Background In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. Methods Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. Findings Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6–103·1). The median time to progression was 57·3 months (95% CI 44·2–73·3) for the lenalidomide group and 28·9 months (23·0–36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46–0·71; p<0·0001). The most common grade 3–4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. Interpretation Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. Funding The National Cancer Institute.
Bibliographical noteFunding Information:
This updated analysis of the phase 3 randomised CALGB (Alliance) 100104 trial investigating lenalidomide versus placebo maintenance after ASCT showed a persistent benefit in time to disease progression and overall survival for lenalidomide. This benefit was maintained despite the crossover of most of the eligible patients in the placebo group to lenalidomide treatment at the time of study unblinding. Survival after progression did not differ between the two treatment groups. The benefit derived from lenalidomide maintenance was independent of induction therapy and the VGPR or complete response status at the time of randomisation. However, lenalidomide maintenance was associated with an increased risk of haematological second primary malignancies. This study and several other randomised trials 3–5,17,18 have shown benefit with prolonged lenalidomide therapy. A meta-analysis 6 of the CALGB, IFM, and GIMEMA studies found that lenalidomide maintenance significantly improved overall survival at a median follow-up of 79·5 months (median overall survival was not reached for lenalidomide vs 86 months for the control; HR 0·75; p=0·001). The study most directly comparable to CALGB (Alliance) 100104 is the IFM 2005-02 trial, 3 which also assessed lenalidomide versus placebo maintenance therapy after ASCT. Although a benefit in progression-free survival with lenalidomide was observed in that study, 3 no difference was seen in overall survival between the study groups. Multiple factors might contribute to the difference in survival outcomes between the studies, including the types of induction regimens, consolidation therapy, number of transplants, duration of lenalidomide maintenance, and available salvage therapies. Overall, the IFM 2005-02 study population was exposed to more traditional chemotherapy, whereas the CALGB (Alliance) 100104 study population was exposed to more novel drug-based therapy. The extent to which therapy before transplantation determines response to subsequent salvage therapies remains to be determined. However, our analysis showed that patients progressing on lenalidomide maintenance had a similar overall survival after progression to placebo patients after progression, which suggested that prolonged lenalidomide maintenance did not confer disease resistance. The optimal dose, schedule, and duration of lenalidomide maintenance continue to be topics for discussion. This study, as well as the GIMEMA RV-209 and Myeloma XI studies, 4,5 continued lenalidomide maintenance therapy until progression, whereas the IFM 2005-02 study 3 discontinued lenalidomide maintenance after a median time of 2 years (range 1–3 years) because of concerns about the risk of second primary malignancies. The IFM 2009 study, 19 which assessed the timing of ASCT, incorporated 1 year of lenalidomide maintenance, while the ongoing DETERMINATION trial ( NCT01208662 ) in the USA is identical in design to the IFM 2009 study except that maintenance is continued until progression. Future comparison of survival outcomes and toxicities, including the incidence of second primary malignancies, between the IFM 2009 and DETERMINATION studies will provide important information about the effect of maintenance duration. Most studies done in the USA and France (eg, CALGB 100104, BMT CTN 0702, IFM 2005-02, and IFM 2009) 2,3,19,20 have used continuous dosing of lenalidomide, whereas other studies done in Europe (eg, Myeloma XI, GIMEMA RV-209, RV-MM-EMN-441, and EMN02/HO95) 4,5,21,22 have used a 21 day out of 28 day schedule. In the absence of a prospective study comparing the two dosing schedules, conclusion of whether one schedule is better than the other from either a survival or toxicity perspective is difficult. However, the largest of the studies, CALGB 100104 and Myeloma XI, have found very similar median durations for time to disease progression or progression-free survival for the lenalidomide groups (57·3 months for this study and 60 months for Myeloma XI), despite their use of different dosing schedules. As ongoing and planned studies involving the addition of other drugs to lenalidomide maintenance progress (eg, NCT02874742 , NCT01718743 , NCT02495922 , and NCT02203643 ), the optimal dosing, schedule, and duration of lenalidomide maintenance will probably continue to evolve. A central review of the response data ( table 1 ) showed that, despite substantial efforts by participating sites to provide follow-up data, data were missing at later timepoints (years 2 and 3). These data include those for bone marrow biopsies, 24 h urine quantitations, and incomplete serum and urine electrophoresis analyses. The independent review committee reviewed all available primary source data. Despite these limitations, this review did show that there was little difference in the rates of complete response or VGPR between the two groups at 1 year. However, most patients who had a complete response or a VGPR after 3 years were in either the lenalidomide group or the