Clinical outcomes with fixed-duration therapy (UK real-world data) compared with continuous lenalidomide and low-dose dexamethasone therapy (FIRST trial; MM-020) for transplant-ineligible patients with newly-diagnosed multiple myeloma

Despite recent approval of lenalidomide by The National Institute for Health and Care Excellence (NICE), fixed-duration therapy (FDT) with thalidomide or bortezomib plus an alkylating agent and steroid remains a frontline standard of care in the UK for patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) [1,2]. In the FIRST trial (MM-020; NCT00689936), overall survival (OS) and progression-free survival (PFS) were significantly longer in patients randomized to lenalidomide and low-dose dexamethasone (Rd) until disease progression versus FDT (72 weeks) with melphalan, prednisone, thalidomide (MPT) [3,4].

The aim of the present study was to compare the clinical outcomes of real-world patients with transplant-ineligible NDMM who received FDT within the Thames Valley Cancer Network, (reflective of UK clinical practice), versus patients who received Rd continuous treatment in the MM-020 trial.

Patients within the UK Thames Valley Cancer Network with transplant-ineligible NDMM and measurable disease (defined by the International Myeloma Working Group guidelines [5,6]) who received ≥1 cycle of FDT outside a clinical trial during 2009–2017 were included in the FDT cohort. Patients in the Rd continuous arm of the MM-020 trial were eligible for inclusion in the Rd continuous cohort (details previously reported in [3]).

To facilitate comparisons between the cohorts in this retrospective evaluation, a subgroup of patients from the Rd continuous arm of the MM-020 trial was selected by random sampling to be proportionally matched to eligible patients who received FDT in real-world practice according to age (≤75 vs. >75 years) and International Staging System (ISS) stage (I or II vs. III), characteristics which are prognostic of survival.

The primary endpoint was OS. Secondary endpoints included: PFS, time to next therapy (TTNT), and treatment-free interval (TFI; only assessed in the FDT cohort) (For additional methodological information see Supplementary Appendix, Methods).

The FDT and matched Rd continuous cohorts comprised 223 and 254 patients, respectively (Supplementary Appendix, Figure S1). The baseline demographic and clinical characteristics of these two cohorts were comparable (Table 1). The median ages of the FDT and Rd continuous cohorts were 75 and 76 years, respectively; 58% and 59% of patients, respectively, had ISS stage III disease.

Table 1. Baseline patient demographic and clinical characteristics.

Characteristic	FDT cohort (n = 223)	Rd continuous cohort (n = 254)
Male, n (%)	126 (57)	149 (59)
Age, median (IQR), years	75 (70–81)	76 (69–79)
≤75 years, n (%)	110 (49)	125 (49)
>75 years, n (%)	113 (51)	129 (51)
ISS stage, n (%)
I or II	93 (42)	105 (41)
III	130 (58)	149 (59)
Serum creatinine ≥140 μmol/L,^a n (%)	62 (29)	56 (22)
Frontline therapy, n (%)
Thalidomide-based	148 (66)	–
Proteasome inhibitor-based^b	53 (24)	–
Lenalidomide-based	–	254 (100)
Alkylator-based	22 (10)	–
Frontline combination regimen, n (%)
Doublet	61 (27)	254 (100)
Triplet	162 (73)	–
Cycles of frontline therapy^c
Median (range)	6 (1–28)	19 (1–91)
1–5 cycles, n (%)	106 (48)	54 (21)
6–10 cycles, n (%)	109 (50)	34 (13)
>10 cycles, n (%)	<5 (≤2)	165 (65)
Duration of frontline therapy, median (range), months^c	4.6 (0.2–25.6)	18.0 (0.1–84.3)
Isotype,^d n (%)
IgG	110 (49)	153 (60)
Kappa light chain/free kappa	36 (16)	–
Lambda light chain/free lambda	30 (13)	–
IgA	41 (18)	71 (28)
IgA/IgG	<5 (≤2)	<5 (≤2)
IgM	<5 (≤2)	<5 (≤2)
IgD	<5 (≤2)	<5 (≤2)
Not available	<5 (≤2)	26 (10)

Where n = 0–4, numbers have been suppressed and reported as <5, to preserve confidentiality.

