Novel combination approaches for myeloma

Transcription

1 MULTIPLE ADVANCES IN MYELOMA Novel combination approaches for myeloma Sagar Lonial 1 and Ajay K. Nooka 1 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA Treatment of newly diagnosed and relapsed myeloma has been a rapidly moving field because of an improved understanding of disease biology and access to new drugs. Decades ago we learned that more was not necessarily better, especially when the more involved combinations of alkylators with steroids, which was associated with greater toxicity and more complications. 1 When the novel agents [immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs)] were brought to the field a decade ago, they subsequently demonstrated greater efficacy and were deemed safer in combinations, leading to a push to combine agents for newly diagnosed patients. This much-needed change is now extending to the relapse setting as well. Recent phase 3 trials have suggested that combinations of these new agents with each other, or with alkylatorbased therapy resulted in deeper responses and prolonged duration of remission and overall survival. 2-5 Given the relative wealth of new agents in development for myeloma, identifying ideal effective combination therapies with minimal overlapping toxicities at various phases of myeloma treatment is an important goal for our current treatment approaches with the intent of curing a larger fraction of newly diagnosed and relapsed myeloma patients. Goals of therapy The goal of therapy in both the transplant-eligible or transplantineligible myeloma patients in the upfront setting is to achieve the maximal possible response rapidly, with minimal toxicity and to improve performance status. In the transplant eligible patients, an additional goal is to utilize therapy that does not limit the peripheral blood stem cell mobilization. The goals of therapy in the relapsed setting are slightly different. With prior regimen and disease related toxicities, the ultimate aim of treatment here is to achieve a good balance between the efficacy and toxicity of the regimen. Several disease-related (biology of disease, staging, chromosomal abnormalities), treatment-related (prior drug therapy, regimen related toxicities, prior depth, and duration of response) and patient-related factors (comorbidities, performance status of the patient, renal and hepatic impairment, susceptibility to infections) influence the choice of the treatment regimen in relapsed patients. Evidence demonstrating benefit with a deeper response Multiple studies have confirmed that attaining a deeper response is the key to improving progression-free survival (PFS) and ultimately overall survival (OS). 6-8 The novel agents are known to be associated with higher response rates, including deeper responses, compared with cytotoxic agents, even among some patients with high-risk disease. 3,9,10 The incremental survival improvements from the last decade to the current are in part related to the use of novel agents resulting in improved depth of response. The goal of adding novel agents to backbone regimens is to increase the number of patients achieving deeper responses, provided the added toxicity is not excessive. One question, in an induction setting is how to manage the patient who does not achieve the desired maximal response after a defined number of cycles of therapy. Is there benefit to treat for a few more cycles to achieve a deeper response prior to autologous transplant? Palumbo et al suggested that maximal response with induction therapy is achieved at the completion of 4-5 cycles and perhaps the benefit to toxicity ratio starts tilting more toward the toxicity side with further therapy. 11 Additional retrospective data from the Center for International Blood and Marrow Transplant Research (CIBMTR) further supports this concept. 12 These observations support using a multi-agent combination therapy with minimal toxicity to achieve the maximal response rapidly, and thereby improve long-term outcomes. As treatment improves, how to define the depth of response also has to improve. Kapoor et al evaluated the impact of achieving stringent complete response (scr) on the outcomes of time to progression (TTP) and OS among myeloma patients post-transplant. 6 Patients that have achieved a sustained scr had 5 year OS of 91% compared with the 5 year OS of 53% among the nonsustained scr patients, indicating that not only attaining a high-quality response, but sustaining the same response is of utmost importance to achieve better long-term outcomes. Another important marker of a deeper response is the imaging based CR. Fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG- PET/CT) demonstrates the presence of active or inactive myeloma bone disease and can be explored to monitor response and to predict the outcomes in myeloma. The 4 year PFS and OS were significantly superior for PET-negative (SUV 4.2) versus PET-positive (SUV 4.2) patients suggesting complete FDG suppression after HDT was an independent favorable prognostic factor on multivariate analysis for durable disease control and prolonged OS, even among patients achieving CR. 13 Most important of all, minimal residual disease (MRD) negative status, as shown by the GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) group resulted in prolonged PFS and OS. MRD negativity was the most important independent prognostic factor for PFS. 14 Similarly, from the Medical Research Council (MRC) Myeloma IX study, MRD had identical prognostic significance as the International Staging System for OS, with the only other factor having a greater prognostic significance being cytogenetics. 