Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data

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• 作者：Prof Dr Antonio Palumbo ; MD^a ; ^{appalumbo@yahoo.com" class="auth_mail} ; Sara Bringhen ; MD^a ; Shaji K Kumar ; MD^d ; Giulia Lupparelli ; BS^a ; Saad Usmani ; MD^e ; Prof Anders Waage ; MD^f ; Alessandra Larocca ; MD^a ; Bronno van der Holt ; PhD^g ; Pellegrino Musto ; MD^h ; Massimo Offidani ; MD^c ; Maria T Petrucci ; MDⁱ ; Andrea Evangelista ; MS^b ; Sonja Zweegman ; MD^j ; Ajay K Nooka ; MD^k ; Prof Andrew Spencer ; MD^m ; Prof Meletios A Dimopoulos ; MDⁿ ; Roman Hajek ; MD^o ; Prof Michele Cavo ; MD^p ; Prof Paul Richardson ; MD^q ; Prof Sagar Lonial ; MD^l ; Giovannino Ciccone ; MD^b ; Prof Mario Boccadoro ; MD^a ; Kenneth Anderson ; MD^q ; Prof Bart Barlogie ; PhD^e ; Prof Pieter Sonneveld ; MD^g ; ^r ; Prof Philip L McCarthy ; MD^s
• 刊名：Lancet Oncology
• 出版年：March, 2014
• 年：2014
• 卷：15
• 期：3
• 页码：333-342
• 全文大小：229 K

文摘

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Summary

Background

Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure.

Methods

We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis.

Findings

We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6路9% (95% CI 5路3-8路5) in patients who received lenalidomide and 4路8% (2路0-7路6) in those who did not (hazard ratio [HR] 1路55 [95% CI 1路03-2路34]; p=0路037). Cumulative 5-year incidences of solid second primary malignancies were 3路8% (95% CI 2路7-4路9) in patients who received lenalidomide and 3路4% (1路6-5路2) in those that did not (HR 1路1 [95% CI 0路62-2路00]; p=0路72), and of haematological second primary malignancies were 3路1% (95% CI 1路9-4路3) and 1路4% (0路0-3路6), respectively (HR 3路8 [95% CI 1路15-12路62]; p=0路029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4路86 [95% CI 2路79-8路46]; p<0路0001). Exposure to lenalidomide plus cyclophosphamide (HR 1路26 [95% CI 0路30-5路38]; p=0路75) or lenalidomide plus dexamethasone (HR 0路86 [95% CI 0路33-2路24]; p=0路76) did not increase haematological second primary malignancy risk versus melphalan alone.

Interpretation

Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma.

Funding

Celgene Corporation.