Original Article | Published:

Myeloma

Lenalidomide−prednisone induction followed by lenalidomide−melphalan−prednisone consolidation and lenalidomide−prednisone maintenance in newly diagnosed elderly unfit myeloma patients

Leukemia volume 27, pages 695701 (2013) | Download Citation

Abstract

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide−prednisone (RP) induction, followed by lenalidomide−melphalan−prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1–21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10–15 mg/day on days 1–21), and maintenance with lenalidomide (10 mg/day on days 1–21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Introduction

Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for 1% of all malignant diseases, with an annual incidence in Western countries of 5.6 cases per 100,000 people. MM is a typical disease of the elderly: median age at diagnosis is 70 years, and 37% of newly diagnosed patients are aged over 75 years.1

The introduction of the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, thalidomide and lenalidomide, has changed the treatment paradigm of newly diagnosed patients and extended overall survival (OS) times.2-5, 3, 4, 5 A significant improvement has been reported in younger patients, although less pronounced in patients older than 70 years of age,1, 2, 3, 4 probably because of increased frequency of disabilities, concomitant diseases and adverse events during treatment.6

The combination of melphalan and prednisone (MP) plus thalidomide or bortezomib is considered as the standard induction therapy for newly diagnosed elderly myeloma patients who are ineligible for stem cell transplant.7, 8, 9

Lenalidomide (Revlimid; Celgene Corporation, Summit, NJ, USA) is an oral immunomodulatory derivative of thalidomide with more potent activity. It possesses a dual mechanism of action, the antineoplastic activity able to decrease initial tumor burden and the immunomodulatory effect that inhibits tumor regrowth.10

Lenalidomide has shown activity both in combination with corticosteroids or melphalan. The combination of lenalidomide plus high-dose dexamethasone showed higher response rate (91%) with lower toxicity in comparison with thalidomide plus dexamethasone.11, 12 To further reduce the toxicity of high-dose dexamethasone, an adapted regimen of lenalidomide plus low-dose dexamethasone has been introduced. In a randomized study, lenalidomide plus low-dose dexamethasone prolonged the time to progression (TTP), progression-free survival (PFS) and OS when compared with lenalidomide plus high-dose dexamethasone, owing to the lower rate of toxic deaths and serious adverse events.13

In a phase 1/2 study, the combination lenalidomide−melphalan−prednisone (MPR) followed by lenalidomide maintenance (MPR-R) was effective with an overall response rate of 81%, a median PFS of 28.5 months and a 2-year OS of 91%. Severe neutropenia and thrombocytopenia were the main reasons for treatment discontinuation, while the incidence of non-hematological adverse events was low.14, 15 Efficacy and toxicity data were confirmed by a large phase 3, international, randomized study comparing MPR-R with MPR alone or with MP.16 Response rates were superior with MPR induction compared with MP. Patients treated with MPR-R showed a significantly longer PFS (31 months) compared with those treated with MP (13 months); MPR-R significantly had an impact on PFS, and reduced the risk of progression in all patients by 66% compared with placebo. MPR followed by lenalidomide maintenance showed a median PFS advantage of 18 months. In the MP plus bortezomib vs MP study,8 MP plus bortezomib improved median PFS by 7 months; in the MP plus thalidomide vs MP meta-analysis7 the PFS prolongation was 5 months. The advantage of MPR vs MP induction was confirmed for patients aged 65–75 years, but was not evident for those aged >75 years, probably because of a higher frequency of adverse events, dose reductions and discontinuations in the older group. By contrast, MPR-R was equally effective in patients aged 65–75 years and in those older than 75 years.16

Based on these considerations, we designed a different MPR schedule to improve the safety profile of this regimen and its feasibility in elderly frail subjects.

