A New Horizon for the Treatment of Multiple Myeloma

review

Investigational agents in immunotherapy: a new horizon for the treatment of multiple myeloma

Cindy Varga,1 Jacob P. Laubach,2 Kenneth C. Anderson2 and Paul G. Richardson2 1Tufts Medical Center, Division of Hematology-Oncology, Boston, MA and 2Dana Farber Cancer Institute, Harvard Medical School, Jerome Lipper Multiple Myeloma Center, Boston, MA, USA

Summary experts must rely on other anti-plasma cell approaches, which include alkylator agents (cyclophosphamide, oral mel- The treatment of multiple myeloma (MM) has gone through phalan), immunomodulators (IMiDs) (thalidomide, lenalido- several major advances over the last 5 years with the intro- mide, pomalidomide) and proteasome inhibitors (PIs) duction of next generation proteasome inhibitors (PI; carfil- (bortezomib, carfilzomib, ixazomib). Triplet combinations of zomib, ixazomib) and immunomodulatory derivatives these agents have proven to be quite effective with manage- (IMiD; pomalidomide), with these new agents having a sub- able toxicity profiles overall. Over the last few years, the stantial impact on patient outcome. However, despite these treatment algorithm for MM has undergone a major over- advances, MM remains a highly resistant disease given its haul with the introduction of humanized monoclonal anti- propensity for clonal heterogeneity and its complex interac- bodies (mAbs). Daratumumab and elotuzumab are mAbs tion with the surrounding bone marrow microenvironment. that effectively target CD38 and signalling lymphocytic acti- Almost all patients eventually relapse despite therapeutic vation family 7 (SLAMF7) on the surface of plasma cells, responses to a PI, IMiD or both. With the regulatory respectively, and have been approved by the US Food and approval of the monoclonal antibodies Daratumumab and Drug Administration (FDA) for the treatment of relapsed Elotuzumab in 2015, impressive and durable responses are refractory disease as of 2015. Response rates observed with being observed, even in heavily pre-treated patients who have some of these agents have been impressive, even among exhausted other therapeutic options, suggesting immunologi- double-refractory patients and those who harbour high-risk cal approaches in this setting have real merit. This review cytogenetics. will focus on newer monoclonal antibodies and chimeric- Immunotherapeutic strategies offer a new and exciting antigen receptor (CAR) T cell strategies currently under approach to target key molecular pathways that continue to investigation and in various stages of clinical development. be implicated in the survival of malignant plasma cells (Bae et al, 2014; Rosenblatt et al, 2014). These targets include cell Keywords: multiple myeloma, monoclonal antibodies, Isatuxi surface proteins [CD38, CD138 (SDC1), B cell maturation mab, Siltuximab, BCMA. antigen (BCMA, TNFRSF17)], cytokines that play a role in plasma cell survival and proliferation [interleukin 6 (IL6) Multiple myeloma (MM) is a clonal plasma cell disorder that and B cell activating factor], signal regulators of bone meta- results in the excess production of a monoclonal protein in bolism [RANKL (TNFSF11), DKK1] and regulators of the the serum and/or urine leading to end organ damage, clini- immune system [PD-1(PDCD1), PD-L1(CD274)]. This cally categorized as CRAB: Hyper Calcaemia, Renal failure, review will focus on new mAbs and related innovative Anaemia, and/or lytic Bone lesions. Unfortunately, MM tar- immunotherapeutic modalities currently under investigation gets the elderly and frail, making treatment of this serious and in various stages of evaluation as part of clinical trials disease very challenging. At the time of diagnosis, not all (Table I). Whilst vaccines in various stages of development patients are eligible or willing to undergo high-dose melpha- are also considered highly promising, especially in smoulder- lan and stem cell transplantation (HDM/SCT), an aggressive ing disease and after initial therapy, these are considered form of therapy that has been shown to prolong progression- beyond the scope of this review, and are addressed elsewhere. free (PFS) and overall survival (OS) in this disease. For patients who are not eligible for HDM/SCT, myeloma Anti-CD38 CD38 is a cell surface protein that has both receptor and Correspondence: Dr Paul Richardson, Dana-Farber Cancer Institute, enzymatic function and is expressed on lymphoid and mye- 450 Brookline Avenue, Mayer 228, Boston, MA 02215, USA. loid cells and on non-haematopoietic tissues (Deaglio et al, E-mail: [email protected] 2001; Malavasi et al, 2008). CD38 mediates adhesion to

ª 2018 John Wiley & Sons Ltd, British Journal of Haematology doi: 10.1111/bjh.15116 2 Table I. Monoclonal antibodies in multiple myeloma currently under investigation. Review

Mechanism of Completed studies Name Target action (Phase) Population Results Adverse events On-going studies (Phase)

