Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial

Abstract

Background: Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan.

Methods: Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively.

Findings: In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed.

Interpretation: This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes.

Funding: Primary financial support was from Cancer Research UK [C1298/A10410].

Keywords: Lenalidomide; Lenalidomide maintenance; Myeloma; SPM; Second primary malignancy; Transplant eligible; Transplant non-eligible.

Consort Diagram A

Transplant eligible consort diagram detailing the number of patients randomised and number of SPMconfirmed.

Consort Diagram B

Transplant non-eligible consort diagram detailing the number of patients randomised and number of SPM confirmed. Consort diagram outlining the number of patients randomized according to treatment allocation in the transplant eligible patients (consort A) and non-eligible patients (consort B). The number and type of SPM (haematological, NMSC and solid) developed during each treatment phase and according to treatment received is detailed. Abbreviations: CTD, cyclophosphamide, thalidomide and dexamethasone; CRD, lenalidomide, cyclophosphamide and dexamethasone; KCRD, carfilzomib, cyclophosphamide, lenalidomide and dexamethasone; len, lenalidomide; vori, vorinostat; SPM, second primary malignancy; haem, haematological; NMSC, non-melanoma skin cancer; solid, solid tumours.

Fig. 1

Cumulative incidence of SPM according to induction treatment received. a) The cumulative incidence of SPM in the TE pathway according to induction. The SPM incidence in patients receiving CTD was 2.0%, 4.7% and 8.3% at 3, 5 and 7 years. In patients receiving CRD the incidence was 3.1%, 5.8% and 9.3% at 3, 5 and 7 years (Pepe–Mori p = 0.08). The data relating to KCRD induction is less mature but the incidence at 3 and 5 years was 2.7% and 8.1% years. b) The cumulative incidence of SPM in the TNE pathway according to induction. The SPM incidence in patients receiving CTDa was 6.5%, 9.8% and 12.5% at 3, 5 and 7 years, respectively. The incidence in patients receiving CRDa was 6.0%, 10.4% and 14.3% at 3, 5 and 7 years, respectively (Pepe–Mori p = 0.47). c) The cumulative incidence of SPM in the TE pathway according to maintenance. The SPM incidence in patients being observed was 2.1%, 4.1% and 5.8% at 3, 5 and 7 years. In patients randomised to lenalidomide ± vorinostat the incidence was 4.5%, 10.5% and 12.2% (Pepe–Mori p = 0.006). d) The cumulative incidence of SPM in the TNE pathway according to maintenance. The SPM incidence in patients being observed was 6.2% and 10.2% and at 3 and 5 years. In patients randomised to lenalidomide ± vorinostat the SPM incidence was 9.9% and 17.2% at 3 and 5 years (Pepe–Mori p = 0.10).

Fig. 2

Number and incidence of SPM type according to maintenance randomisation. a) The type, incidence and number diagnosed in all trial patients randomised through maintenance. The overall incidence of all cancer types was low. In the lenalidomide maintenance patients, only SCC (2.7%) and BCC (2.2%) were diagnosed in >1% of patients. No cancers were diagnosed in >1% of the patients being observed. Haematological malignancies were almost exclusively seen in the lenalidomide maintenance patients, with MDS and AML forming the majority of cases. Of the 38 cancer types, more cases were noted in the lenalidomide treated patients, except for prostate, pancreas, ovary, renal cell, bile duct, gastric and testes, where there was either 1 or 2 extra cases in those randomised to observation. b) The type, incidence and number diagnosed in TE pathway patients randomised through maintenance. The overall incidence of most SPM types was low, noted in <1% of patients. In the lenalidomide maintenance patients, BCC (1.6%), MDS (1.3%) and SCC (1.1%) were noted in >1%. In the observation series only prostate cancer (1.2%) was diagnosed in >1%. Haematological malignancies were almost confined to the patients receiving lenalidomide, with most cases being AML and MDS. Only two haematological SPM were diagnosed in the observed patients, compared to 24 in those receiving lenalidomide. BCC and SCC were also almost completely confined to lenalidomide maintenance patients. Most other cancer types were diagnosed in a small number of patients, although the majority in those receiving lenalidomide. c) The type, incidence and number diagnosed in TNE pathway patients randomised through maintenance. SCC and BCC were the most diagnosed SPM in both the lenalidomide and observation patients, although most cases were noted in the lenalidomide maintenance patients, where the overall incidence of SCC and BCC was 5.5% and 2.6%, respectively. Only eight patients were diagnosed with a haematological SPM, 7 of which were in the lenalidomide maintenance patients. More SPM and SPM types were diagnosed in the lenalidomide maintenance patients. Abbreviations: MDS, myelodysplastic syndrome; AML, acute myeloid leukaemia; B-ALL, B lymphocyte acute lymphoblastic leukaemia; DLBCL, diffuse large B cell lymphoma; CML, chronic myeloid leukaemia; T-ALL, T lymphocyte acute lymphoblastic leukaemia; GIST, gastrointestinal stromal tumour; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; Haem, haematological malignancy; NMSC, non-melanoma skin cancer; solid, solid tumour.