Patients and methods

Patients selection

Previously untreated symptomatic MM patients aged over 65 years, or younger, but ineligible for high-dose therapy, were enrolled. Patients were required to have measurable disease, defined as having one of the following: any quantifiable serum monoclonal protein value (>1 g/dl of immunoglobulin G M-protein and >0.5 g/dl of immunoglobulin A M-protein) or urine light-chain excretion of >200 mg per 24 h for secretory MM, >30% plasma cells in the bone marrow and at least 1 plasmacytoma >2 cm, as determined by clinical examination or applicable radiographs for non-secretory MM. No exclusion criteria were planned in the protocol, to avoid the selection of fit elderly subjects only. Patients with low blood count, abnormal performance status, hepatic, renal, cardiac or pulmonary functions were enrolled. Patients agreed to use effective contraception and women of childbearing age had to give a negative pregnancy test before enrollment. The study was approved by the institutional review board at each participating center. All patients gave a written informed consent before entering the study in accordance with the Declaration of Helsinki.

Study design and treatment

The trial was a multicenter two-stage phase 2, non comparative, open label study, designed according to Bryant and Day method.17 The treatment schedule consisted of four induction cycles of lenalidomide−prednisone (RP), followed by six consolidation cycles with the addition of melphalan (MPR) and then maintenance therapy with RP. During each RP induction cycle, patients received lenalidomide 25 mg/day for 21 days every 4 weeks, plus prednisone 50 mg three times/week for 4 weeks. Each MPR consolidation cycle consisted of melphalan 2 mg and prednisone 50 mg for three times/week for 4 weeks, plus lenalidomide 10 or 15 mg/day for 21 days every 4 weeks. MPR-R 10 mg/day for 21 days every 4 weeks, plus prednisone 25 mg three times/week was planned until unacceptable adverse events or relapse or disease progression occurred (Figure 1).

Figure 1
Figure 1

Treatment schedule at the tolerated dose. Four 28-day induction cycles were followed by six 28-day consolidation cycles and maintenance until any sign of relapse or disease progression.

Two different doses of lenalidomide were tested in combination with MP: 15 mg (dose level 1) and 10 mg (dose level 2). Each cohort included 12 patients, with additional 22 patients enrolled at the tolerated dose.

All patients received aspirin 100 mg daily as thromboprophylaxis throughout lenalidomide treatment. Antiviral prophylaxis was administered in case of history of HZV infection. Appropriate antibacterial, antifungal or antiviral therapy was used in case of infections. All subjects were allowed to receive bisphosphonate therapy, hematopoietic growth factors and antibacterial prophylaxis as per medical judgment.

Lenalidomide dose reduction was applied based on creatinine clearance, for MM patients presenting with renal impairment at baseline: patients with creatinine clearance 50 ml/min received the full-planned dose, patients with creatinine clearance 30–50 ml/min received lenalidomide 10 mg/day, patients with creatinine clearance <30 ml/min, not requiring dialysis, received lenalidomide 15 mg every 48 h, patients requiring dialysis received 5 mg three times a week following each dialysis.

Dose adjustment for prednisone, lenalidomide and melphalan were planned based on toxicity. Subjects experiencing grade 3 or greater non-hematological adverse event had the drug held until the event resolved, and then drug was resumed at the next lower dose. Grade 4 hematological toxicity (except neutropenia) required dose reduction of both lenalidomide and melphalan. In case of grade 4 neutropenia, granulocyte colony-stimulating factor was added and drugs were resumed at the same dose, if neutropenia was the only toxicity. A new cycle was allowed if the neutrophil count was 1 × 109 l, platelet count was >50 × 109 l and hemoglobin >8 g/dl, but these hematological parameters were not considered if cytopenia was supposed to be related to plasma cell infiltration and not to drug-induced toxicity. A delay of 2 weeks was allowed without any dose modification. A new cycle delay beyond a maximum of 2 weeks required dose reduction.

Assessment of efficacy and safety

Assessment of efficacy was done every 28 days. Safety was assessed every 14 days during induction treatment, weekly during the first consolidation cycle, every 2 weeks during the remaining consolidation chemotherapy and monthly during the maintenance phase.