15 Ultimately, the depth of response directly influences OS and a major push should be attempted to attain this endpoint, though MRD by flow cytometry or nextgeneration sequencing (NGS) remains an important question for future. Conflict-of-interest disclosures: S.L. has received research funding from BMS, Novartis, Millennium, Celgene, and Janssen, and has consulted for Onyx, BMS, Novartis, Millennium, Celgene, and Janssen; A.K.N. declares no competing financial interests. Off-label drug use: drugs in development for MM. 286 American Society of Hematology

2 Novel combination therapies in the induction setting The role of combination therapy in the induction setting was cemented by the phase 3 trial from Cavo et al 2 in younger patients. This trial randomized newly diagnosed myeloma patients to induction therapy with bortezomib, thalidomide, and dexamethasone (VTD) versus thalidomide and dexamethasone (TD), and demonstrated the importance of achieving the depth of response with a 3 drug induction followed by auto-transplant and consolidation in first response. After the first auto-transplant, complete response (CR) rates were 38% versus 23% (p ) and very good partial response (VGPR) rates were 79% versus 58% (p ) favoring the combination arm. The PFS was significantly longer for patients on VTD arm than in those on TD (HR 0.63, 95%; ; p ). More importantly, receiving VTD induction and consolidation therapy overcame the adverse effect of t(4;14) on 3 year PFS: 69% [with t(4;14)] versus 74% [without t(4;14)] (p 0 66), where TD arm failed to achieve similar benefit for the t(4;14) patients. 2 Similar impressive results were seen with carfilzomib, thalidomide and dexamethasone (CTD) among the newly diagnosed patients with 25% of patients achieving CR, 68% achieving at least a VGPR, and 90% at least a partial response (PR) after induction therapy. VGPR rates increased to 76% after auto-transplant and to 89% as best response after four cycles of consolidation therapy signifying that a PI, IMiD, and steroid combination is efficacious. 16 Lenalidomide, a more potent immunomodulatory agent in combination with bortezomib and dexamethasone (RVD) exerted 100% PR rates and VGPR rates of 67%. 17 Deeper responses were seen with less peripheral neuropathy, with the combination of carfilzomib, lenalidomide and dexamethasone (CRD) demonstrating a near complete response (ncr) rate among 62% of the patients in the trial. 18 An argument has been made with regard to the use of a proteasome inhibitor in combination with cyclophosphamide and dexamethasone as a cheaper alternative option. The EVOLUTION study is a phase 2 study that examined combination of RVD and bortezomib in combination with cyclophosphamide and dexamethasone (VCD). 19 The response rates and the 1 year PFS seem to be similar between both arms, but the study is limited by small numbers of patients enrolled and shorter duration of follow-up. In a recent retrospective study presented by Cavo et al, 20 VCD was compared to VTD in 2 large phase 3 trials, the overall response rate and complete remission rate for both standard and high-risk patients was higher with the IMID/PI combination of VTD than with VCD. Randomized trials are currently ongoing to formally compare the two approaches, but for now it appears that the IMID/PI combination is superior to that of PI/cyclophosphomide, favoring IMID/PI use in newly diagnosed myeloma. 20 With the availability of currently available novel agents, deeper responses are within reach for many different subsets of myeloma patients including those with high-risk disease. Table 1 illustrates the response rates achieved with novel agent 3 drug combination therapy. Strategies to deepen the response in the current era of active agents With the results of the 2 recently published randomized control trails supporting the benefit of oral lenalidomide therapy in the maintenance setting, 21,22 the Intergroupe Francophone du Myélome (IFM) group evaluated the outcome benefit of the transplantationbased approach with the most active 3-drug combination regimen bortezomib, lenalidomide, and dexamethasone (RVD) 17 as induction and consolidation followed by lenalidomide maintenance. Among the 31 patients, with median follow-up of 39 months, the estimated 3 year PFS was 77% (95% CI: 57%-88%). Among the 21 patients who have achieved MRD negativity by MFC, no one has Table 1. Response rates with selected induction regimens among newly diagnosed myeloma patients Best response, % Regimen N PR VGPR CR/nCR VTD CTD RVD CRD CyBorD VD dara NR VMD dara NR VTD dara NR VTD indicates bortezomib, thalidomide, and dexamethasone; CTD, carfilzomib, thalidomide, and dexamethasone RVD, lenalidomide, bortezomib, and dexamethasone; CRD, carfilzomib, lenalidomide, and dexamethasone; CyBorD, cyclophosphamide, bortezomib, and dexamethasone; VD, bortezomib and dexamethasone; dara, daratumumab; VMD, bortezomib, melphalan, and dexamethasone; PR, partial response; VGPR, very good partial response; CR, complete response; ncr, near complete response; and NR, not reported. progressed but among the 10 patients that