Lenalidomide in multiple myeloma — a practice guideline

Lenalidomide was first approved for use in multiple myeloma patients who had received at least 1 prior therapy, based on results from two large randomized trials comparing lenalidomide plus dexamethasone with placebo plus dexamethasone1,2. Since then, the role of lenalidomide has been investigated in expanded roles and novel combinations. Toxicities such as cytopenias, venous thromboembolism (vte), and the potential risk of second primary malignancies (spms) pose challenges in the management of patients receiving lenalidomide. The Cancer Care Ontario (cco) Hematology Disease Site Group (dsg), in collaboration with the Program in Evidence-Based Care (pebc) developed recommendations for the use of lenalidomide in multiple myeloma as part of a trilogy of guidelines for the treatment of myeloma using three novel backbone agents: thalidomide, bortezomib, and lenalidomide. The recommendations presented here provide practical, evidence-based guidance concerning indications for use, dosing, combinations under investigation, and management of key toxicities.


INTRODUCTION
Lenalidomide was first approved for use in multiple myeloma patients who had received at least 1 prior therapy, based on results from two large randomized trials comparing lenalidomide plus dexamethasone with placebo plus dexamethasone 1,2 .Since then, the role of lenalidomide has been investigated in expanded roles and novel combinations.Toxicities such as cytopenias, venous thromboembolism (vte), and the potential risk of second primary malignancies (spms) pose challenges in the management of patients receiving lenalidomide.
The Cancer Care Ontario (cco) Hematology Disease Site Group (dsg), in collaboration with the Program in Evidence-Based Care (pebc) developed recommendations for the use of lenalidomide in multiple myeloma as part of a trilogy of guidelines for the treatment of myeloma using three novel backbone agents: thalidomide, bortezomib, and lenalidomide.The recommendations presented here provide practical, evidence-based guidance concerning indications for use, dosing, combinations under investigation, and management of key toxicities.

METHODS
This practice guideline was developed by the Hematology dsg of cco's pebc using the methods of the practice guidelines development cycle 3 .The pebc is editorially independent of cco and the Ontario Ministry of Health and Long-Term Care.

Questions
• Does lenalidomide (alone or in combination with other therapies) improve outcomes in patients with

Background
Promising new drugs such as lenalidomide, an immunomodulatory agent, are available for the treatment of multiple myeloma.We describe the process of creating a provincial guideline for the use of lenalidomide, alone or in combination with other drugs, in relapsed, refractory, or newly diagnosed disease (including smoldering and symptomatic patients, and candidates and non-candidates for transplant) and in maintenance treatment (after transplant or non-transplant therapy); and for strategies to manage lenalidomide-related toxicities.

Methods
Outcomes of interest included overall survival, event-free survival, progression-free survival, time to progression, time to next treatment, response rate, and incidence of serious toxicity.The medline, embase, and Cochrane Library databases, as well as meeting abstracts and the Web sites of relevant organizations, were systematically searched for relevant literature.
previously untreated multiple myeloma (including smoldering and symptomatic patients, and candidates or non-candidates for transplant) compared with non-lenalidomide-containing treatments?• Does lenalidomide (alone or in combination with other therapies) improve outcomes in patients with relapsed or refractory multiple myeloma compared with non-lenalidomide-containing treatments?• Which multiple myeloma patients, both previously untreated and relapsed or refractory, are more or less likely to benefit from treatment with lenalidomide?• Are outcomes in myeloma patients improved with the use of lenalidomide as maintenance or consolidation treatment (after transplant and non-transplant treatments) compared with either non-lenalidomide-containing treatment or no maintenance or consolidation treatment?• What are the best strategies to manage lenalidomide-induced toxicity?

Target Population
The target population for this guideline is adult patients with previously untreated, relapsed, or refractory multiple myeloma.

Systematic Review
The literature was systematically searched using electronic databases (medline, embase, and the Cochrane Library; meeting proceedings of the American Society of Hematology, the American Society of Clinical Oncology, and the International Myeloma Workshops), relevant Web sites such as CancerGuidelines.ca, the U.S. National Guideline Clearinghouse, the Canadian Medical Association Infobase, the Physician Data Query database, and the American College of Physicians Journal Club; and reference lists of included articles.

