Abstract
Background
In recent years, the introduction of the immunomodulatory drugs (IMiDs) thalidomide & lenalidomide & the proteasome inhibitor (PI) bortezomib has substantially improved the therapeutic options & prolonged survival of patients (pts) with multiple myeloma (MM). Current treatment strategies involve sequential exposure to these agents, though the most effective sequencing of exposure has yet to be determined. MM is still, for the majority of pts, a relapsing & incurable disease with poor survival outcomes & alternative treatment approaches in relapsing disease after exposure to currently available novel agents is an on-going unmet need. We report the results of extended follow-up in this patient cohort.
Objectives
We examined outcomes in pts with progressive disease following sequential exposure to thalidomide, bortezomib & then lenalidomide, to assess responses to these & subsequent therapies in a “real-life” single centre setting.
Methods
Pts were eligible for this retrospective study if they had received sequentially thalidomide-, bortezomib- then lenalidomide-based combination therapy (LenCom) for MM as per The National Institute for Health & Care Excellence (NICE) guidance. Case records were examined for diagnostic details, depth & duration of response to PI treatment & regimens employed. T0 was defined as the time point at which LenCom was discontinued, whether for progressive disease (PD) or intolerance (I). Response to therapy subsequent to T0& Progression Free Survival/Overall Survival (PFS/OS) were assessed & factors predicting outcome analysed (e.g. ISS stage at diagnosis, age, previous therapies received, previous depth & length of response to treatment).
Results
Between Jan’07-Sept’12, 55 pts (27 Male & 28 Female) were enrolled. Median age at diagnosis was 59 yrs (range 33-89);ISS scores were: 20% stage I, 28% stage II & 28% stage III (23% unclassified). The median number of lines of therapy prior to LenCom was 3 (range 2-6). First line therapy was thalidomide-based in 64%; 36% underwent ASCT & 4 pts underwent tandem ASCT/RIC AlloSCT. Second line therapy was bortezomib-based in 42% & 53% pts received lenalidomide as > 4th line. Median time from diagnosis to commencing LenCom was 52.5mns (range 4-146). 43 pts (77%) had reached T0 (PD n=29, I n=14). At a median of 66 mns follow up (range 12-162 mns), a median of 9 cycles (range 1-32) of LenCom were administered to all pts & 7 cycles (range 1 -32) to those who had discontinued LenCom. Dexamethasone was discontinued after median 12 cycles in pts reaching T0, being stopped in 28% (median 6 cycles before T0). Median PFS from commencement of LenCom was 16.2 mns. At 4 mns median follow-up post T0, a total of 26 pts have received therapy after T0, of whom 3 received lenalidomide-based treatment (11.5%) & 3 received bortezomib-based treatments (11.5%). Thalidomide based treatment was received by 13 pts (combined with Bendamustine in 3 & bortezomib in 2). Post-T0 pts also received clinical trial therapies (3 pts on SRT501 trial, 1 pt on pomalidamide companion study & 1 pt on KW2478 – a heat shock protein 90 inhibitor), thalidomide-based treatment (10 pts, 2 with bortezomib), & high dose dexamethasone. 13 pts (50%) demonstrated PD as maximum response to first post-T0 therapy. Duration of response was generally very limited (median 0 mns, range 0-6 mns). Second line post T0 treatments, including pomalidomide, were received by 12 pts with only 2 pts pts achieving a PR or better to Thalidomide & bortezomib based regimens. Third line post T0 treatments were given to 2 pts with 1 pt achieving a further brief PR to DT-PACE. With a median follow-up of 6.4mns (1-37), 31 pts have died (PD n=18, infection n=6, other n=7). Median OS from diagnosis & commencement of LenCom were 100 mns & 18.4 mns, respectively. Median OS from T0 was 3.9mns (range 0-33 mns), influenced by the b2-microglobulin at T0 (<vs.³ 3.0 mg/L: 9 vs. 4.8 mns, p=0.027). The depth of response to LenCom correlated with PFS (P<0.001) but not post-T0OS (p=0.68).
Conclusion
Pts with MM who have relapsed after sequential exposure to thalidomide, bortezomib & lenalidomide have very limited treatment options. At present, a wide range of treatments are used, including re-challenging with lenalidomide, bortezomib & trial based treatments. However, few pts achieve a meaningful response to therapy & survival is consequently extremely poor.
Disclosures:
No relevant conflicts of interest to declare.
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