Current Status of Maintenance Therapy in Multiple Myeloma

Oncology & Hematology Review, 2014;10(2):90–6

Abstract:

Despite the introduction of autologous hematopoietic stem cell transplant (AHSCT) and novel agents, myeloma is considered to be incurable. The majority of patients will have disease progression or relapse at some point after AHSCT or after the initial front-line therapy. The depth and duration of the response achieved after AHSCT or front-line therapy is closely related to the long-term outcomes. Trying to develop strategies in order to prevent or delay disease progression or relapse has resulted in the concepts of consolidation or maintenance. Initial maintenance attempts with single agent corticosteroids, interferon-α, conventional chemotherapies, or a combination of these agents have shown a variably prolonged progression-free survival (PFS) but no benefit to overall survival (OS) with high toxicity rates. Maintenance approaches with a prolonged course of novel agents have improved PFS and OS to a certain degree with tolerable drug-related toxicities. Despite contradictory data, maintenance therapy with novel agents can be a reasonable approach for those patients who have failed to achieve at least very good partial response (VGPR) after AHSCT or front-line therapy, or for the patients presented with high-risk disease based on genetic abnormalities as well as other laboratory features. Here, we review the available data on the various maintenance strategies that have been evaluated in the setting of myeloma.

Keywords: Myeloma, maintenance therapy, overall survival, lenalidomide, bortezomib
Disclosure: Omur Sevindik, MD, and Shaji K Kumar, MD, have no conflicts of interest to declare. No funding was received in the publication of this article.
Received: September 30, 2014 Accepted October 09, 2014 Citation Oncology & Hematology Review, 2014;10(2):90–6
Correspondence: Shaji K Kumar, MD, Professor of Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, US. E: kumar.shaji@mayo.edu

Multiple myeloma (MM) is manifested by abnormal clonal plasma cell proliferation and accounts for approximately 1 % of all cancers and nearly 10 % of hematologic malignancies in the US.1,2 It is considered to be incurable, probably as a consequence of the ongoing clonal evolution over the course of disease. Although the disease remains incurable, with the introduction of autologous hematopoietic stem cell transplant (AHSCT) and novel agents, such as thalidomide, bortezomib, lenalidomide, and carfilzomib, median overall survival (OS) has increased from nearly 3 years a decade ago to over 8 years currently.3,4 Advances in the understanding of disease biology and better stratification of risk groups according to the genetic abnormalities have led to the development of a risk-based individualized therapeutic approach.5 AHSCT is an effective therapy for MM and remains a standard of care in eligible patients.6 However, the majority of patients will have disease progression or relapse at some point after AHSCT or after the initial frontline therapy. Unfortunately, patients with high-risk disease based on genetic abnormalities as well as other laboratory features are likely to relapse even faster. Maintaining response after AHSCT is an important goal and the depth of the response correlates with improved long-term outcomes, especially progression-free survival (PFS).7–10 Trying to develop strategies in order to prevent or delay disease progression or relapse has resulted in the concepts of consolidation and maintenance therapies. Consolidation is a short-term therapy administered to enhance the rate and depth of a previously obtained response. By contrast, the goal of maintenance therapy is the extension of response duration, and ultimately of PFS and OS with the use of lower doses of drugs given with minimal toxicity over a long period of time.3 An optimal maintenance treatment should have the following characteristics: (1) should maintain and maybe deepen the response achieved after front-line therapy or AHSCT, (2) should prolong OS, (3) should be well tolerated and simple to administer (preferably as a single agent regimen and orally), with manageable drug-related toxicities, and no long-term deleterious effects, (4) should not decrease quality of life, and (5) should be cost-effective. This review summarizes the evolution and the current status of maintenance therapy in MM.

Initial Studies of Maintenance in Multiple Myeloma
Over the past 40 years, several maintenance strategies for MM have been investigated. Initial attempts in the 1960s to early 1980s were with single agent corticosteroids, continuous conventional chemotherapies, or interferon (IFN), many demonstrating the ability to prolong relapse-free survival but without prolongation of OS. Alexanian and colleagues evaluated various melphalan-based regimens in 508 patients with MM, randomly allocating 96 responders to one of three maintenance regimens, namely intermittent courses of carmustine with prednisone, continued courses of melphalan with prednisone (MP), or no chemotherapy. There were no differences in the relapse rate, the remission duration, or survival among these maintenance groups. The frequencies of pneumonia and herpes zoster were higher in patients receiving continuous chemotherapy.11

In the MRC trial, after 1 year of allocated treatment, 297 survivors were randomized to either stopping all treatment until relapse, or to continue treatment with azathioprine and vincristine, interrupted every 3 months for a course of the first-allocated treatment. The overall results demonstrated a trend toward benefit with maintenance, though the differences were not statistically significant. Most of the difference was found among a few patients with unfavorable prognostic features who survived 1 year and were eligible for randomization.12

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Keywords: Myeloma, maintenance therapy, overall survival, lenalidomide, bortezomib