Treatment response was monitored by the measurement of protein in serum and urine at each participating center, and defined according to the International Response Criteria for MM.18 Briefly, complete response required the disappearance of myeloma protein in serum and urine, and negative immunofixation. Very good partial response (VGPR) required at least 90% reduction of myeloma protein in serum, or a urine M-protein level <0.100 mg per 24 h. Partial response (PR) required at least 50% reduction of myeloma protein in serum and at least 90% decrease in urine. Stable disease was defined as a response that did not meet the criteria for complete response, VGPR, PR or progressive disease (PD). PD was defined as an increase of 25% of M-protein from baseline. PFS was calculated from the time of enrollment until the date of progression, relapse, death or the date the patient was last known to be in remission. TTP was calculated from the time of enrollment to the time the patient was first recorded as having disease progression or the date the patient was last known to be in remission. OS was calculated from the time of enrollment until the date of death or the date the patient was last known to be alive. All adverse events were assessed at each visit and graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0).19

End points and statistical analysis

The primary safety end points of the study were grade 3 non-hematological and grade 4 hematological (except neutropenia) toxicity rate <30%. The primary efficacy end point was a significant number of PR (>70%) following the proposed therapy. Secondary efficacy points were PFS, TTP and OS. Time-to-event analysis were assessed using the Kaplan−Meier method.20 The analysis were performed with SAS version 8.2 (SAS Institute, Cary, NC, USA).

Results

Patients

From July 2008 to December 2009, 46 patients were enrolled in nine Italian centers. Patient demographics and baseline characteristics are reported in Table 1. According to study design a PR rate 50% and a grade 3−4 toxicity <50% were required to define the tolerated dose. All patients received induction with RP. The first 12 patients enrolled, received consolidation with lenalidomide 15 mg/day (dose level 1). After completion of at least two MPR cycles, the PR rate was 66.6% and the grade 3−4 toxicity rate was 58.3%. Grade 3−4 adverse events were cutaneous toxicity (three patients), infections (two patients) fatigue and depression (one patient each). Subsequent 12 patients were therefore enrolled to receive consolidation with lenalidomide 10 mg/day (dose level 2). In this cohort, response rate was 67.7% and grade 3−4 toxicity rate 41.6%. Grade 3−4 adverse events were skin rash (two patients), pneumonia and fatigue (one patient each). According to protocol design, lenalidomide 10 mg/day was defined as the tolerated dose and additional 22 patients were enrolled and treated at this dose level.

Table 1: Baseline clinical characteristics

At the time of analysis, all patients had completed the induction and consolidation treatment, and six patients are still on maintenance (Figure 2). The median time to completion of induction was 3.9 months, and the median time to completion of consolidation was 6.3 months. Patients with worse Karnofsky performance status (60%) had slightly longer time to complete therapy compared with patients with better performance status (70%; 4.3 vs 3.9 months for induction and 6.8 vs 6.3 months for consolidation). Two out of forty-six patients who received RP induction died (sudden death): one patient died during the first induction cycle and another during the third; both patients were aged >75 years, they had good performance status and mild concomitant disease (diabetes in one case and arterial hypertension plus chronic obstructive pulmonary disease in another). Five patients did not complete the assigned RP induction cycles because of cutaneous toxicity (four patients) and pneumonia (one patient); one patient experienced PD. Thirty-eight patients (82.6%) entered the MPR consolidation phase. Twelve patients did not complete the assigned six cycles for infection (one patient), fatigue (one patient), treatment discontinuation and switched to alternative therapy (three patients), lost to follow-up (one patient) and PD (six patients). Twenty-three patients entered the maintenance phase and received a median of 14 months of therapy with RP. Three patients did not receive maintenance due to PD (two patients) and poor clinical condition (one patient).

Figure 2
Figure 2

CONSORT diagram of patients enrolled in the study.

Safety

In this study, two sudden deaths (4%) were reported during the treatment, both occurred during RP induction, but none of these deaths were considered treatment related. The most frequent grade 3−4 adverse events were neutropenia, anemia, cutaneous reactions and infections (Table 2).

Table 2: Grade 3−4 adverse events, all patients

The majority of grade 3−4 adverse events occurred during RP induction cycles and decreased during consolidation, with the exception of neutropenia. During induction, the most frequent hematological grade 3−4 toxicities were neutropenia (ten patients, 22.2%) and anemia (five patients, 11.1%); granulocyte colony-stimulating factor was required in eight patients (17.7%), red blood cell support was required in twelve patients (26%) and platelet transfusion was required in one patient (2.2%). Common non-hematological grade 3−4 adverse events included cutaneous rash (eight patients, 17.7%), pneumonia (four patients, 8.8%) and hyperglycemia (three patients, 6.7%). Lenalidomide was reduced in thirteen patients (28.8%) because of cutaneous reactions (four patients), infections (three patients), anemia (two patients), fatigue (one patient), gastrointestinal toxicity (one patient) and medical decision (two patients: grade 1 infection in one patient and poor compliance in one patient). Therapy was discontinued in five patients (11.1%) because of cutaneous reactions (four patients), pneumonia and pulmonary edema (one patient).