crossover subgroup of the placebo group. This updated analysis of CALGB (Alliance) 100104 showed an increased risk of second primary malignancies associated with lenalidomide maintenance therapy, although the risks of progressive disease and death due to myeloma were substantially higher than the risk of second primary malignancies in both cohorts. The risk of second primary malignancies is associated with multiple factors, including the underlying disease, age of the patient, and type of myeloma therapy used. Several patients who were enrolled in the study but never randomised developed second primary malignancies ( appendix p 36 ). This finding is consistent with the underlying risk of a second primary malignancy in this patient population. The risk of malignancy increases with advancing age, and age-related clonal haemopoiesis is associated with increased risk of haematological malignancies. 23,24 Numerous studies 25–27 have shown that monoclonal gammopathy of undetermined significance and myeloma, even in the absence of therapy, are associated with an increased risk of haematological malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. This finding implicates the presence of an intrinsic defect in the haemopoietic system of patients with plasma cell dyscrasias. An increased risk of solid tumours in patients with myeloma has also been reported. 28 We did not find a predominant type of solid tumour second primary malignancy in this study. With respect to lenalidomide, a meta-analysis 29 of 3254 newly diagnosed patients treated in seven randomised, phase 3 trials showed that the cumulative 5 year incidence of all second primary malignancies was 6·9% in patients who received lenalidomide compared with 4·8% in those who did not (p=0·037). An increase in haematological malignancies (3·1% vs 1·4%; p=0·029), but not solid tumours (3·8% vs 3·5%; p=0·72), was observed in that meta-analysis. 29 Since the time of first publication of CALGB 100104, 2 four new solid tumour second primary malignancies and ten new haematological second primary malignancies were reported in the lenalidomide group. The risk of solid tumours appeared to be primarily incurred during the first several years of lenalidomide therapy after ASCT, with haematological malignancies continuing to be diagnosed at later follow-up ( appendix pp 13,14 ). However, given the overall small number of second primary malignancies, it was difficult to draw any definite conclusions regarding the temporal association between the type of second primary malignancy and lenalidomide exposure. Genetic analysis, particularly of the haematological second primary malignancies, is needed to better determine the mechanisms by which lenalidomide contributes to the pathogenesis of these malignancies. Although myelodysplastic syndrome and acute myeloid leukaemia have previously been associated with high-dose melphalan and myeloma therapy, the appearance of B-cell acute lymphoblastic leukaemia as a second primary malignancy has been somewhat unexpected. Further studies are needed to determine whether the effects of lenalidomide on IKZF1, a transcription factor that has been associated with B-cell acute lymphoblastic leukaemia, 30–32 contribute to the development of acute lymphoblastic leukaemia as a second primary malignancy. In conclusion, our study shows that lenalidomide maintenance therapy after ASCT confers significant benefit in time to disease progression and overall survival. The overall survival data (a median overall survival of 9·5 years from the time of ASCT with lenalidomide) provide a new benchmark for survival, particularly noteworthy because this study was done in an era when triplet regimens containing immunomodulatory drugs and proteasome inhibitors were not routinely used. Cytogenetic and fluorescence in-situ hybridisation testing of diagnostic samples was not available for most patients, thus the effect of lenalidomide maintenance on different cytogenetic risk groups could not be determined. Preliminary results from the Myeloma XI trial 5 showed benefit for lenalidomide maintenance in patients with high-risk or low-risk cytogenetic abnormalities. This study showed that patients in complete response after ASCT benefited from lenalidomide maintenance; however, determination of a complete response was done by the numbers of bone-marrow plasma cells and immunofixation testing. The revised IMWG criteria now include minimal residual disease assessment, and multiple studies 33–35 have shown superior outcomes for patients who achieve minimal residual disease negativity after ASCT. Thus, the extent to which lenalidomide maintenance improves survival outcomes for patients who are negative for minimal residual disease, compared with those who are positive for minimal residual disease, remains to be determined. One limitation of the study is that quality-of-life data were not prospectively collected. However, this study is among an increasing number of studies showing the feasibility of long-term maintenance therapy with lenalidomide. Lenalidomide maintenance until progression after ASCT might be considered a standard of care and should form the backbone of future maintenance studies incorporating novel drugs, such as monoclonal antibodies or vaccine-based approaches. This online publication has been corrected. The corrected version first appeared at thelancet.com/haematology on November 27, 2018 Contributors SAH did the literature search, figure design and construction, data collection, data analysis, data interpretation, and writing. S-HJ contributed to the data analysis, data interpretation, and