Study Selection Criteria
Articles published from January 2000 to February 2012, inclusive, were selected for this systematic review if they were • studies of adult patients with multiple myeloma.
• studies that tested the role of lenalidomide alone or in combination with other agents.• studies that reported results for any of the following outcomes: x overall survival (os) x event-free survival x progression-free survival (pfs) x time to progression (ttp) x time to next treatment x response rate (complete and partial) x incidence of serious toxicity (that is, grade 3 or 4 adverse events by the National Cancer Institute toxicity criteria) • studies that were systematic reviews or randomized controlled trials (rcts: phase ii or phase iii).• nonrandomized studies that were follow-ups or subanalyses of previous pivotal studies.• studies with a trial sample size of 30 or more.
• studies published in English.
Narrative reviews, phase i trials, observational studies, case reports, noncomparative studies, and publication types such as commentaries, editorials, and letters were excluded.Conference abstracts that were reports of non-final analyses were also excluded.Cost-effectiveness and health-related quality of life were not outcomes of interest for this document.

Selection of Studies
Citations located in the search were screened independently by the methodologist and by two clinician members of the Working Group.

Development of Recommendations
The Hematology dsg developed draft recommendations based both on consensus and on evidence from the systematic review.

Internal and External Review
Before submission of the draft report for external review, the systematic review and practice guideline were reviewed by the pebc Report Approval Panel.The draft report was distributed to health care providers in the province of Ontario for feedback, the results of which can be found in the full guideline report on the cco Web site: https://www.cancercare.on.ca/toolbox/qualityguidelines/.
A search for ongoing trials at ClinicalTrials.gov, performed April 2, 2012, identified 134 trials involving lenalidomide and multiple myeloma.Of those trials, thirty-four were rcts, either phase ii or phase iii.Details of the included trials can be found in the full guideline report at the cco Web site (https:// www.cancercare.on.ca/toolbox/qualityguidelines/).

Question 1-Previously Untreated Patients
Does lenalidomide (alone or in combination with other therapies) improve outcomes in patients with previously untreated multiple myeloma (including smoldering and symptomatic patients, and candidates or non-candidates for transplant) compared with nonlenalidomide-containing treatments?

Recommendations Previously Untreated Smoldering Multiple Myeloma:
In asymptomatic patients with no evidence of myeloma-related hypercalcemia, renal dysfunction, anemia, or bone disease (smoldering myeloma), the use of lenalidomide alone or in combination cannot be recommended.

Previously Untreated Symptomatic Multiple Myeloma:
Single-Agent Lenalidomide: Lenalidomide alone cannot be recommended for standard use in this setting.

Lenalidomide and Dexamethasone:
The combination of lenalidomide and dexamethasone is an acceptable first-line treatment option for myeloma.Recommended dosing options for lenalidomide include either giving 25 mg daily on days 1-28 every 35-day cycle for the first 3 cycles, followed by 25 mg daily on days 1-21 every 28-day cycle thereafter; or proceeding directly to the 28-day cycle dosing at onset.The use of low-dose dexamethasone-40 mg daily on days 1, 8, 15, and 22 of a 28-day cycle-is preferred for safety; however, select patients with acute myeloma complications such as renal dysfunction, hypercalcemia, or hyperviscosity may benefit from high-dose dexamethasone (that is, 40 mg daily on days 1-4, 9-12, and 17-20 of a 28-day cycle).
Other Lenalidomide Combinations: No other combinations can be recommended.

Key Evidence Previously Untreated Smoldering Multiple Myeloma:
In asymptomatic smoldering myeloma, an ongoing randomized trial that is evaluating lenalidomide in combination with dexamethasone, compared with the conventional watch-and-wait approach until symptomatic disease progression, is showing promising preliminary results favouring the use of early lenalidomide 59 .However, no recommendations can be made for this population until the data have matured.

Previously Untreated Symptomatic Multiple Myeloma:
No rcts comparing lenalidomide alone with a non-lenalidomide regimen for first-line therapy both in candidates and in non-candidates for transplant were located.
The study by Zonder et al. 9 showed an improved median 1-year pfs (78% vs. 52%, p = 0.002) and improved os (77% vs. 48%, p < 0.0001) in patients receiving lenalidomide plus dexamethasone compared with placebo plus dexamethasone.Rajkumar et al. 10 demonstrated a longer median pfs for lenalidomide plus low-dose dexamethasone than for lenalidomide plus high-dose dexamethasone (25.3 months vs. 19.1 months, p = 0.026), with an improved safety profile (grade 3 or greater adverse events: p = 0.02 for neutropenia, p = 0.0003 for dvt, and p = 0.04 for infections) in favour of the low-dose dexamethasone arm.
No rcts of lenalidomide in combination with other agents in this setting were identified.