^aData available for 217 patients in the FDT cohort.

^b52 patients received bortezomib and 1 patient received carfilzomib.

^cData available for 219 patients in the FDT cohort and 253 patients in the Rd continuous cohort.

^dPercentages may not total 100% due to rounding.

FDT: fixed-duration therapy; Ig: immunoglobulin; IQR: interquartile range; ISS: International Staging System; Rd: lenalidomide and low-dose dexamethasone.

In the FDT cohort, the most common frontline therapies included thalidomide (66%) or proteasome inhibitors (PI) (24%) (Table 1). The most commonly used combinations were attenuated cyclophosphamide, thalidomide, and dexamethasone (CTDa) (35%) and cyclophosphamide, thalidomide, and dexamethasone (CTD) (21%) (Supplementary Appendix, Table S1). A larger proportion of patients (50%) receiving PI regimens had renal impairment in the FDT cohort (Supplementary Appendix, Figure S2) [2].

Median OS was significantly shorter in the real-world FDT cohort than in the MM-020 trial-derived continuous cohort (30.3 vs. 58.6 months; p < 0.0001) (Figure 1(A)); and 5-year OS was lower (27% vs. 47%). Similarly, median PFS (Figure 1(B)) and TTNT (Figure 1(C)) were significantly shorter in the FDT cohort (9.0 vs. 25.7 months; p < 0.0001 and 16.7 vs. 42.2 months; p < 0.0001, respectively); after 5 years, more patients in the FDT cohort had progressed to second-line treatment (94% vs. 61%). The longest median TFI in the FDT cohort was after frontline therapy (6.9 months), decreasing to 1.9 and 0.5 months after second- and third-line therapy, respectively (Supplementary Appendix, Table S2).

Figure 1. OS (A), PFS (B), and TTNT (C) were all significantly shorter in the real-world FDT cohort than in the MM-020 trial-derived Rd continuous cohort (Kaplan–Meier analyses). Time-dependent variables were compared between the FDT and Rd continuous cohorts using unstratified log-rank tests and Cox regression analyses, with proportionality of hazards evaluated using Schoenfeld residuals. ^aOne patient died before the start of the treatment. ^bDue to lack of progression-onset information, patients were censored at time 0; n = 3 in the FDT cohort, and n = 7 in the Rd continuous cohort. CI: confidence interval; FDT: fixed-duration therapy; HR: hazard ratio; OS: overall survival; PFS: progression-free survival; Rd: lenalidomide and low-dose dexamethasone; TTNT: time to next treatment.

In the present study, real-world patients with transplant-ineligible NDMM who received FDT had worse OS, PFS, and TTNT than age- and ISS stage-matched patients who received Rd continuous treatment in the MM-020 trial. Our results are consistent with other studies reporting benefits with continuous treatment compared with FDT in patients with transplant-ineligible NDMM [7,8], as well as with a recent meta-analysis featuring data from the FIRST trial [9]. These data further support that Rd continuous treatment helps provide sustained disease control.

Delaying disease progression may be particularly beneficial for older transplant-ineligible NDMM patients who may not respond to further therapy at first relapse, or who do not have the opportunity to receive multiple lines of treatment due to cumulative adverse events and/or comorbidities. In our real-world FDT cohort, the median TFI following frontline therapy was short (6.9 months) and decreased with subsequent lines of therapy. These results confirm observations of a large European retrospective chart review study, which highlighted that adverse events, comorbidities, and older age were negatively associated with treatment continuation, with only 61% and 38% of patients reaching second- and third-line treatments, respectively [10]. Conversely, a study that evaluated patient preferences for multiple myeloma (MM) treatment attributes reported that achieving TFI after frontline therapy can sometimes drive patient preference for FDT [11]. However, with the introduction of newer, more tolerable drugs, continuous active treatment has the advantage over FDT of delaying relapse. Thus, any benefits of the first TFI on health-related quality of life with FDT are likely to be limited for most patients and should be balanced against the significant physical and emotional burden associated with relapse [12,13]. These findings suggest that highly effective treatments, given until disease progression, may be more beneficial than FDT followed by a TFI.