have not achieved MRD negativity, 70% progressed, with an estimated 3 year PFS of 23% (95% CI: 4%-53%). Survival outcomes among the patients with high-risk cytogenetics were similar to the group as a whole, with an estimated 3 year PFS of 86% (95% CI: 33%-98%) suggesting that this active RVD combination therapy followed by auto-transplant, RVD consolidation and lenalidomide maintenance therapy would deliver deeper molecular responses and a lengthier PFS. 23 Similar results were observed with upfront combination therapy with CRD followed by lenalidomide maintenance inducing high-quality responses of MRD negativity among newly diagnosed myeloma patients. Among the 41 patients enrolled, 14 CR/sCR and 3 ncr patients who underwent MRD assessment were negative for MRD suggesting the benefit of such combination followed by consolidation and maintenance therapy. Can we achieve deeper responses by combining more agents? Prior studies combining more cytotoxic agents to the triplet regimens did not yield superior results. The role of quadruplet therapies remains unclear in both the transplant-eligible and -ineligible populations. The results from the EVOLUTION study that evaluated adding cyclophosphamide to RVD (VCRD) versus RVD suggested that efficacy of VCRD was similar to RVD although, the VCRD arm was associated with an increased incidence of hematologic toxicities. 19 Similar results were seen with the RVDD 24 regimen, which demonstrated similar efficacy to the 3-drug RVD regimen but increased toxicity. At this point, results from available studies suggest that quadruplet combinations combining cytotoxic agents are associated with greater toxicity without gaining any additional anti-myeloma effect. Taking the example of the FIRST trial, it is not the number of agents, but it is the quality of the newer agents that demonstrate superiority. Lenalidomide and dexamethasone (Rd) was superior to the alkylator-based melphalan, prednisone, and thalidomide (MPT) regimen among newly diagnosed elderly myeloma patients. 25 Rather than using these historically ineffective alkylator-based therapies in combination regimens, adding an investigational biologic agent might hold promise. Induction therapy with RVD in combination with histone deacetylase (HDAC) inhibitors,such as vorinostat 26 and panobinostat, 27 have deepened the responses as illustrated in Table 2 with acceptable toxicity, but significant dose reductions were needed. More Hematology

3 Table 2. Outcomes and toxicities with RVD combination regimens as induction therapy Best response, % Grade 3/4 toxicities, % Estimated Regimen N PR VGPR CR/nCR Fatigue PN DVT/PE Diarrhea Infection Neutropenia Thrombocytopenia PFS, % (y) RVD (1.5) RVD D (1.5) RVD C (1.0) RVD P NR RVD V (2.0) RVD indicates lenalidomide, bortezomib, and dexamethasone; D, pegylated doxorubicin; C, cyclophosphamide; P, panobinostat; V, vorinostat; PR, partial response; VGPR, very good partial response; CR, complete response; ncr, near complete response; PFS, progression-free survival; and NR, not reported. importantly, preliminary results with combination of daratumumab in the front-line setting gives a safety signal and able to exert good responses with various backbone therapies as depicted in Table 2. Future trials of induction therapy may incorporate the 2 active monoclonal antibodies daratumumab (anti-cd38) and elotuzumab (anti-slamf7) to other active regimens such as RVD or CRD with goal of attaining MRD negativity and better long-term outcomes. Thus, addition of a conventional cytotoxic agent to an IMiD/PI combination does not appear to confer benefit and future studies that include the use of monoclonal antibodies as the fourth agent, and will likely be associated with improved outcomes compared with even the best 3-drug novel agent regimen. Novel combination therapies in relapsed setting Recognizing the significance of attaining a deep response and with the availability of the newer anti-myeloma agents with novel mechanisms of action, a question arises as to why we do not take the same aggressive 3-drug approach in the context of early relapse (1-3 prior lines of therapy). To date the use of 2 drug salvage with bortezomib or lenalidomide has demonstrated benefit in overall survival compared with dexamethasone alone. 28,29 However, additional new drugs are being studied as part of 3-drug regimens with either bortezomib- or lenalidomide-based salvage as the control arm, and are demonstrating significant benefit. IMIDS Lenalidomide combinations Lenalidomide is a second-generation IMiD with greater potency and less toxicity than thalidomide. Rd is an effective regimen delivering superior responses compared to dexamethasone alone in 2 randomized phase III trials MM and MM Lenalidomide is highly active in combination with bortezomib from the phase 2 trial by Richardson et al demonstrating high response rates of PR rates of 64%, VGPR rates of 28%, and a PFS of 9.5 months. 32 In a different phase I combination trial with the other PI, carfilzomib, CRD resulted in VGPR rates of 22%, and an impressive PFS of 15.4 months. 33 It also exhibits synergy when combined with antibodies elotuzumab 34 and daratumumab 35 as shown in Table 3 and will be discussed in the antibody section. Pomalidomide combinations Pomalidomide is the third-generation IMiD that shares a number of the beneficial pharmacologic properties lenalidomide. The response rates are accentuated when combined with dexamethasone and further synergizes with PIs bortezomib and carfilzomib. Pomalidomide, bortezomib, and dexamethasone (PVD) in the relapsed setting resulted in PR rates of 70% and VGPR rates of 43%. 