSIE. The SIE administered all aspects of the meetings. The fundingsources had no role in identifying statements, abstracting data, synthe-sizing results, grading evidence, or preparing the manuscript or in thedecision to submit the manuscript for publication.

Authorship contribution GB and ST designed research; GB, AB,and MM performed the systematic review of literature, graded theevidence, and prepared the summary tables of evidence. GM, MB,PC, MM, PT, AP, MC, and ST formed the Panel of experts whodiscussed the summaries of evidence and produced recommendations.GB wrote the preliminary version of the paper. All authors participatedin writing significant sections of the paper.

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