writing. PGR, CCH, DDH, HH, SG, EAS, DJW, RV, JSM, NSC, KvB, TGG, LI, RTM, AB, HL, TM, MHQ, CR, BM, RLS, PH, MCP, and MMH contributed to the data interpretation and writing. SES contributed to the data interpretation. VH and CJ contributed to the data analysis, data interpretation, figures, and writing. KO, TCS, SMD, CL, and KCA contributed to the study design, data interpretation, and writing. MB, CS, and MW contributed to the data collection and data analysis. PLM contributed to the literature search, study design, data collection, data analysis, data interpretation, and writing. Declaration of interests KCA reports personal fees from Celgene, Millennium Takeda, Gilead, and Bristol-Myers Squibb. SG reports research funding and personal fees from Celgene and Takeda, research funding from Sanofi, and personal fees from Jazz and Amgen. PH reports grants and personal fees from Celgene. HH reports grants from CALGB (Alliance) during the study and grants from Celgene outside of the study. CCH reports other support (local principal investigator for clinical trial using drug made by Celgene) from Celgene. SAH reports personal fees from Celgene, Takeda, and Amgen, and travel support and honoraria for response adjudication of this study by the Alliance for Clinical Trials in Oncology. HL reports grants from Celgene during the study and personal fees from Spectrum Pharmaceuticals, Prothena, Janssen, and Takeda. PLM reports research support and personal fees from Celgene; personal fees from Bristol-Myers Squibb, Karyopharm, Gamida Cell, Janssen, Sanofi, and The Binding Site; and travel support and honoraria for response adjudication of this study by the Alliance for Clinical Trials in Oncology. MCP reports personal fees from Atara Biotherapeutics, Pfizer, and Baxalta. PGR reports personal fees from Celgene. EAS reports personal fees from Celgene and Takeda. RV reports personal fees from Celgene, Bristol-Myers Squibb, Janssen, AbbVie, and Karyopharm, and research support and personal fees from Amgen and Takeda. TM reports grants from Sanofi and Amgen, outside of the study. DJW, MW, AB, MB, NSC, SMD, TGG, VH, MMH, DDH, LI, CJ, S-HJ, CL, RTM, BM, JSM, KO, MHQ, CR, RLS, CS, TCS, SES, and KvB declare no competing interests. Acknowledgments This study was funded by the National Cancer Institute of the National Institutes of Health (award numbers U10CA031946, U10CA033601, U10CA180821, and U10CA180882 to the Alliance for Clinical Trials in Oncology; U01HL069294, U10CA021115, U10CA004457, U10CA007968, U10CA016450, U10CA021060, U10CA032291, U10CA047559, U10CA059518, U10CA077298, U10CA077440, U10CA077651, U10CA077658, U10CA138561, U10CA180791, U10CA180799, U10CA180833, U10CA180838, U10CA180850, U10CA180858, U10CA180866, and U10CA180867). Support for this study was provided in part by the Blood and Marrow Transplant Clinical Trials Network through grant number U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. Support was also provided in part by the Eastern Cooperative Oncology Group, supported by CA21115. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported in part by Celgene. We thank the patients and families who participated in this study and the clinical teams who provided care for the patients. We thank the research nurses, data coordinators, and investigators who participated in the data cleaning efforts. We thank those members of the Alliance who assisted with the protocol development and amendments, including Michael Kelly, Destin Carlisle, and Guadalupe Aquino. We thank Michelle Maglio for administrative support. We thank John Postiglione for his efforts on this study. Finally, we wish to honour the memory of Dan Sargent who died in 2016. Dan Sargent was the head of the Alliance Statistics and Data Center and facilitated the publication of the first report of the CALGB (Alliance) 100104 study, as well as the update; he provided sage advice throughout the analysis.
This study was funded by the National Cancer Institute of the National Institutes of Health (award numbers U10CA031946, U10CA033601, U10CA180821, and U10CA180882 to the Alliance for Clinical Trials in Oncology; U01HL069294, U10CA021115, U10CA004457, U10CA007968, U10CA016450, U10CA021060, U10CA032291, U10CA047559, U10CA059518, U10CA077298, U10CA077440, U10CA077651, U10CA077658, U10CA138561, U10CA180791, U10CA180799, U10CA180833, U10CA180838, U10CA180850, U10CA180858, U10CA180866, and U10CA180867). Support for this study was provided in part by the Blood and Marrow Transplant Clinical Trials Network through grant number U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. Support was also provided in part by the Eastern Cooperative Oncology Group, supported by CA21115. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported in part by Celgene. We thank the patients and families who participated in this study and the clinical teams who provided care for the patients. We thank the research nurses, data coordinators, and investigators who participated in the data cleaning efforts. We thank those members of the Alliance who assisted with the protocol development and amendments, including Michael Kelly, Destin Carlisle, and Guadalupe Aquino. We thank Michelle Maglio for administrative support. We thank John Postiglione for his efforts on this study. Finally, we wish to honour the memory of Dan Sargent who died in 2016. Dan Sargent was the head of the Alliance Statistics and Data Center and facilitated the publication of the first report of the CALGB (Alliance) 100104 study, as well as the update; he provided sage advice throughout the analysis.
© 2017 Elsevier Ltd