36 Pomolidomide combinations with carfilzomib, 37 daratumumab, 38 HDAC inhibitors are ongoing and showing promising anti-myeloma effect, especially among patients with high-risk genetics features. PIs Bortezomib combinations The first in class PI bortezomib not only had single-agent activity, but also combined well with many other agents. Similar to the front-line setting of myeloma treatment, VTD was shown to be superior to TD among relapsed myeloma patients. The phase 3 trial led by Gardaret et al cemented the superiority of the combination regimens by signifying the role of VTD exerting deeper responses as evident by attaining VGPR in 56% (vs 35% for TD) of the patients and subsequently improving the median PFS of 18.3 months (vs 13.6 months for TD) and 2 year OS of 71% (vs 65% for TD; P NS). 39 Though the OS difference is not evident because of shorter follow-up or better salvage options, the authors felt that OS for VTD may prove to be greater than that for TD if the follow-up period is prolonged. Additionally, bortezomib is synergistic with lenalidomide ( PR: 64%, VGPR 28%) 32 and pomalidomide ( PR: 70%, VGPR 43%) 36 especially among heavily pretreated patients. The combination regimen of PVD demonstrated deep responses among high-risk patients suggesting that this is an active combination for high-risk myeloma. The combination with the histone deacetylase inhibitors (vorinostat 40 and panobinostat 41 ) also demonstrated synergy with higher response rates, as shown in Table 3. Several combination regimens with other novel agents in the pipeline (eg, ARRY-520) are in development. Though there are concerns about neurotoxicity, the use of subcutaneous and/or weekly dosing is not only associated with a lower rate of neuropathy, it is also more convenient for patients as part of a combination regimen. 42 Bortezomib combined well with elotuzumab in a phase I study with PR rates seen in 48% of patients, even in bortezomibrefractory patients. 43 Further daratumumab-based combinations may be potential options for improving efficacy. Carfilzomib combinations The second generation epoxyketone, which induces irreversible proteasome inhibition, carfilzomib combines well with other agents to make active combination therapies. With an additional advantage of its lack of neurotoxicity, it proved to be a safe combination with IMiD lenalidomide and delivered good efficacy. CRD in a phase 2 trial exerted an impressive PFS of 15.4 months and resulted in high-quality responses with VGPR rates of 22%. 33 Further data from the phase 3 trial in the early relapsed setting comparing CRD versus Rd demonstrated the longest PFS reported to date in a relapsed myeloma trial with a median PFS benefit of close to 9 months of 26.3 versus 17.6 months (HR 0.690; 95% CI, ; p ). 4 Similar superior results with carfilzomib in combination with pomalidomide were seen with PR rates of 64% and VGPR rates 26% among heavily pretreated myeloma patient population with a median of 6 prior lines of therapy. The PFS is 12 months. 37 Though there are concerns about potential cardiotoxicity, data from emerging phase 3 clinical trials suggests no increase in 288 American Society of Hematology

4 Table 3. Selected relapsed combination regimens Study Phase N Regimen Prior lines PR, % VGPR, % PFS, mon OS, mon Median f/u, mon IMiD-based regimens Richardson et al 32 II 64 RVD Chari et al 69 II 13 Rd Panobinostat NR NR 4.5 Richardson et al 34 II 36 Rd Elotuzumab 10 mg/kg NR Rd Elotuzumab 20 mg/kg NR Richardson et al 70 II 113 Pd 5 33 NR P 5 18 NR Richardson et al 36 II 28 PVD NR NR NR PI-based regimens Dimopoulos et al 48 III 317 V Vorinostat * NR 7.63* NR V NR Richardson et al 41 II 55 VD Panobinostat NR 5.4 NR Garderet et al 39 III 135 VTD 87* 56* 18.3* 71% (2 y) TD % (2 y) 30 Popat et al 71 I/IIa 55 VTD Panobinostat NR NR NR NR Wang et al 33 II 52 CRd NR NR 24.4 Stewart et al 4 III CRd 87.1* 69.9* 26.3* 73.3% (2 y) 32.3 Rd % (2 y) 31.5 San Miguel et al 72 III 387 VD Panabinostat VD Placebo Shah et al 37 I/II 72 CPd Shah et al 73 I 20 C ARRY NR NR NR HDAC inhibitor-based regimens Kaufman et al 74 I 20 C Panobinostat NR NR Berdeja et al 46 I/II 44 C Panobinostat Vesole et al 75 I 21 CRD Vorinostat 3 53 NR NR NR NR Antibody-based regimens Lonial et al 57 II 106 Daratumumab (16 mg/kg) % (1 y) 9.3 Plesner et al 58 I 13 Rd Daratumumab (2-16 mg/kg) NR NR NR 30 Rd Daratumumab (16 mg/kg) NR NR NR Moreau et al 38 I 6 Pd Daratumumab NR NR NR Lonial et al 59 III 321 Rd Elotuzumab 2 79* NR Rd NR VTD indicates bortezomib, thalidomide, and dexamethasone; TD, thalidomide and dexamethasone; RVD, bortezomib, lenalidomidee, and dexamethasone; Rd, lenalidomide and dexamethasone; V, bortezomib; PVD, pomalidomide, bortezomib, and dexamethasone; CRd, carfilzomib, lenalidomide, and dexamethasone; CPd, carfilzomib, pomalidomide, and dexamethasone; C, carfilzomib; Pd, pomalidomide and dexamethasone; PR, partial response; VGPR, very good partial response; PFS, progression-free survival; TTP, time to progression; OS, overall survival; f/u, follow-up; and NR, not reported. * p cardiac toxicity compared with control patients. 