3.2.3
Qualifying Statements The Zonder and Rajkumar studies 9,10 have limitations: Both studies were stopped early because of observed benefit, and the Rajkumar study used overall response rate as a primary outcome.In the Rajkumar study, the improved safety profile and lower rate of early deaths with low-dose dexamethasone has led to widespread adoption of that approach.From a safety perspective, the Hematology dsg endorses it.It should be noted, however, that compared with low-dose dexamethasone, high-dose dexamethasone, although more toxic, was associated with higher response rates.Therefore, in select patient populations with acute myeloma-related complications, benefit might still be obtained from the robust efficacy of high-dose dexamethasone.

Question 2-Patients with Relapsed or Refractory Multiple Myeloma
Does lenalidomide (alone or in combination with other therapies) improve outcomes in patients with relapsed or refractory multiple myeloma compared with non-lenalidomide-containing treatments?

Recommendations Single-Agent Lenalidomide:
Lenalidomide alone cannot be recommended for standard use in the relapsed or refractory setting.

Lenalidomide and Dexamethasone:
The combination of lenalidomide and dexamethasone is recommended for myeloma patients who have received at least 1 prior line of therapy.The recommended dosing is lenalidomide 25 mg daily on days 1-21, plus dexamethasone (either low-dose 40 mg daily on days 1,8,15, and 22, or high-dose 40 mg daily on days 1-4, 9-12, and 17-20) in a 28-day cycle.

Other Lenalidomide Combinations:
No other combinations can be recommended.

Key Evidence
No randomized trials that compared lenalidomide as a single agent with a non-lenalidomide regimen in previously treated patients were located.
Although high-dose dexamethasone in combination with lenalidomide was used in the two pivotal rcts of relapsed or refractory myeloma, low-dose weekly dexamethasone with lenalidomide appears less toxic when used in the first line 10 .From a safety perspective, the Hematology dsg considers low-dose dexamethasone a reasonable option for the relapsed or refractory setting.Again, select subgroups with acute myeloma complications may benefit from the greater response rates achievable with high-dose dexamethasone.
No rcts of lenalidomide in combination with other agents in this setting were identified.

3.3.3
Qualifying Statements Both of the seminal studies 1,2 were stopped at the first preplanned interim analysis for benefit and were funded by the drug's manufacturer.However, the studies enrolled more than 300 patients before stopping and had a large number of events.
The recommendation to use low-dose dexamethasone with lenalidomide in the relapsed or refractory setting is generalized from the first-line Rajkumar study 10 45 Extended results

Question 3-Subgroups Most Likely to Benefit
Which multiple myeloma patients, both previously untreated and relapsed or refractory, are more or less likely to benefit from treatment with lenalidomide?

Recommendations
For patients with untreated myeloma, the evidence is insufficient to recommend lenalidomide in specific patient subgroups.When lenalidomide is combined with dexamethasone, the use of low-dose rather than high-dose dexamethasone may be preferable from a safety perspective, regardless of age.
For patients with relapsed or refractory multiple myeloma, lenalidomide plus dexamethasone is reasonable for the following patient subgroups: For patients with relapsed or refractory multiple myeloma, the following treatment guidelines for lenalidomide and dexamethasone may be considered: • Full-dose lenalidomide may be initiated (25 mg daily), but it is reasonable to consider dose reductions for use beyond 12 months.• A longer period of lenalidomide use, if possible until progression, is a reasonable target.• Dexamethasone dose reductions may be used as needed for improved tolerability.