Patients in our real-world FDT cohort received a variety of different frontline regimens, with the majority receiving CTDa or CTD (56%) or bortezomib and dexamethasone (16%); while <10% patients received a bortezomib-containing triplet regimen and <10% received MPT. These treatment patterns are likely due to NICE prescribing guidelines [1,2], the wide clinical trial experience with CTD in the UK, and because bortezomib was not available as frontline treatment during the earlier years of the current study.

The median frontline treatment duration of 4.6 months for patients in our real-world FDT cohort was substantially shorter than the 15.4 months for patients treated with MPT in the MM-020 trial [3]. The mean daily dose of thalidomide in the real-world FDT cohort was also lower than that specified for the MPT arm of the MM-020 trial (51.4 mg vs. up to 200 mg [3]). Clinical experience suggests that this difference reflects a failure to escalate the dose of thalidomide from the 50 mg starting dose due to poor tolerability, and this is reflected in the high discontinuation rates seen in randomized controlled trials (RCTs) [14].

Our study has some limitations. First, we compared real-world patients on FDT with patients on Rd continuous in an RCT. Although the results of such a comparison should be interpreted with caution, we note that the median OS and PFS in the FDT cohort (30.3 and 9.0 months, respectively) are in line with those reported for CTDa in a large RCT, where median OS and PFS were 33.2 and 13.0 months, respectively [15]. This suggests that our real-world data may be comparable with RCT data. Second, the Rd continuous cohort comprised patients from the MM-020 trial [3,4], which mandated exclusion and data-censoring criteria that were not applied to the real-world FDT cohort. The patients in the Rd continuous cohort included in this analysis tended to be older and have more advanced disease than the entire cohort of patients receiving Rd continuous treatment in the MM-020 trial [3,4]. However, the median OS and PFS for our matched subgroup of patients were very similar to those in MM-020 [4]. In addition, the Rd continuous arm of the MM-020 trial contained a high proportion of patients aged >75 years (35%), ISS stage III (40%), high-risk cytogenetics (17%), and those with severe renal impairment not requiring dialysis (8%) [3], thus making it more likely that the population reflected real-world patients with transplant-ineligible NDMM. Third, although the cohorts in the present analysis were matched by age and ISS stage, other prognostic factors were not available for the FDT cohort. The matching approach resulted in the Rd continuous and FDT cohorts having comparable characteristics in terms of age, sex, ISS stage, renal impairment, and MM isotype. However, we cannot dismiss that patients receiving FDT may have had more complex clinical presentations, which may have influenced outcomes.

In conclusion, this retrospective study that compared transplant-ineligible NDMM patients in a real-world setting in the UK with those in RCT provides evidence of therapeutic survival benefits among patients who received Rd continuous treatment until disease progression versus FDT treatment predominately comprising thalidomide-based regimens.

Acknowledgements

The authors would like to thank pH Associates (Sam Oliver and Angela Carter) for their support with data analysis, medical writing services, and assistance, funded by Celgene Corporation. Additional medical writing support was provided by Excerpta Medica (Mauro Locati, PhD), funded by Celgene Corporation, Summit, NJ, USA. The authors are fully responsible for all content and editorial decisions for this manuscript.

Disclosure statement

F.A.S. has received an educational grant and personal travel expenses from Celgene Corporation. F.D. has received grants and honoraria from Celgene Corporation. S.F. and J.K. have no conflicts of interest to disclose. J.A.L. is an employee of Celgene Corporation and holds shares in Celgene Corporation. S.M-S. is an employee of Open Vie. K.R. has received grants and honoraria from Amgen, Celgene Corporation, Janssen, and Takeda and honoraria from AbbVie, Oncopeptides, and Sanofi.

Additional information

Funding

Celgene Corporation provided FIRST trial data and funded this research.