Abstract

A 51-year-old male was diagnosed with an IgA multiple myeloma (MM) after having back pain for several months. His bone marrow showed 30% involvement with plasma cells and his cytogenetics showed t(4:14). His β2-microglobulin was 6.5 mg/dL at diagnosis and he had multiple lytic lesions, along with a creatinine of 2.3 mg/dL and significant anemia. Induction therapy with lenalidomide, bortezomib and dexamethasone was used, and he was able to achieve complete remission after 4 cycles of therapy. He then went on to receive high-dose chemotherapy with a single autologous stem cell transplant. He tolerated it well and now comes to discuss follow-up treatment plans. He wants to discuss maintenance therapy.

Despite recent advances in its care, MM remains an incurable disease, although an operational cure may be achieved in some patients. Even with modern induction regimens and stem cell transplantation relapse will usually occur within 3 to 5 years, suggesting that effective maintenance therapy is needed to control or delay disease progression.1 Studies in the relapsed or refractory setting, which use thalidomide, bortezomib and lenalidomide and continue therapy until progression, have shown high responses with long duration.2,4 Despite these positive results, maintenance therapy post-induction has not been extensively studied. For this article, we performed a Medline search for all the clinical trials that included maintenance therapy in multiple myeloma using the terms “maintenance therapy, myeloma, and clinical trials.” We also reviewed recent abstracts accepted in the American Society of Hematology and the American Society of Clinical Oncology. A total of 218 manuscripts were identified. Review articles were excluded and original clinical trials were included as shown below (Table 1 ).

Mandelli et al performed the first trials of maintenance therapy. They studied the role of interferon-alpha 2b in MM.5 Interferon significantly improved the response duration (26 vs 14 months) with no significant improvement in overall survival (OS; 52 vs 39 months).5 However, follow-up studies failed to confirm these results.6,7 A meta-analysis on the use of interferon, both as maintenance and as part of the induction therapy, showed that progression-free survival (PFS) and response duration were improved compared with no maintenance; conversely, patients who received interferon as maintenance therapy had decreased OS (P = .007).8 

Based on the observation that MM is often responsive to steroids, a randomized trial (Southwest Oncology Group [SWOG] No. 9210) evaluated the benefit of prednisone maintenance therapy in 125 patients.9 Patients who received high-dose steroids had significantly longer PFS (14 vs 5 months) and OS (37 vs 26 months). However, given the small sample size and the long-term toxicities observed with steroids, this maintenance regimen has not been widely adopted. Phase 3 studies of steroids in conjunction with thalidomide are ongoing. When used alone prednisolone alternate-day therapy was inferior to prednisolone and thalidomide.10 

Thalidomide has been considered for maintenance. The randomized phase III French Myeloma Intergroup (IFM-99 02) trial assessed the impact of thalidomide maintenance on duration of response post-stem cell transplantation in 780 patients.11 At a 29-month median follow-up from randomization (2 months after the second transplant), patients randomized to thalidomide (Arm 3) demonstrated improvement in event-free survival (EFS) compared with those patients randomized to no treatment (Arm 1) or to pamidronate alone (Arm 2) (52% in Arm 3 vs 36% in Arm 1 and 37% in Arm 2; P = .002). In addition, there was a substantial improvement in OS for the patients randomized to receive maintenance thalidomide compared with the other two arms (87% in Arm 3 vs 77% in Arm 1 and 74% in Arm 2; P = .04).11 Patients who had at least a very good partial response did not benefit from thalidomide (P =.4).11 Barlogie et al randomized patients to thalidomide or no thalidomide during induction therapy and as maintenance in combination with dexamethasone and interferon following tandem transplants.12,13 When initially reported with a median follow-up of 42 months, complete response rate and EFS were superior among the 323 patients randomized to thalidomide, whereas OS was indistinguishable from that of the 345 patients treated on the control arm. With further follow-up of 72 months, a trend to increased OS with thalidomide was seen. In a post-hoc, subgroup analysis, thalidomide reduced the hazard of death by 41% among patients with abnormal cytogenetics (P = .008).13 Spencer et al randomized 269 patients post-autologous stem cell transplantation to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group).10 After a median follow-up of 3 years, the post-randomization 3-year PFS rates were 23% and 42% (P < .001) and the OS rates were 75% and 86% (P = .004), respectively. Thus, three separate phase III studies found thalidomide maintenance to improve OS. Despite these findings thalidomide is not being widely used for maintenance, presumably reflecting concerns about cumulative toxicity. Lenalidomide may offer the same advantages with less toxicity, and large randomized trials are now addressing its role both after melphalan in the post-transplantation setting and in the management of more elderly patients. Bortezomib has been used in maintenance therapy following stem cell transplantation in a large phase III randomized study.14 This study randomized patients to vincristine, adriamycin and dexamethasone (VAD) or bortezomib, adriamycin and dexamethasone (PAD), with maintenance using thalidomide (50 mg/daily) in the VAD arm, or bortezomib twice a month in the PAD arm post–stem cell transplantation. The response rates were significantly higher on the PAD arm. Current studies using weekly bortezomib maintenance therapy after 8 cycles of therapy, such as in the phase I/II trial of bortezomib, lenalidomide and dexamethasone study conducted by Richardson et al and the phase I/II study of bortezomib, lenalidomide, cyclophophamide and dexamethasone conducted by Kumar et al, will help delineate the role of bortezomib in maintenance therapy.