4 Among heavily pretreated myeloma patients, in combination with the kinesin spindle protein inhibitor AARY-520, 44 the response rate was 35% and in combination with the HDAC inhibitors, 45,46 a response rates of 50%-60% were seen, approximately one-half of which are VGPR, supporting the use of carfilzomib with many new drugs and drug classes. HDACIs Vorinostat combinations Vorinostat is a pan-deacetylase inhibitor that was evaluated in combination with bortezomib in the VANTAGE-095 trail. This trial included heavily pretreated myeloma patients and the reported PR rates were seen in 17% patients suggesting activity of the combination. 47 More importantly, among these bortezomib-refractory patients, addition of vorinostat regained bortezomib sensitivity. In a similar patient population, the ORR was 34.5% for bortezomib in combination with panabinostat in the PANORAMA-2 trial. 41 The VANTAGE-088 that followed, randomized 637 patients to vorinostat and bortezomib or placebo and bortezomib in the early relapsed setting. Higher toxicity and the marginal clinical benefit in this trial (PFS favoring vorinostat and bortezomib combination: 7.63 vs 6.83 months; p 0.01; HR 0.77), precluded the combination in regular use. 48 Another combination trial of vorinostat with CRD as illustrated in Table 3 suggested that higher responses are possible by in heavily pretreated patients and by effectively managing the toxicities, the efficacy can be retained. Panobinostat combinations Panobinostat is the first HDACi that was FDA approved among myeloma patients who have received at least 2 prior standard therapies, including bortezomib and an immunomodulatory agent. This approval was based on the phase 3 randomized trial, PANORAMA-1, that randomized 768 patients to receive combination of panabinostat, bortezomib, and dexamethasone or placebo, bortezomib, and dexamethasone. The combination panobinostat arm demonstrated a significant increase in median PFS ( 4 months) compared with that of the placebo arm (median PFS: 12 vs 8.1 months; p ) favoring the use of panobinostat. Patients who received a longer duration of treatment on the panobinostat arm demonstrated improved outcomes of higher ncr/cr rates and median PFS suggesting that by optimizing the management of adverse events by appropriate dose adjustments or interruptions and/or supportive therapy, we can derive the clinical benefit of this combination. 49 Hematology

5 ACY-1215 combinations Rocilinostat (ACY1215) is a selective HDAC-6 inhibitor, developed in an effort to preserve the clinical efficacy of histone deacetylase inhibition while minimizing toxicity. Early trials combining rocilinostat with bortezomib and dexamethasone, 50 lenalidomide, and dexamethasone 51 are promising. Combination trial with pomalidomide and dexamethasone is in process. The current oral formulation and the preliminary potency, safety suggests for a potential combination regimen with PIs or IMiDS in 3 or 4 drug regimens. Other new targets in development KSP inhibitors ARRY-520. Inhibiting the spindle formation during mitosis results in cell death. ARRY-520, a kinesin spindle protein (KSP) inhibitor targets the KSP for exerting the anti-myeloma effect. Another agent where modest activity was seen as single agent, but in combination with steroids, showed good anti-myeloma activity among heavily pretreated multi-refractory myeloma patients. 52 It is showing promising activity in combination with bortezomib and dexamethasone, 53 and in combination with carfilzomib. 54 The agent potentially may be combined with most anti-myeloma agents to improve on the efficacy to use the advantage of the alternate mechanism of additive cell death and due to its non-overlapping toxicities. AKT inhibitors Afuresertib. Selective oral AKT kinase inhibitors have shown promising anti-tumor activity in the solid tumors. In combination with bortezomib at the MTD of 150 mg PO daily, increased phospho-akt levels were seen in myeloma cells, demonstrating achievement of target inhibition and clinically impressive results were observed. 55 Further trials with carfilzomib combinations are underway. SINE XPO1 inhibitors Selenexor is a first in class selective inhibitor of nuclear export (SINE) molecule that inhibits the nuclear export protein exportin 1 (XPO1), currently being evaluated in multiple myeloma. It demonstrated synergy in combination with dexamethasone and delivered 10% scr and 50% PR rates among the 10 patients treated at 45 mg/m 2 on the phase I trial. 56 Further phase 2 trials at 80 mg dose are underway. Immune approaches Antibodies Daratumumab. Daratumumab, a humanized anti-cd38 antibody is the most active monoclonal antibody in myeloma clinical trials today and was recently granted breakthrough status by the FDA. It acts through multiple mechanisms of action by directly targeting tumor cells and also effectively mediates killing of CD38 expressing plasma cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The MTD and active dose was confirmed to be 16 mg/kg resulting in response rates of 29%, and one-half of which are VGPR. 57 In combination with Rd, among heavily pretreated myeloma patients that have received a median of 4 lines of therapy, response rates of 100% and three-quarters (75%) of which are VGPR were observed. At the active dose of 16 mg/kg, in combination with Rd, the response rates were 87% and VGPR rates seen at 50%. 