Key Evidence
The subgroup analyses of data are derived primarily from the Rajkumar study 10 in the first-line setting and from pooled data from the Weber and Dimopoulos studies 1,2,10,18,34,35,39 in the relapsed or refractory setting.These data have been integrated with the clinical expertise of the Hematology dsg to provide support for the recommendations.
Evidence to recommend lenalidomide in specific subgroups of previously untreated patients is limited.When lenalidomide is combined with dexamethasone, the use of low-dose dexamethasone may be preferable in older and younger patients alike.Two subgroup analyses based on the age of patients participating in the Rajkumar study 10 reported improved os in all age groups when treated with low-dose rather than high-dose dexamethasone 47,49 .
• The recommendation for lenalidomide plus dexamethasone in patients who have received at least 1 prior line of therapy derives from study stratification results and a pooled subgroup analysis by Stadtmauer et al. 39 from the Weber and Dimopoulos studies 1,2 .• The subgroup analysis by Wang et al. 28 showed that there may be partial cross-resistance between thalidomide and lenalidomide, but that prior thalidomide exposure should not absolutely contraindicate the use of lenalidomide in the relapsed or refractory setting.The recommendation for patients who have undergone prior autologous stem-cell transplantation is based on study stratification results and a pooled subgroup analysis by Dimopoulos et al. 26 .• The recommendation for use of lenalidomide in older as well as younger patients is based on a subgroup analysis of the Weber and Dimopoulos studies 1,2 reported by Chanan-Khan et al. 35 .• Lenalidomide is excreted primarily by the kidneys, posing a risk for cumulative drug-related toxicity with renal dysfunction.The recommendation for use in mild-to-moderate renal dysfunction (creatinine clearance ≥30 mL/min and ≤60 mL/min) is based on a subgroup analysis of pooled data from the pivotal relapsed or refractory studies 1,2 reported by Dimopoulos et al. 18 Given the small sample of patients with severe renal failure (creatinine clearance <30 mL/min) enrolled in the studies, the Hematology dsg cannot make recommendations for that population.• Lenalidomide and dexamethasone were found to be consistently superior to dexamethasone alone in several subgroup analyses 24,32,37 .• The guideline on dose reduction is supported by the Dimopoulos et al. subgroup analysis of patients remaining on lenalidomide beyond 12 months 25 .Those authors report that patients requiring dose reductions were able to stay on study longer, tolerated therapy as well as those not requiring dose reductions, and achieved a longer pfs.• The guideline suggesting continuing treatment until progression, if feasible, is based on two subgroup analyses by San Miguel et al. 30 and Harousseau et al. 19 suggesting that continued therapy after achievement of a partial response is beneficial, possibly by improving quality of response, which in turn prolongs survival.• The guideline on dexamethasone reduction for tolerability is based on a subgroup analysis by San Miguel et al. 33 that associated dose reductions of dexamethasone with improved survival outcomes.

Qualifying Statements
All subgroup analyses upon which the recommendations are based are retrospective post hoc analyses.In isolation, they represent a weak evidence base and therefore have been integrated with the expert opinion and clinical experience of the Hematology dsg.Validation of these recommendations through further clinical investigation is required.

Question 4-Maintenance or Consolidation Treatment
Are outcomes in myeloma patients improved with the use of lenalidomide as maintenance or consolidation treatment (after transplant and non-transplant treatments) compared with either non-lenalidomidecontaining treatment or no maintenance or consolidation treatment?

Recommendations Non-Candidates for Transplant:
The evidence is insufficient to support the use of lenalidomide maintenance or consolidation treatment after initial non-transplant therapy.

Candidates for Transplant:
In the absence of a final full publication of supporting trials in the post-transplant setting (currently published as conference abstracts 14,54,55,60 ), the Hematology dsg recommends that lenalidomide maintenance at 10-15 mg daily continuously until progression is a reasonable option.

Current OnCOlOgy-VOlume 20, number 2, April 2013
Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

Key Evidence
In non-candidates for transplant, a randomized trial reported by Palumbo et al. 61 evaluating lenalidomide as maintenance after melphalan, prednisone, and lenalidomide therapy showed promising preliminary results, but did not provide adequate mature evidence to support a recommendation for use.
In three companion abstract publications 14,54,55 , a significant improvement in pfs (p < 0.0001) was reported with maintenance compared with no maintenance after transplant.In addition, an ongoing randomized study, presented in preliminary form, strongly supported the benefit of post-transplant maintenance, with an os advantage.The median ttp was 43.6 months compared with 21.5 months, and pfs was also favourable for the lenalidomide group (hr: 0.43; one-sided unadjusted p < 0.0001) 60 .These combined data provide emerging support for the use of lenalidomide maintenance post transplant, which the Hematology dsg considers a reasonable post-transplant option.