Fig. 2

Number and incidence of SPM type according to maintenance randomisation. a) The type, incidence and number diagnosed in all trial patients randomised through maintenance. The overall incidence of all cancer types was low. In the lenalidomide maintenance patients, only SCC (2.7%) and BCC (2.2%) were diagnosed in >1% of patients. No cancers were diagnosed in >1% of the patients being observed. Haematological malignancies were almost exclusively seen in the lenalidomide maintenance patients, with MDS and AML forming the majority of cases. Of the 38 cancer types, more cases were noted in the lenalidomide treated patients, except for prostate, pancreas, ovary, renal cell, bile duct, gastric and testes, where there was either 1 or 2 extra cases in those randomised to observation. b) The type, incidence and number diagnosed in TE pathway patients randomised through maintenance. The overall incidence of most SPM types was low, noted in <1% of patients. In the lenalidomide maintenance patients, BCC (1.6%), MDS (1.3%) and SCC (1.1%) were noted in >1%. In the observation series only prostate cancer (1.2%) was diagnosed in >1%. Haematological malignancies were almost confined to the patients receiving lenalidomide, with most cases being AML and MDS. Only two haematological SPM were diagnosed in the observed patients, compared to 24 in those receiving lenalidomide. BCC and SCC were also almost completely confined to lenalidomide maintenance patients. Most other cancer types were diagnosed in a small number of patients, although the majority in those receiving lenalidomide. c) The type, incidence and number diagnosed in TNE pathway patients randomised through maintenance. SCC and BCC were the most diagnosed SPM in both the lenalidomide and observation patients, although most cases were noted in the lenalidomide maintenance patients, where the overall incidence of SCC and BCC was 5.5% and 2.6%, respectively. Only eight patients were diagnosed with a haematological SPM, 7 of which were in the lenalidomide maintenance patients. More SPM and SPM types were diagnosed in the lenalidomide maintenance patients. Abbreviations: MDS, myelodysplastic syndrome; AML, acute myeloid leukaemia; B-ALL, B lymphocyte acute lymphoblastic leukaemia; DLBCL, diffuse large B cell lymphoma; CML, chronic myeloid leukaemia; T-ALL, T lymphocyte acute lymphoblastic leukaemia; GIST, gastrointestinal stromal tumour; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; Haem, haematological malignancy; NMSC, non-melanoma skin cancer; solid, solid tumour.

Fig. 3

SPM incidence and profile according to lenalidomide exposure at induction and maintenance. a) SPM type, incidence and number of patients diagnosed in TE patients following maintenance randomisation according to lenalidomide exposure. Patients not treated with lenalidomide (grey star/bar) during the trial relates to those who received CTD induction and randomised to observation (n = 701). Patients who received lenalidomide at one time-point i.e., single exposure (red circle/bar), received KCRd or CRD at induction and randomised to observation, or patients who received CTD and were randomised to lenalidomide maintenance (total = 1263). The blue diamond/bar details SPM cases diagnosed in patients exposed to lenalidomide at both induction and maintenance (double exposure) and includes patients who received CRD or KCRD and were randomised to lenalidomide maintenance (n = 568). Most SPM were diagnosed in patients who had been exposed to lenalidomide, with the greatest incidence noted in the double exposed group. Haematological SPMs were almost confined to the lenalidomide treated patients, with a greater incidence in those who had received lenalidomide at induction and maintenance. Few SPM were noted in the patients who were not exposed to lenalidomide. b). SPM type, incidence and number of patients diagnosed in TNE patients following maintenance randomisation according to lenalidomide exposure. Patients not treated with lenalidomide (grey star/bar) during the trial includes those who received CTDa induction and were randomised to observation (n = 677). Patients who received lenalidomide at one time-point i.e., single exposure (red circle/bar), received CRDa at induction and were randomised to observation, or patients who received CTDa and were randomised to lenalidomide maintenance (total = 899). The blue diamond/bar details SPM cases diagnosed in patients exposed to lenalidomide at both induction and maintenance (double exposure) and includes patients who received CRDa and lenalidomide maintenance (n = 260). Non-melanoma skin cancers dominated, particularly in the lenalidomide exposed patients, with the greatest incidence in the double exposed group. Haematological SPMs were rare, although almost confined to the lenalidomide treated patients. Solid tumours were also noted more frequently in the lenalidomide treated patients, with the greatest incidence in those who were exposed at induction and maintenance. Abbreviations: MDS, myelodysplastic syndrome; AML, acute myeloid leukaemia; B-ALL, B lymphocyte acute lymphoblastic leukaemia; DLBCL, diffuse large B cell lymphoma; CML, chronic myeloid leukaemia; T-ALL, T lymphocyte acute lymphoblastic leukaemia; GIST, gastrointestinal stromal tumour; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; Haem, haematological malignancy; NMSC, non-melanoma skin cancer; solid, solid tumour; CTD, cyclophosphamide, thalidomide and dexamethasone; CRD, lenalidomide, cyclophosphamide and dexamethasone; KCRD, carfilzomib, cyclophosphamide, lenalidomide and dexamethasone; len, lenalidomide; vori, vorinostat.

Fig. 4

Outcome of patients treated in the TE and TNE pathway according to maintenance randomisation. Outcomes according to pathway and maintenance randomisation. In both the TE and TNE pathways, a greater proportion of patients receiving lenalidomide were alive at the data cut-off, compared to those who were being observed. The main cause of death in all groups was progressive myeloma, although the incidence was lower in both the TE and TNE lenalidomide maintenance series, compared to the patients being observed. Non myeloma related death was low in patients treated in the TE pathway, reported in 2.5% of the lenalidomide maintenance patients and 3.7% of patients being observed. The non-myeloma death rate was higher in TNE patients, reported in 10.8% of those receiving lenalidomide maintenance and 8.9% of patients being observed. The SPM death rate was low in all groups, but highest in the TNE patients treated with maintenance lenalidomide, where 6.1% of patients died as a consequence of a second cancer.