58 The interference of the daratumumab (an IgG kappa antibody) may also spuriously be accounted for a paraprotein in the disease assessment and possibly could explain the inconsistent complete response rates observed at the active dose of daratumumab. Nevertheless, no doubt it is an active drug and in combination with pomalidomide and dexamethasone had a VGPR rate of 50% (Table 3). 38 Multiple combination trials are ongoing for its rapid approval. Elotuzumab. Elotuzumab is a humanized anti-slamf-7 antibody targeting the cell surface cell surface glycoprotein CS1 (SLAMF7) on the myeloma cell and on NK cells resulting in activation of the NK cells. It exerts anti-myeloma effect via ADCC in myeloma cell lines and myeloma cells. Although as a single agent no objective responses were observed, in combination with Rd impressive response rates of 82% were observed suggesting that lenalidomide upregulates the NK cells, which are necessary for the NK-cellmediated cell kill by elotuzumab. It offers a novel synergistic mechanism with lenalidomide. Response rates in the phase 3 study (ELOQUENT-2) elotuzumab at a dose of 10 mg/kg in combination with Rd (ERd) versus Rd were 79% versus 66% and median PFS was 19.4 versus 14.9 months (P 0.001), respectively. 59 An ongoing phase 3 trial (ELOQUENT-1) is evaluating the efficacy and the safety of Rd with or without elotuzumab at the active dose of 10 mg/kg among newly diagnosed myeloma patients. Checkpoint blockade Programmed cell death protein (PD-1) or its ligand, programmed cell death-ligand 1 (PD-L1) interactions may indirectly modulate the response to tumor antigens through T cell/antigen-presenting cell (APC) interactions. PD-1 engagement may represent one means by which tumors evade immunosurveillance. 60 PD-1/PD-L1 pathway is shown by multiple groups to promote progression of myeloma indirectly by undermining immune control of the malignancy. 61 PD-1 blockade has been pursued as a promising therapeutic strategy to reverse immune tolerance and enhance T-cell effector function in several tumor types. The broad expression of PD-1 and its ligands in the microenvironment of myeloma and the preclinical data revealing an important role of the PD-1 pathway in immune evasion by myeloma cells, there may an immunotherapeutic potential of PD-1/PD-L inhibition in myeloma. Several PD-1 antibodies, such as nivolumab, pembrolizumab, pidiluzumab (CT-011), and PDL-1 antibodies (MEDI4736), are under investigation. Adoptive cellular therapy Chimeric antigen receptor (CAR) T cells. Modifying autologous T cells with CARs against CD19 provides a promising therapeutic strategy for myeloma. CTL019 cells, consisting of autologous T cells transduced with an anti-cd19 CAR, administered following high-dose therapy (HDT) with melphalan 140 mg/m 2 and autologous transplant resulted in durable remission in a heavily pretreated myeloma patient suggesting cellular therapy as a potential therapeutic option for myeloma patients. 62 Another early phase trial with T cells engineered to target NY-ESO-1 antigen is ongoing. Regulatory T cells. Regulatory T cells (Tregs) are CD4 T-cell population (CD4 CD25 FoxP3 T cells) that strongly inhibit anti-tumor immune responses in myeloma patients. Treg depletion may enhance the function of tumor antigen-specific T cells. Among 10 patients undergoing ASCT, Treg depletion in myeloma patients was safe and further studies are ongoing. 63 Therapeutic vaccinations Dendritic cell (DC) vaccines. DCs are APCs that can stimulate vigorous T-cell immune responses. Unfortunately in myeloma, 290 American Society of Hematology

6 because of various factors, such as down regulation of costimulatory surface receptor expression and changes in T-cell repertoire, the anti-tumor immune response fails. Novel approaches of combining DC vaccine and PD-1 antibody (CT-011), post-autologous transplant are underway. Peptide vaccines. PVX-410 is composed of a tetrapeptide from 3 unique regions of myeloma-associated antigens (XBP1, CD138, and CS1). The goal is to induce immunity against myeloma cells by selectively stimulating tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs). The safety and tolerability of PVX-410, alone and in combination with lenalidomide, are being evaluated for the treatment of smoldering myeloma patients currently. 64 Immucin, an anti-muc1 signal peptide vaccine, induced a robust CD8 and CD4 specific T-cell responses in all 15 patients post-asct and demonstrated a marked anti-tumor humoral response. 65 Conclusions It is an exciting time for the myeloma patients with more new therapeutic options available with the availability of new drugs and understanding the potential targets. Realizing the futility of the ineffective past regimens and understanding the therapeutic efficacy of the currently available agents and the ones in pipeline, we have made a significant progress as evident by the improved survival over the past 15 years. With a better understanding of the clonal heterogeneity and the recognition of the significance of achieving the depth of response as measured by minimal residual negativity, we are in the process to start a new journey of finding the ideal non-cytotoxic combinations both among the newly diagnosed and the relapsed/refractory myeloma patients that are more effective and more tolerable too. Trials are on way, and more should be planned in pursuit of effective targeted combination therapies to provide durable long-term remissions, if not cure, with lesser toxicity and a promise for a better quality of life for the myeloma patients. With availability of next generation sequencing techniques, the identification of driver mutations that lead to myeloma progression clearly seems within reach. One such example is the BRAF V600E mutation that is seen in 4% of relapsed myeloma patients. A commercially available V600E mutation-specific BRAF inhibitor, vemurafenib, resulted in durable response in a relapsed myeloma patient. 