The 51-year-old patient looking for advice regarding maintenance therapy had high-risk disease but was already in a complete remission; thus, thalidomide is of unknown utility. The available data suggest that patients may benefit from this approach with higher response rates and improved PFS and, in some studies, OS. The patient elected to participate in a cooperative group post-stem cell transplantation trial comparing low-dose lenalidomide with placebo. Based on our review, we recommend the use of maintenance thalidomide for patients who are not in a complete remission after induction therapy. However, due to concerns about the toxicity of thalidomide, further clinical trials using alternative novel therapeutic agents such as lenalidomide and bortezomib should be explored to better define the efficacy, toxicity and quality of life during maintenance therapy in patients with MM.

Table 1.

Summary of agents and grade of recommendation.

AgentStudyResultsRecommendationLevel of evidence
PFS indicates progression-free survival; OS, overall survival; PAD, bortezomib, adriamycin, dexamethasone ; VAD, vincristine, adriamycin, dexamethasone 
Interferon Mandelli et al5  PFS and response duration were improved; but interferon decreased OS Not recommended Grade 2A 
Prednisolone SWOG study9
 Spencer et al10  High toxicity
 Thalidomide was superior Recommended, but not used widely because of toxicity concerns. Grade 2A 
Thalidomide IFM-99 0211  3 randomized studies showing benefit to thalidomide in PFS Recommended but not used widely because of toxicity concerns. Grade 2A 
Lenalidomide Ongoing studies No data Not recommended until data matures and results are available Grade 1C 
Bortezomib HOVON14
 Ongoing studies by Richardson et al and Kumar et al Bortezomib had superior response and PFS in the PAD arm compared to thalidomide in the VAD arm. Not widely used until data from ongoing studies are available Grade 1B 
AgentStudyResultsRecommendationLevel of evidence
PFS indicates progression-free survival; OS, overall survival; PAD, bortezomib, adriamycin, dexamethasone ; VAD, vincristine, adriamycin, dexamethasone 
Interferon Mandelli et al5  PFS and response duration were improved; but interferon decreased OS Not recommended Grade 2A 
Prednisolone SWOG study9
 Spencer et al10  High toxicity
 Thalidomide was superior Recommended, but not used widely because of toxicity concerns. Grade 2A 
Thalidomide IFM-99 0211  3 randomized studies showing benefit to thalidomide in PFS Recommended but not used widely because of toxicity concerns. Grade 2A 
Lenalidomide Ongoing studies No data Not recommended until data matures and results are available Grade 1C 
Bortezomib HOVON14
 Ongoing studies by Richardson et al and Kumar et al Bortezomib had superior response and PFS in the PAD arm compared to thalidomide in the VAD arm. Not widely used until data from ongoing studies are available Grade 1B 

Disclosures
 Conflict-of-interest disclosures: AKS is a consultant for Takeda-Millenium, Celgene, Novartis, and Amgen; receives research funding from Takeda and Millennium; and he receives honoraria from Genzyme, Celgene, Millennium, and Proteolix. IMG receives honoraria from Novartis, Celgene, and Millennium and in on their speakers’ bureaus; receives research funding from Millennium; and is on an advisory committee for Celgene.
 Off-label drug use: None disclosed.

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Author notes

1

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

2

Mayo Clinic College of Medicine, Scottsdale, AZ