3.5.3
Qualifying Statements The Palumbo 62 , Attal 63 , and McCarthy 64 maintenance trials were recently published in full, but were not captured within our search cut-off dates.Therefore all recommendations in the present guidelines are based on ongoing trial data available at the time of the literature search.Data from the study by Attal et al. 14,54,55 is based on a final analysis of the completed data, but presented in abstract form.That study was stopped early for benefit.Data from the study by McCarthy et al. 60 is based on an interim analysis that had already shown os benefit.Although the abstract data are adequately compelling for the Hematology dsg to recommend maintenance in post-transplant patients, evaluation of the full publications with further maturation is required before full recommendations can be made.

Question 5-Management of Toxicity
What are the best strategies to manage lenalidomideinduced toxicity?

3.6.1
Recommendations VTE: For newly diagnosed patients, and for relapsed or refractory patients who are not at high risk for bleeding or vte, either daily low-dose acetylsalicylic acid (asa) 100 mg given orally or daily enoxaparin (low molecular weight heparin) 40 mg given subcutaneously can be used in patients treated with lenalidomide-based therapy to prevent vte.For patients at high risk of vte or bleeding, the evidence is insufficient to support a specific thromboprophylactic approach.If asa in a 100 mg dose form is not available, the Hematology dsg suggests that replacement with the 81 mg dose form is reasonable.

Cytopenias:
The evidence is insufficient to recommend a uniform approach for the management of cytopenias.Lenalidomide dose reductions can be considered for patients who have responded to fulldose lenalidomide.For those who require the full dose of lenalidomide for efficacy, the use of granulocyte colony-stimulating factor can be considered for neutropenia support.
For the management of anemia and thrombocytopenia, there are no randomized data evaluating approaches in the lenalidomide setting, including the use of erythropoiesis-stimulating agents (esas).

SPMs:
The evidence to date is insufficient to confirm or refute the association of spm with lenalidomide or to identify specific subgroups of patients at risk of spm when treated with lenalidomide.

Key Evidence
The recommendation on vte is based on a published substudy of patients participating in a lenalidomidebased study for first-line use, randomized to either oral asa 100 mg daily or subcutaneous enoxaparin 40 mg daily for vte prophylaxis 51 .Equally low rates of vte, with no major hemorrhagic complications were reported for both trial arms, and therefore the Hematology dsg recommends either option as reasonable.Given the favourable safety profile of both asa and enoxaparin in prophylactic dosing, generalization of the recommendation to the relapsed or refractory setting is not unreasonable until randomized data in that setting become available.Patients at high risk for vte (prior deep vein thrombosis in the preceding 12 months) or bleeding were not enrolled in the supporting study; the recommendation therefore cannot be extended to that subgroup.
The cytopenia recommendation for lenalidomide dose reductions was based on a subgroup analysis of data pooled from the Weber and Dimopoulos trials 1,2,25 suggesting that dose reductions might allow patients to tolerate therapy longer, leading to prolonged pfs.However, in the pivotal rcts, routine use of granulocyte colony-stimulating factor with full-dose lenalidomide was mandated as initial management for severe neutropenia 1,2 .Based on those data and the clinical expertise of the Hematology dsg, the recommended options include either dose reductions in patients with responsive disease or granulocyte colony-stimulating factor support if full-dose lenalidomide is required for efficacy.

3.6.3
Qualifying Statements The Larocca et al. superiority trial 51 showed no difference between two drugs for the prevention of vte; untreated patients were 65 years of age or younger, the power of the study ranged from 47% to 80%, and for ethical reasons, a placebo arm was not used.However, this trial was the only rct to study Current OnCOlOgy-VOlume 20, number 2, April 2013 Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
vte prophylaxis in patients with myeloma treated with lenalidomide.Despite the study limitations, the Hematology dsg felt that, based on clinical experience, the results could be generalized to other patient groups.
In the absence of evidence for esa use specific to lenalidomide, the Hematology dsg suggests that published evidence-based guidelines for esa use in cancer may be applied 65,66 .In a subgroup analysis of the Weber and Dimopoulos studies published as a letter to the editor and excluded from our systematic review, the rates of vte were significantly higher with concomitant use of esa and lenalidomide than with lenalidomide without esa 67 .Because these observations mandate further validation, the Hematology dsg advises consideration of risks and benefits before initiating esa with lenalidomide, followed by careful monitoring for vte.