66 Although, we are in early phases of exploring and identifying the druggable targets, the potential to target an activating driver mutation is promising. The availability of future technologies for personalized immune approaches, identifying actionable mutations, and establishing biomarkers for treatment responsiveness opens the doors for personalized medicine in management of relapsed myeloma for future. Correspondence Sagar Lonial, MD, FACP, Professor and Executive Vice Chair, Department of Hematology and Medical Oncology, Chief Medical Officer, Winship Cancer Institute, Emory University, 1365 Clifton Rd, Building C, Rm 4004, Atlanta, GA 30322; Phone: ; Fax: ; sloni01@emory.edu. References 1. Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer. 1997;79(8): Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 376(9758): Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24): Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2): Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7): Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol. 2013;31(36): Nooka A, Kaufman J, Lonial S. The importance of complete response in outcomes in myeloma. Cancer J. 2009;15(6): Harousseau JL, Palumbo A, Richardson PG, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 2010;116(19): Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM phase III trial. J Clin Oncol. 2010;28(30): Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10): Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalanprednisone-thalidomide followed by maintenance with bortezomibthalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28(34): Vij R, Kumar S, Zhang MJ, et al. Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2015;21(2): Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118(23): Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10): Rawstron AC, Gregory WM, de Tute RM, et al. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood. 2015;125(12): Sonneveld P, Asselbergs E, Zweegman S, et al. Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015;125(3): Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5): Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9): Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119(19): Cavo M, Pantani L, Pezzi A, et al. Superior efficacy of VTD over VCD as induction therapy for autotransplantation-eligible, newly diagnosed, myeloma patients. Blood. 2014;124(21). Abstract 197. Hematology

7 21. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012;366(19): McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012; 366(19): Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II Study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014;32(25): Jakubowiak AJ, Griffith KA, Reece DE, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial. Blood. 2011;118(3): Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10): Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (rvd) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase 1 study. Blood. 2012;120(21). Abstract Shah JJ, Feng L, Manasanch EE, et al. Phase I/Ib trial of the efficacy and safety of combination therapy with lenalidomide/bortezomib/dexamethasone (RVD) and panobinostat in transplant-eligible patients with newly diagnosed multiple myeloma. Blood. 2014;124(21). Abstract Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24): Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23(11): Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21): Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21): Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123(10): Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX ) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013;122(18): Richardson PG, Jagannath S, Moreau P, et al. A phase 2 study of elotuzumab (Elo) in combination with lenalidomide and low-dose dexamethasone (Ld) in patients (pts) with relapsed/refractory multiple myeloma (R/R MM): updated results. Blood. 2012;120(21). Abstract Plesner T, Lokhorst H, Gimsing P, Nahi H, Lisby S, Richardson PG. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma: data from a dose-escalation phase I/II study. ASH Annual Meeting Abstracts. 2012;120(21). Abstract Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM). Blood. 2013; 122(21): Shah JJ, Stadtmauer EA, Abonour R, et al. Phase I/II dose expansion of a multi-center trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood. 2013;122(21): Moreau P, Mateos MV, Bladé J, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma. Blood. 2014;124(21): Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30(20): Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013;14(11): Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122(14): Arnulf B, Pylypenko H, Grosicki S, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012;97(12): Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-cs1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2012;30(16): Shah JJ, Feng L, Thomas SK, et al. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Blood. 2013;122(21): Kaufman J, Zimmerman T, Jakubowiak A, et al. Phase I study of combination of carfilzomib ad panabinostat for patients with relapsed and refractory myeloma: a multicenter MMRC clinical trial. Paper presented at 18th Congress of European Hematology Association. June 13-16, Stockholm, Sweden. 46. Berdeja J, Savona M, Mace JR, et al. A single-arm, open-label, multi-center phase I/II study of the combination of panobinostat and carfilzomib in patients (pts) with relapsed or relapse/refractory multiple myeloma (MM). Blood. 2013;122(21): Siegel D, Dimopoulos M, Yoon S, et al. VANTAGE 095: final results from a global, single-arm, phase 2b trial of vorinostat in combination with bortezomib in salvage multiple myeloma patients. Eur Hematol Assoc. 2012;97(S1): Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013;14(11): Richardson PG, Hungria VTM, Yoon S-S, et al. Panorama 1: a randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. ASCO Meeting Abstracts. 2014;32(Suppl 15). Abstract Raje NS, Vogl DT, Hari PN, et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor: interim results of combination therapy with bortezomib in patients with multiple myeloma (MM). Blood. 2013;122(21): Yee A, Vorhees P, Bensinger WI, et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor, in combination with lenalidomide and dexamethasone (dex), is well tolerated without dose limiting toxicity (DLT) in patients (Pts) With multiple myeloma (MM) at doses demonstrating biologic activity: interim results of a phase 1b trial. Blood. 2013;122(21). Abstract Shah JJ, Zonder JA, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. ASH Annual Meeting Abstracts. 2012;120(21). Abstract Chari A, Htut M, Zonder J, et al. A phase 1 study of ARRY-520 with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). Blood. 2013;122(21): Lonial S, Shah JJ, Zonder J, et al. Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma (RRMM) patients with low -1 acid glycoprotein (AAG) levels: results 292 American Society of Hematology

8 from a phase 2 study. ASH Annual Meeting Abstracts. 2013;122(21). Abstract Voorhees PM, Spencer A, Sutherland HJ, et al. Novel AKT inhibitor afuresertib in combination with bortezomib and dexamethasone demonstrates favorable safety profile and significant clinical activity in patients with relapsed/refractory multiple myeloma. Blood. 2013;122(21): Chen CI, Gutierrez M, Siegel DS, et al. Selinexor demonstrates marked synergy with dexamethasone (Sel-Dex) in preclinical models and in patients with heavily pretreated refractory multiple myeloma (MM). Blood. 2014;124(21): Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with 3 lines of prior therapy or double refractory multiple myeloma (MM): MMY2002 (Sirius). ASCO Meeting Abstracts. 2015;33(Suppl 18). Abstract LBA Plesner T, Arkenau H-T, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood. 2014;124(21): Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7): Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26): Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19): Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373(11): Keudell Gv, Rosenbaum CA, Zimmerman TM, et al. Pilot study of regulatory T cell depletion in the setting of autologous stem cell transplantation for multiple myeloma. Blood. 2013;122(21): Wang M, Nooka AK, Yee AJ, et al. Initial results of a phase 1/2a, dose escalation study of PVX-410 multi-peptide cancer vaccine in patients with smoldering multiple myeloma (SMM). Blood. 2014;124(21): Carmon L, Avivi I, Riva K, Dary L, Shapira MY. Phase I/II trial of immucin a Pan HLA, anti-muc1 signal peptide vaccine, in multiple myeloma patients with residual disease or progression following autologous stem cell transplantation. Blood. 2013;122(21): Andrulis M, Lehners N, Capper D, et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013;3(8): Rosiñol L, Oriol A, Teruel AI, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120(8): Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115(16): Chari A, Cho HJ, Parekh S, et al. A phase II, single-center, open-label study of oral panobinostat in combination with lenalidomide and weekly dexamethasone in patients with multiple myeloma. Blood. 2014;124(21): Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12): Popat R, Brown S, Flanagan LM, Cavenagh JD. Velcade, Thalidomide, dexamethasone and panobinostat (VTD-P) for patients with relapsed and relapsed/ refractory myeloma: preliminary results of the Muk-Six phase I/IIa trial. Blood. 2014;124(21): San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11): Shah JJ, Weber DM, Thomas SK, et al. Phase 1 study of the novel kinesin spindle protein inhibitor arry-520 carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood. 2012;120(21): Kaufman JL, Zimmerman T, Rosenbaum CA, et al. Phase I study of the combination of carfilzomib and panobinostat for patients with relapsed and refractory myeloma: a Multiple Myeloma Research Consortium (MMRC) clinical trial. Blood. 2014;124(21): Vesole DH, Siegel DSD, Richter JR, et al. A phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone (QUAD) in relapsed and/or refractory multiple myeloma (MM). ASCO Meeting Abstracts. 2014;32(Suppl 15). Abstract Hematology