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Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy

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Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy KRISHNAN ET AL Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy Amrita Krishnan, MD, Ravi Vij, MD, MBA, Jesse Keller, MD, Binod Dhakal, MD, and Parameswaran Hari, MD, MRCP OVERVIEW For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, sig- nificant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also in- creasing rates of minimal residual disease–negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance—a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease–driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma–specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment. utologous hematopoietic cell transplantation with high- ASCT (planned consolidation or maintenance), allo-HCT, and Adose chemotherapy and autologous cell rescue is a emerging immune therapies, are discussed. mainstay of therapy for patients with multiple myeloma and induces a response in a large proportion of patients. CONSOLIDATION THERAPY IN MULTIPLE However, relapse is near universal as a result of either MYELOMA measurable disease or minimal residual disease (MRD) after Consolidation therapy following ASCT for multiple myeloma ASCT, and multiple myeloma remains incurable.1 Effective implies a short period of intensive treatment with a single- therapies for sustained disease control after ASCT and agent or a combination of agents. Depth of response is prevention of repeated relapses in high-risk subgroups are widely accepted as prognostic for outcomes with multiple unmet needs. Consolidation and maintenance after ASCT is myeloma, and this strategy further reduces disease burden one route to overcome residual disease, whereas immune following ASCT.5,6 Yet, compared with lower-dose long-term approaches such as allogeneic transplantation (allo-HCT), maintenance, consolidation mostly remains confined to adoptive cellular therapies, vaccines, or antibody-based clinical trials. Historically, efforts of post-transplant con- immune manipulations represent another approach. Allo- solidation have ranged from aggressive attempts to eradi- HCT, despite its toxicities, has been known to cure a cate disease with tandem autologous transplantation and minority of patients by establishing myeloma-specific consolidation cytotoxic chemotherapy, to modern novel alloimmunity.2-4 Herein, potential treatments beyond agent–based approaches6,7 From the Judy and Bernard Briskin Center for Myeloma, City of Hope Cancer Center, Duarte, CA; Division of Medical Oncology, Washington University School of Medicine in St. Louis, St Louis, MO; Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI. Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook. Corresponding author: Parameswaran Hari, MD, MRCP, Froedtert Hospital and Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI 53226; email: phari@mcw. edu. © 2016 by American Society of Clinical Oncology. 210 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook BEYOND AUTOLOGOUS TRANSPLANTATION IN MULTIPLE MYELOMA TABLE 1. Lenalidomide and Bortezomib Monotherapy Consolidation Consolidation Induction Comparison Before After Study Regimen Regimen Arm Duration Consolidation Consolidation PFS OS Attal et al11 Lenalidomide VAD (46%) None 2 cycles $ VGPR: 58% $ VGPR: 69% 4-year: 43% 4-year : 73% (614 patients) (all treated) (p , .001) vs. 22% vs. 75% VD (46%) Uy et al13 Bortezomib Bortezomib-naive None 6 cycles CR + VGPR: 43% CR + VGPR: 43% NR 3-year: 63.1% (40 patients) Mellqvist et al14 Bortezomib Bortezomib-naive Placebo 6 cycles $ nCR: 20.1% $ nCR: 45.1% 27 vs. 3-year: 80% (187 patients) 20 months vs. 80% $ VGPR: 39.7% $ VGPR: 70.9% Abbreviations: PFS, progression-free survival; OS, overall survival; VAD, vincristine/doxorubicin/dexamethasone; VD, bortezomib/dexamethasone; VGPR, very good partial response; nCR, near CR; NR, not reported. TANDEM TRANSPLANTATION AND CYTOTOXIC IMMUNOMODULATORY AGENT CHEMOTHERAPY CONSOLIDATION THERAPY Initial efforts of post-ASCT consolidation therapy evolved Novel agents such as proteasome inhibitors and immuno- from the University of Arkansas Total Therapy trials and modulatory agents (IMIDs) have advanced all aspects of mirrored prolonged treatment regimens in pediatric acute multiple myeloma treatment. Evaluation of consolidation lymphocytic leukemia. Total Therapy 1 (TT1) (which did not therapy with IMID monotherapy was undertaken in a phase III include consolidation) used aggressive induction chemo- study by Intergroupe Francophone du Myelome (IFM 05-02; therapy and tandem ASCT combined with maintenance Table 1).11 Newly diagnosed patients with multiple myeloma interferon (IFN) to produce results superior to contemporary who underwent post-ASCT consolidation therapy with lena- standard therapy in a SWOG cooperative group trial.8 Total lidomide were randomly assigned to receive maintenance Therapy 2 (TT2), which expanded on TT1, evaluated ag- lenalidomide versus placebo. Two cycles of lenalidomide gressive induction chemotherapy, tandem ASCT followed (25 mg daily) improved the rate of complete response (CR) or by four cycles of dexamethasone, cisplatin, doxorubicin, very good partial responses (PR) from 58% to 69% (p , .001), cyclophosphamide, and etoposide (DPACE) consolidation respectively, among all participants, but maintenance was not chemotherapy; patients were then randomly assigned to associated with improvement of overall survival (OS). A receive maintenance therapy with IFN with or without similarly designed phase III U.S. study (CALGB 100104) lacked thalidomide.9 Total Therapy 3 (TT3A) included the addition the lenalidomide consolidation phase, but randomly assigned of bortezomib-based chemotherapy induction, tandem patients to receive maintenance lenalidomide versus placebo ASCT followed by DPACE plus thalidomide and bortezomib and reported an OS benefit in the maintenance arm.12 One of (V-DTPACE) consolidation and then maintenance.10 The role the possible explanations for the lack of OS benefit in the of maintenance in these trials was evaluated in a non- former study is that a short period of consolidation given to all randomized fashion, making its individual contribution dif- subjects in IFM 0502 may have abrogated the survival benefit ficult to discern; however, they spawned further interest for for protracted maintenance therapy. improved post-ASCT strategies. PROTEASOME INHIBITOR–BASED CONSOLIDATION KEY POINTS Bortezomib Uy et al13 evaluated pre- and post-ASCT bortezomib con- • Induction with novel agent combinations followed by high- solidation in a phase II study with 40 patients (all newly di- dose chemotherapy ASCT is the standard of care in patients agnosed with multiple myeloma) who received two cycles of with multiple myeloma who are eligible for transplant. intravenous bortezomib followed by ASCT, and six cycles of • Relapse is inevitable in the majority of the patients intravenous bortezomib after ASCT. Only 28 patients received despite recent improvements in progression-free post-ASCT bortezomib, with two upgraded responses—one survival. from very good PR to CR and one from PR to very good PR. The • Effective strategies to overcome residual disease and 3-year OS and disease-free survival (DFS) were 63.1% and prevent relapse is an unmet need. 38.2%, respectively.13 • Post-transplant consolidation and minimal residual The NORDIC Myeloma Study Group randomly assigned disease–directed maintenance are promising new bortezomib-naive patients post-ASCT to receive either no avenues. • Emerging post-ASCT immunotherapy to establish further treatment or bortezomib consolidation for six cycles. myeloma-specific immunity and allotransplant are tools With a median follow-up of 38 months, PFS for the bortezomib- for long-term disease control, especially for young high- treatment group was 27 months compared with 20 months risk patients. for the control group (p = .05), and no difference in OS. Patients who experienced at least a very good PR asco.org/edbook | 2016 ASCO EDUCATIONAL
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