What is the Benefit of Maintenance Therapy with Lenalidomide or Bortezomib after Autologous Stem Cell Transplantation in Multiple Myeloma and What is the Risk of Developing a Secondary Primary Malignancy?

Maintenance therapy was recently defined by the myeloma consensus panel as any treatment administered after the completion of induction therapy in patients whose disease is either responsive or nonprogressive at that time, with the goal of prolonging survival. The immunomodulatory drug thalidomide has been studied rigorously with 7 randomized trials evaluating post-ASCT thalidomide maintenance.^1–7  They differ with respect to induction regimen, single or tandem ASCT, dose and duration of thalidomide, concomitant corticosteroid usage, and comparator arm; however, thalidomide maintenance was consistently associated with longer progression-free survival (PFS; 32%-62% vs 14%-43% 3-5yr) but variable overall survival (OS) benefit (57%-87% vs 44%-77% at 3-8 years), but it led to a reduction in quality of life parameters and early discontinuation of even low-dose thalidomide due to intolerable toxicities. Therefore, focus recently has turned to the newer immunomodulatory drug lenalidomide and the proteasome inhibitor bortezomib as potential maintenance therapies.

We performed a comprehensive computerized literature search of the PubMed database from January 1, 2005 until June 6, 2011 using the terms multiple myeloma (MESH, clinical trials, randomized clinical trials and review articles, title/abstract 36 571 hits), AND maintenance (MESH, in title/abstract 4300 hits), AND stem cell transplantation (MESH, title/abstract, 395 hits) AND lenalidomide (MESH, no restrictions, 20 hits) OR bortezomib (MESH, no restrictions, 6 hits). Review articles were excluded. We also reviewed recent abstracts from the American Society of Hematology 52nd Annual Meeting in December 2010, the International Myeloma Workshop in May 2011, and the American Society of Clinical Oncology Annual Meeting in June 2011. We found 2 phase 3 trials of lenalidomide and 1 of bortezomib maintenance after ASCT (Table 1).

Lenalidomide maintenance was studied in 2 randomized, controlled trials comparing low doses of lenalidomide (10-15 mg/d) with placebo after ASCT: the IFM 2005-02 trial⁸  and the CALGB-100104 trial.⁹  Induction regimens were unspecified in both trials, and some patients received a tandem ASCT in the IFM 2005-02 trial and all patients on this trial received 2 cycles of post-ASCT consolidation lenalidomide 25 mg before randomization to placebo or lenalidomide maintenance. Both of these trials reported excellent time to progression (CALGB) and PFS (IFM) of 42-43.6 months in the lenalidomide arm compared with 21-24 months in the placebo arm, with a significant survival benefit in the CALGB study reported at the International Myeloma Workshop in May 2011 (IFM survival data not available). This benefit was observed across all stratified subgroups of patients, including beta-2 microglobulin level above or below 3 mg/L in both studies, cytogenetic profile (del 13+ or del 13−) and response after transplantation in the IFM 2005-02 trial. Whereas short-term toxicity was acceptable in these trials, a concerning finding is the increase in the incidence of secondary malignancies (SMs) at a median follow-up of 1.6-3.1 years (6.5% in the lenalidomide arms vs 1.6%-2.6% in the placebo arms), and in particular, acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) (1.7%-3.4% in the lenalidomide arms vs 0.4%-0.7% in the placebo arms). However, these are based on unpublished, interim analyses and longer follow-up is needed to accurately evaluate time to progression, PFS, OS, and the risk of SMs.

To further elucidate the potential risk of SMs associated with lenalidomide, we reviewed data from trials of lenalidomide therapy in non-ASCT patients. A retrospective review of SMs in 2 phase 3 trials (MM-009 and MM-010) revealed 8 (2.3%) SMs on the lenalidomide/dexamethasone arm of which 2 (0.6%) were MDS and 6 (1.7%) solid tumors compared with 2 (0.6%) on the placebo/dexamethasone arm, of which none were hematologic and 2 (0.6%) were solid tumors.^10,11  Updates of the lenalidomide maintenance trial (MM-015) in > 65-year-old newly diagnosed ASCT-ineligible patients by Palumbo et al (MP 9 cycles vs MPR 9 cycles vs MPR 9 cycles followed by lenalidomide maintenance until progression) revealed incidence rates of SMs of 4 of 150 in MPR-R (IR = 1.40), 6 of 152 in MPR (IR = 2.05), and 2 of 153 in the MP (IR = 0.67) arms, including 2 MDS in MPR-R and 2 AML cases in each of MPR-R and MPR (AML incidence was 0.7% vs 0% in the MP arm).¹²  Finally, Durie presented a retrospective review of pooled data from lenalidomide-based treatment arms of 11 Celgene-sponsored studies in relapsed refractory MM patients who received ≥ 24 months of lenalidomide. Of 3839 subjects, a total of 57 SMs were identified (8 MDS, 1 AML, 2 B-cell malignancies, and 46 solid tumors). Of these, 22 of 313 (7%) were in patients with ≥ 24 months of treatment (4 MDS, 1 AML, and 17 solid tumors). Overall, SM IR was 2.35 for ≥ 24 months of treatment.¹³ 

It should be noted that an analysis of 23 838 MM patients in general in the US SEER registry demonstrated an 8- to 9-fold risk of AML,¹⁴  and that other drugs commonly used in myeloma therapy, such as alkylating agents, are associated with a low but measurable risk of MDS/AML.¹⁵ 

Only one phase 3 trial of bortezomib maintenance post-ASCT with PFS and survival data has been reported. The HOVON 65/GMMG-HD4 study compared 2 overall approaches of vincristine, adriamycin, dexamethasone VAD induction, ASCT and low-dose thalidomide 50 mg/d for 2 years with bortezomib, doxorubicin and dexamethasone (PAD), ASCT, and then bortezomib every 2 weeks for 2 years. Both the PFS and OS rates and toxicity profiles were significantly better in the PAD arm (3-year PFS, 48 vs 42% and OS, 78 vs 71%). Patients with high-risk MM derived a particular benefit from bortezomib: the 3-year PFS for patients with t(4;14) was 32% compared with 22% in the controls.¹⁶  It may be difficult to determine the value of maintenance therapy alone in this study, which was designed to evaluate an entire transplantation approach.

For this patient with high-risk MM post-ASCT, we recommend maintenance therapy with lenalidomide 10-15 mg/d due to the significant reduction in risk of progression and death found in the CALGB 100104 and IFM 2005-10 trial interim analyses, although this recommendation is weak based on the considerations discussed above. Secondary AML/MDS remains an uncommon event after ASCT for MM with or without continued maintenance therapy, but ongoing analysis of lenalidomide maintenance therapy to determine the long-term risk of SMs is warranted. In view of the fact that bortezomib may have beneficial effects, particularly in patients with t(4;14), this would be our recommendation if stronger evidence for the role of this drug as maintenance therapy becomes available in the future. For standard-risk MM patients, we are less enthusiastic about post-ASCT maintenance therapy due to the immaturity of evidence supporting this strategy and the need for longer follow-up studies to assess true risk of SMs.

Conflict-of-interest disclosures: E.S. declares no competing financial interests. D.R. has received research funding from Millennium, Otsuka, Merck, Johnson & Johnson, Janssen, Celgene, and Bristol Meyers Squibb and has received honoraria from Otsuka, Merck, Janssen, Celgene, Bristol Meyers Squibb, and Amgen. Off-label drug use: lenalidomide for initial and maintenance therapy of myeloma; bortezomib for initial therapy before stem cell transplantation and as maintenance therapy in myeloma.