During MPR consolidation at the tolerated dose, the most frequent grade 3−4 adverse event was neutropenia (10 patients, 34.5%). No grade 4 anemia or thrombocytopenia was observed. Granulocyte colony-stimulating factor was required in 11 patients (37.9%), red blood cell support was required in 3 patients (10.3%), and no platelet transfusion was needed. Non-hematological adverse events were reported in two patients (6.9%): one patient had cutaneous toxicity and one patient experienced myocardial infarction (Table 3). Four patients (12.1%) had to reduce lenalidomide and melphalan doses due to neutropenia and/or thrombocytopenia (three patients), and grade 3 cutaneous rash (one patient). One patient (3%) discontinued the drugs because of poor general conditions.

Table 3: Grade 3−4 adverse events, tolerated dose

During maintenance, the most frequent grade 3−4 adverse events was neutropenia (17.4%), no grade 3−4 thrombocytopenia or anemia were reported. Grade 3−4 non-hematological adverse events occurred in three patients (13.3%) and are listed in Table 2. Seventy-three months after enrollment, a patient who received 12 cycles of MPR-R developed a second cancer (bladder carcinoma).

In patient >75 years of age, grade 3−4 neutropenia and granulocyte colony-stimulating factor use were slightly increased compared with subjects <75 years (50 vs 41.2 and 50 vs 29.4%, respectively). No other differences in hematological and non-hematological toxicity rates were observed in patients aged >75 years compared with younger subjects. Dose reduction and drug discontinuations were equally distributed in the two subgroups.

Fourteen out of 46 patients (30.4%) received continuous cotrimoxazole antimicrobial prophylaxis during treatment, whereas 13 out of 46 (28.3%) received transient fluoroquinolone prophylaxis (ciprofloxacin or levofloxacin) in case of neutropenia. No correlation was observed between prophylaxis and infectious events.

All patients received anticoagulant prophylaxis, and no venous thromboembolic complications were reported during treatment.

Efficacy

One patient died during the first induction cycle (sudden death), and responses could be evaluated in 45 patients. At least VGPR was obtained in 13/45 (28.9%) patients, and 36/45 (80.0%) achieved at least a PR. In the subgroup of patients treated at the tolerated dose, complete response or VGPR was observed in 10/33 (30.3%) patients and at least PR in 28/33 (84.8%) patients.

At the tolerated dose, MPR consolidation improved response in 8/29 (27.6%) subjects (two patients improved from SD to PR, five from PR to VGPR, and one from VGPR to complete response). Further improvement in response during maintenance occurred in one (6.3%) of sixteen patients (Table 4).

Table 4: Response to therapy

The median duration of follow-up from study entry was 28.7 months (range, 9.5–40.2 months) for survivors. The median time from enrollment to initiation of therapy was 2 days. Progression or relapse occurred in 28/46 patients (60.9%), and death from any cause in 9/46 patients (19.6%). Median TTP was 19.6 months, median PFS was 18.4 months, and 2-years OS was 80% (Figure 3).

Figure 3
Figure 3

TTP, PFS and OS. Kaplan-Meier curves for the (a) TTP, (b) PFS and (c) OS. Median follow-up was 28.7 months. All 46 patients included in the study were censored.

No difference in survival was observed according to age: 2-year TTP was 48.9% in patients aged 75 years and 47.6% in patients aged <75 years, HR 1.01 (confidence interval (CI) 0.45–2.28, P=0.97); 2-year PFS was 45% in patients aged 75 years and 44% in patients aged <75 years, HR 1.08 (CI 0.50–2.31, P=0.85); 2-year OS was 82.5% in patients aged 75 years and 82% in patients aged <75 years, HR 1.32 (CI 0.36–4.96, P=0.67).

