Lenalidomide Maintenance Prolongs Progression-Free Survival and Does Not Impact the Aggressiveness of Clinical Relapse: Data from Long-Term Follow up of the Myeloma XI Trial
Authors: Pawlyn Charlotte , Davies Faith E. , Royle Kara-Louise , Cairns David , Cook Gordon , Drayson Mark T , Gregory Walter M , Jenner Matthew , Jones John R , Kaiser Martin F. , Owen Roger G. , Russell Nigel H. , Morgan Gareth , Jackson Graham 
Published: November 2019

Background:

The impact of the selective pressure of maintenance Lenalidomide has the potential to enhance disease aggressiveness at relapse and if this were the case would shorten the time to next therapy. Previously we have shown that Lenalidomide maintenance therapy in myeloma is associated with improved progression-free survival (PFS). This initial analysis defined PFS as the time to biochemical progression but at that time point not all patients will go on to second line treatment, with the time to treatment being variable dependent on the aggressiveness of disease behavior at relapse. We have used time to next treatment as a marker of the impact of maintenance on disease behavior by analyzing long-term follow-up data from 1971 patients in the Myeloma XI trial.

Methods:

Myeloma XI is a phase III trial with pathways for transplant eligible (TE) and transplant ineligible (TNE) newly diagnosed myeloma patients who, after immunomodulatory agent-based induction therapy +/- autologous stem cell transplant, were randomized between lenalidomide maintenance (Len, 10mg 21/28 days) or observation (Obs). Maintenance Len ceased at the time of biochemical progression; neither the timing of commencement, nor agents used for second line therapy were mandated in the protocol. Taking advantage of the large sample size and median 50 months of follow-up we present updated PFS data, time to next treatment (TTNT) and an exploratory analysis to compare an estimate of the aggressiveness of relapse. We included all patients who progressed on trial excluding that defined by death. From the time of biochemical progression we compared the time to the start of next line of therapy between those patients who had received Len vs observation defining this as Time to Clinical Relapse (TCR). Hazard ratios (HR) were adjusted for induction/consolidation treatment and pathway.

Results:

Len was associated with a significant improvement in PFS compared to Obs. The median PFS was 41 months [95% CI 38,45] for those allocated to Len and 21 [19,23] for Obs (HR 0.50 [0.44,0.56], P <0.01). This was consistent in both the TE (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61] P <0.01) and TNE (median PFS Len 26 [22,31] vs Obs 11 [9,13], HR 0.47 [0.40,0.55] P <0.01) pathways.

TTNT was also significantly longer with Len compared to Obs. The median TTNT was 52 months [95% CI 46,60] for those allocated to Len and 28 [26,32] for Obs (HR 0.55 [0.49, 0.62] P < 0.01). This was consistent in both the TE (median TTNT Len 72 [64,NR] vs Obs 43 [38,49], HR 0.59 [0.49,0.70] P<0.01) and TNE (median TTNT Len 33 [28,38] vs Obs 17 [15,20], HR 0.51 [0.43,0.60] P <0.01) pathways.

At the time of analysis 569 patients had progressed on trial without progression defined by death. Of these 254 (148 TE, 106 TNE) were receiving Len and 315 (189 TE, 126 TNE) Obs. 422 (74.2%) had received a subsequent line of therapy or had died following progression. The most common second line therapy was a bortezomib containing regimen (45.6%). Overall the median TCR was 7.6 months [95%CI 6.4, 8.5]. There was no difference in TCR between patients receiving Len (median 6.3 months [95% CI 5.0, 8.1]) and Obs (8.1 months [7.0, 9.7]), HR 1.06 [0.87, 1.29]. This was consistent for both the TE and TNE pathways.

Conclusions:

We found no difference in the aggressiveness of relapse dependent upon whether patients received Lenalidomide maintenance or observation, using long term follow-up data and an exploratory analysis of time to clinical relapse. This is consistent with our data showing an absence of a significant change in mutational landscape between the groups. Further, the data are consistent with results of meta-analyses showing improved PFS and OS providing further support for the use of maintenance strategies with IMiD drugs.

on behalf of the NCRI Haematological Oncology Clinical Studies Group

Disclosures

Pawlyn: Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Cook:Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding; Abbvie, Janssen: Honoraria. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Owen:Celgene, Janssen: Honoraria; Celgene: Research Funding; Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria.

OffLabel Disclosure:

Lenalidomide for myeloma as maintenance therapy 10mg 21/28 days