CONCLUSIONS
Lenalidomide is an active agent for the treatment of multiple myeloma.There is sufficient evidence to recommend lenalidomide for myeloma patients who are previously untreated, who have received at least 1 prior line of and who are posttransplant, for maintenance.to guidance for patient selection, dosing, and management of toxicities are increasing.There is, however, an ongoing need for studies comparing lenalidomidebased regimens with regimens utilizing other novel agents such as bortezomib, and studies evaluating rational lenalidomide combinations, novel roles such as consolidation or maintenance, strategies for the management of toxicities, and the long-term risks with lenalidomide.In this rapidly evolving field, vigilant scrutiny of the literature on an ongoing basis is required.

REVIEW AND UPDATE
Practice guidelines developed by the pebc are reviewed and updated regularly.Please visit the cco Web site (http://www.cancercare.on.ca) for the full evidence-based series report (https://www.cancercare.on.ca/toolbox/qualityguidelines/) and subsequent updates.

ACKNOWLEDGMENTS
The authors thank the members of the Hematology dsg for their contributions to the development of this practice guideline.The guideline was created by the pebc, a provincial initiative of cco, supported by the Ontario Ministry of Health and Long-Term Care through cco.The full version of this guideline is published on the cco Web site at https:// www.cancercare.on.ca/common/pages/UserFile. aspx?fileId=137819.

CONFLICT OF INTEREST DISCLOSURES
Among the authors of this report, CC has received research support from Celgene, and MC is a site investigator on trial MM020, sponsored by Celgene.Among the members of the dsg, Dr. Donna Reece has received trial support from Celgene, BMS, Janssen, Johnson & Johnson, Otsuka, Novartis, and Merck; Dr. Ralph Meyer has received research funding from Celgene and is an independent research assessment committee member in a Celgene-sponsored trial, receiving an annual honorarium of less than $5000; Dr. Andre Schuh is a principal investigator on a clinical trial of lenalidomide; Dr. Tom Kouroukis is a member of the Celgene Canadian Advisory Board and a local principal investigator in the first study, sponsored by Celgene.All the other members of the Working Group and of the dsg declared no conflict of interest.
All members of the Report Approval Panel declared no conflict of interest.
Among the four external reviewers constituting the technical expert panel, Dr. Vishal Kukreti declared honoraria for acting as a consultant to Celgene, Roche, and Janssen-Ortho that exceeded $5,000 in one year.Dr. Kukreti also declared principal investigator status in a phase iii lenalidomide trial.All the other member of the panel declared no conflict of interest.

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44d is based primarily on improved safety.No comparative studies have evaluated low-dose dexamethasone dosing in the relapsed or refractory setting.Lenalidomide (len) in multiple myeloma (mm): primary and ancillary publications of identified randomized trials and their objectives Baz et al., 2009 (abstract)22Compare len plus dex with plc plus dex in relapsed or refractory mm Pooled subgroup analysis investigating the effect of len plus dex on levels of immunoglobulin A (IgA) Zonder et al., 2008 (abstract)44.Compare len plus dex with plc plus dex as first-line treatment for mm 30pyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).San Miguel et al., 201130Pooled subgroup analysis investigating the effect on survival of continuing therapy after achievement of a partial response or betterCurrent OnCOlOgy-VOlume 20, number 2, April 2013Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

20, number 2, April 2013
Harvey et al., 2011 (abstract) 50 Evaluate the impact of renal function on len dosing, cytopenias, and response Richardson et al., 2006 11 Evaluate 2 dose regimens of len for relapsed or refractory mm RV-MM-PI-209 Palumbo et al., 2011 (abstract) 15 Larocca et al., 2011 51 To compare len plus melphalan (mel) plus prednisone with tandem mel [200 mg/m 2 (mel200)] in newly diagnosed mm patients who received Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e143 Current OnCOlOgy-VOlume 20, number 2, April 2013
= fluorescence in situ hybridization; asa = acetylsalicylic acid; fda = U.S. Food and Drug Administration; asco = American Society of Clinical Oncology; nice = U.K. National Institute for Health and Clinical Excellence.
Copyright © 2013 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).fish