Fifteen patients had at least one high-risk cytogenetic abnormality (del13, del17, t4;14, t14;16) and were defined to have high-risk MM. In this subset of patients, a trend toward a shorter TTP was observed as compared with standard-risk patients (2-year TTP 31% vs 67.50%, HR 2.948; CI 0.826-10.523; P=0.095), but this difference was not statistically significant. No differences in PFS (2-year PFS 36% vs 55.4%, HR 1.92; CI 0.682–5.439; P=0.22) and OS (2-year OS 85.6% vs 84.6%, HR 1.349; CI 0.225–8.083; P=0.743) were observed between high- and standard-risk patients.

Discussion

In this phase 2 study, we evaluated safety and efficacy of an oral MPR combination with reduced melphalan dose, in newly diagnosed elderly myeloma patients. Our study shows that RP–MPR–RP could be a suitable treatment option for elderly patients with concomitant diseases. At the tolerated consolidation dose of melphalan 25 mg/month, plus lenalidomide 10 mg/day, the treatment appeared to be effective (PR rate 85%) and safe with a reduced hematological toxicity profile (grade 4 neutropenia 12%).

Elderly patients are more susceptible to side effects and are often unable to tolerate full drug doses. In frail patients, with reduced organ function and comorbidity, full-dose treatment might cause high rate of toxicity and discontinuation, and might negatively affect outcome.6 Vulnerable elderly patients are underrepresented in clinical trials and are not well studied.21

The strength of our study lies in its design specifically meant for elderly patients with concomitant diseases. No exclusion criteria were planned in the protocol, and patients were enrolled despite low blood count, abnormal performance status and impaired organ function. Median age was 75 years, one of the oldest population analyzed in studies published so far. About 60% of these patients had at least one concomitant disease, a third of the population presented more than one comorbidity, and renal function was impaired in 30%. Twenty-five percent of the patients had poor performance status. These patients are commonly excluded from clinical trials.

Lenalidomide proved to be effective in newly diagnosed elderly myeloma patients. Recently, a larger international phase 3 study comparing MPR-R with MPR or MP confirmed the efficacy of the combination of lenalidomide plus melphalan and defined the positive impact of MPR-R, which reduced the risk of progression by 66% compared with placebo.16 With the standard MPR schedule, major grade 3−4 adverse events were neutropenia and thrombocytopenia, while incidence of non-hematological adverse events was low; prolonged or severe neutropenia and thrombocytopenia were the main reasons to reduce or discontinue treatment.14, 15, 16

We designed a different schedule in the attempt to reduce the frequency of hematological toxicities and to improve the safety profile for elderly unfit patients. In previous studies, the majority of adverse events were reported during the first three cycles. Therefore, we planned four cycles of an alkylating-free induction with lenalidomide and prednisone to reduce tumor mass with few side effects, and then a melphalan-based consolidation to achieve the maximum cytoreduction.

During RP induction the most frequent grade 3−4 adverse events were neutropenia (22.2%), anemia (11.1%), cutaneous reactions (17.7%) and infections (11.1%). Incidence of neutropenia and infections did not significantly differ from those reported in previous studies with low-dose dexamethasone.11, 12, 13, 22, 23 Despite the exclusion of melphalan from the first four induction cycles, the majority of non-hematological adverse events occurred again in the first 3 months of treatment, suggesting that an early lenalidomide dose reduction could be useful in this class of patients. Recently, the Australian group showed that low dose dexamethasone in combination with reduced lenalidomide dose (15 mg/day on days 1−21, every 28 days) could be an effective induction regimen before autologous transplantation.24 Response rates appeared to be similar to those obtained in our trial, suggesting that induction with lenalidomide 15 mg/day could be a valid option to improve toxicity profile without affecting efficacy.

In the MPR consolidation regimen, schedule of lenalidomide was unchanged and the total dose of melphalan was halved in comparison with standard MPR studies. The major adverse events of MPR consolidation were hematological; however, their incidence was significantly reduced. At the tolerated dose, the rate of grade 4 neutropenia was 10.3% and grade 4 thrombocytopenia was not observed. These figures were significantly lower than those reported after therapy with standard MPR, in which the incidence of grade 4 neutropenia was 35% and grade 4 thrombocytopenia was 11%.16 These results were reported despite a major difference in patient population: in the current study the median age was 75 years and 59% of patients had concomitant diseases, in the other study the median age was 71 years and no patient had concomitant diseases.16

Melphalan dose reduction did not affect overall response rate. The addition of the alkylating agent during consolidation improved response: two patients with stable disease achieved a PR, and the depth of response was improved in about 25% of the subjects. At the tolerated dose, 85% of patients achieved at least a PR and 30% at least a VGPR; these results were similar to those previously reported with the standard dose of MPR. By contrast, the dose reduction of melphalan may have affected the duration of disease remission: median PFS with RP−MPR schedule (18.4 months) was shorter compared with standard MPR-R (28−31 months).14, 15, 16 In a recent study, where 50% of patients had concomitant disease and median age was 73 years, three different bortezomib combinations, followed by bortezomib maintenance showed a median PFS ranging from 13.8 to 17.3 months.25

Previous studies showed that high-risk patients had inferior outcomes compared with standard-risk patients when treated with lenalidomide plus dexamethasone.26, 27 In another trial, where an alkylating agent was added, these results were not confirmed.28 In our study, OS and PFS are not different between the high- and standard-risk group; however the small number of patients with bone sample available for cytogenetic studies and the presence of a trend towards longer TTP in standard-risk patients make it difficult to draw any conclusion.

In the last few years, clinical trials have shown the efficacy of the combination of alkylating agents and new drugs in MM patients who are ineligible for stem cell transplantation. The elderly frail, MM population could benefit from these combinations, but dose reductions are often mandatory to reduce the incidence of adverse events and improve outcome. The RP−MPR−RP strategy may represent a valid treatment option for elderly patients with disabilities or concomitant diseases requiring an oral outpatient treatment easy to manage and free of long-term toxicity.

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Acknowledgements

We thank the patients who took part in the study, the Rete Oncologica del Piemonte e della Valle d’Aosta, the nurses Manuela Grasso and Loredana Puccio, the data managers Federica Leotta and Elena Tigano and the editorial assistant Giorgio Schirripa.

Author information

Affiliations

  1. Division of Transfusional Medicine and Hematology, Cirié, Italy

    • P Falco
    •  & R Freilone
  2. Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy

    • F Cavallo
    • , A Larocca
    • , A Rocci
    • , S Oliva
    • , R Mina
    • , F Gay
    • , P Omedè
    • , S Bringhen
    • , M Boccadoro
    •  & A Palumbo
  3. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    • D Rossi
    • , L De Paoli
    •  & G Gaidano
  4. Unit Of Hematology, S Luigi Gonzaga Hospital, Orbassano, Italy

    • T Guglielmelli
  5. Department of Hematology, S Croce e Carle Hospital, Cuneo, Italy

    • M Grasso
  6. SOS Hematology, Department of Internal Medicine, Infermi Hospital, Biella, Italy

    • M L M Siez
  7. Department of Hematology-Oncology, A.O. Pugliese-Ciaccio, Catanzaro, Italy

    • S Molica
  8. Division of Haematology 2, ASO San Giovanni Battista, Torino, Italy

    • G Benevolo
  9. Unit of Hematology and Stem Cell Transplantation, IRCCS-CROB, Centro di Riferimento Oncologico, della Basilicata, Rionero in Vulture, Italy

    • P Musto
  10. Division of Hematology, S Martino Hospital, Genova, Italy

    • A M Carella

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Competing interests

PF has received honoraria from Celgene, Janssen-Cilag and Novartis; FC has received honoraria from Celgene, Janssen-Cilag, Onyx, and served on the advisory committee for Celgene; AL has received honoraria from Celgene and Janssen-Cilag; TG has received honoraria from Celgene and Janssen-Cilag; PM has received honoraria from Celgene; MB has received research funding from and served on the advisory board for Celgene and Janssen-Cilag; AP has received honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Merck, Onyx, and served on the advisory board for Celgene and Janssen-Cilag. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to A Palumbo.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/leu.2012.271

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