Isatuximab (ISA) CD38 ADCC, ADCP, ISA + Len/Dex (Ph RRMM (83% Len No MTD, IRR 56% (84% grade 1/2) ISA + CYBORD/RVD in CDC, apoptosis 1b) refractory) ORR 56%, mPFS TEAEs: diarrhoea (53%), fatigue NDMM (Ph I) 8Á5 months (49%), URTI (40%), nausea ISA in high-risk SMM (35%) (Ph II) ISA + Pom/Dex in RRMM (Ph Ib) ISA + carﬁlzomib in RRMM (Ph Ib) ISA/Pom/Dex vs. Pom/Dex (Ph III) MOR202 CD38 ADCC, ADCP N/A N/A N/A N/A MOR202 + /-Dex or MOR202/ Len/Dex or MOR202/Pom/Dex (Ph I/IIa) Indatuximab CD138 Antibody drug BT062 alone RRMM 4% PR, 7% MR, 40% SD MTD 200 mg/m2 (mucositis as BT062 with Len or Pom in Ravtansine conjugate (Ph 1) DLT) RRMM (Ph I/II) (BT062) (DM4) BT062/Len/Dex (Ph RRMM (30% Len ORR 78% (at all doses) MTD 100 mg/m2 (mucositis as I/II) refractory) DLT) 89% of AEs grade 1/2 (diarrhoea, fatigue, nausea) Siltuximab (S) IL6 Prevents binding S alone (Ph I) RRMM No response No toxicity S+ Bort vs. Bort alone in ª +

08Jh ie osLtd, Sons & Wiley John 2018 of IL6 to S Dex (Ph II)_ RRMM 62% SD, 19% PR, 28% MR Infections (any grade) 57% RRMM (Ph I) receptors S+VMP vs VMP NDMM ORR 88% vs. 80% Grade ≥3 AE 92% vs. 81%. S+ RVD in NDMM alone (Ph II) CR 27% vs. 20% Trend towards more (Ph I/II) mPFS and OS at 1 year haematological/infectious S post-ASCT (Ph II) identical in 2 arms events in S+ VMP Tabalumab BAFF Binds BAFF Taba+Bort (Ph I) RRMM (77% prior ORR 42%, 73% progressed, Common grade 3 or 4 AEs: None (Taba) exposure to Bort) mTTP 4Á8 months thrombocytopenia, pneumonia, neuropathy Taba+Bort/Dex vs. RRMM No difference in mPFS thrombocytopenia (38%), Bort-Dex (Ph II) fatigue (37%), diarrhoea rts ora fHaematology of Journal British (35%), constipation (35%) Denosumab RANKL Inhibits bone Denosumab vs. ZA RRMM Non-inferior in delaying More renal events in ZA Denosumab vs. ZA in NDDMM resorption (Ph III) time to ﬁrst skeletal event More hypocalcaemia with (Ph III) Ad hoc OS analysis favoured denosumab Denosumab in renal ZA AEs the same in both arms insufﬁciency (Ph II) ª 08Jh ie osLtd, Sons & Wiley John 2018

Table I. (Continued)

Mechanism of Completed studies Name Target action (Phase) Population Results Adverse events On-going studies (Phase)

BHQ880 DKK1 Increases BHQ880 + ZA RRMM Trend towards increased No DLTs, no MTD None osteoblast (Ph Ib) bone density (spine) over differentiation time rts ora fHaematology of Journal British BHQ880 alone High-risk SMM No anti-MM activity Common AEs: arthlargia (16%), (Ph II) Evidence of anabolic bone fatigue (12%), fever (12%), activity on CT URTI (12%) Pembrolizumab PD-1 Restores T-cell Pom/Dex +/-MK3475 RRMM (90% Len ORR 60% (sCR 6%, CR 2%, Grade 3 neutropenia in 43% Len/Dex/MK3475 in RRMM (Ph (MK3475) response (Ph II) refractory) VGPR 19%, PR 33%) Non-haem AEs: fatigue, I)* mPFS 17 months hyperglycaemia, dizziness, Len/Dex +/À MK3475 in constipation NDMM (Ph III)* 1/3 had respiratory symptoms Pom/Dex +/À MK375 in (dyspnoea, URTI, RRMM (Ph III)* pneumonia) Nivolumab PD-1 Restores T-cell Nivo alone (Ph I) RRMM SD was best response No MTD Nivo/Len/Dex in high risk SMM (Nivo) response Median duration of response 18% grade 3 AEs (Ph II) 11Á4 weeks Immune events 34% (1 death Nivo/Dara +/À Pom/Dex due to pneumonitis) in RRMM (Ph I)* Nivo/Elo/Pom/Dex om RRMM (Ph III)** Elo/Pom/Dex vs. Elo/Nivo in RRMM (Ph II)* Durvalumab PD-1 Restores T-cell None N/A N/A N/A Durva/Dara in RRMM (Ph II)* (Durva) response Durva +/À Durva/Pom+/À Durva/Pom/Dex (Ph Ib) in RRMM * Durva/Len/Dex in NDMM (PhI)*

ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; AE, adverse event; ASCT, autologous stem cell transplant; BAFF, B-cell activating factor; Bort, bortezomib; CDC, complement-dependent cytotoxicity; CR, complete response; CT: computed tomography; CYBORD, cyclophosphamide- bortezomib-dexamethasone; Dara: daratumumab; DDK1, Dickkopf-related protein; Dex, dexamethasone; DLT: dose-limiting toxicity; Elo, elotuzumab; IL6: interleukin 6; IRR, infusion-related reaction; Len, lenalidomide; MM: multiple myeloma; mPFS, median progression-free survival; MR, minimal response; MTD, maximum tolerated dose; mTTP, median time to progression; N/A: not available; NDMM, newly-diagnosed multiple myeloma; ORR, overall response rate, OS, overall survival; PD-1, programmed cell death protein 1; Ph, phase; Pom, pomalidomide; PR, partial response; RANKL, receptor activator of nuclear factor j-B ligand; RRMM, relapsed refractory multiple myeloma; RVD, lenalidomide-bortezomib-dexamethasone; SD, stable disease; SMM, smouldering multiple myeloma; TEAE, treatment-emergent adverse event; URTI, upper respiratory infection; VGPR, very good partial response; VMP, bortezomib-melphalan-dexamethasone; ZA, zoledronic acid. Review *The US Food and Drug Administration has placed clinical holds on these studies due to safety signals. 3 4 Review

Table II. Clinical trials investigation of BCMA-CAR T cells in relapsed/refractory multiple myeloma

Manufacturer Clinicaltrials.gov Cohort: Dose of BCMA Product identiﬁer Conditioning regimen CAR+ T cells/kg Preliminary Results Toxicity

NCI NCT02215967 CTX 1: 0Á3 9 106 Cohorts 1 and 2 (n = 6): 1 PR, 5 SD Grade 3–4 CRS in both responding patients at highest mBCMA-CAR Fludarabine 2: 1 9 106 Cohort 3 (n = 3): 1 VGPR (PET/CT neg), 2 SD dose cohort 3: 3 9 106 Cohort 4 (n = 3): 1 sCR, 1 VGPR, 1 SD Grade 4 AEs included leucopenia and neutropenia 4: 9 9 106 BluebirdBio Inc. NCT02658929 CTX 1: 50 9 106 Cohort 1 (n = 3): 1 PR, 1 SD, 1 PD 71% had CRS, mostly grade 1and 2 bb2121 Fludarabine 2: 150 9 106 Cohort 2 (n = 4): 2 sCR with durable Four patients received tocilizumab 3: 450 9 106 responses >20 weeks, 1 VGPR, 1 PR Grade 3–4 TEAEs: hyponatremia (n = 4), CRS (n = 2), 4: 800 9 106 Cohort 3 (n = 8): 1 CR, 5 VGPR, 2 PR URTI (n = 2) and syncope (n = 2) Cohort 4 (n = 3): 1 CR, 1 VGPR, 1 PR UPenn NCT02546167 Cohort 1: none 1: 1–5 9 108 Cohort 1 (n = 6): 1 sCR >12 months, 1 5 patients developed CRS, 2 were grade 3 requiring huBCMA-CAR Cohorts 2 and 3: CTX 2: 1–5 9 107 VGPR, 1 SD, 2 MR, 1 PD Tocilizumab 3: 1–5 9 108 Cohort 2: data not yet reported 1 DLT (grade 4 PRES, n = 1) ª Cohort 3: data not yet reported Other grade 3–4 AEs: hypophosphataemia (n = 3), 08Jh ie osLtd, Sons & Wiley John 2018 hypocalcaemia (n = 2), cytopenias, fatigue, hypertension, pleural effusion (n = 1 each) MSKCC NCT03070327 Cohort 1: CTX Data not yet reported Data not yet reported huBCMA-CAR Subsequent cohorts: CTX and ﬂudarabine Nanjing Legend NCT03090659 CTX 0Á5–5 9 106 by split N = 22, ORR 100% Most common AE was CRS (grade 3 in 2 patients) LCAR-B38M dose (10%, 30%, 50%) 6 CRs (MRD-negative No DLTs or treatment-related deaths by ﬂow cytometry), 14 VGPR, 1 PR

rts ora fHaematology of Journal British AE, adverse event; BCMA, B-cell Maturation Antigen; CAR: chimeric-antigen receptor; CR, complete response; CRS, cytokine release syndrome; CT: computed tomography; CTX, cyclophosphamide; DLT, dose-limiting toxicity; MR, minimal response; MRD: minimal residual disease; MSKCC: Memorial Sloan Kettering Cancer Center; Nanjing Legend: Nanjing Legend Pharmaceutical & Chemical Co.; NCI: National Cancer Institute; ORR, overall response rate; PD, progressive disease; PET: positron emission tomography; PR, partial response; PRES: posterior reversible encephalopathy syndrome; sCR, stringent complete response; SD, stable disease; TEAE, treatment-emergent adverse event; UPenn: University of Pennsylvania; VGPR, very good partial response. Review endothelium and promotes associations with surface mole- Infusion reactions were reported in 56% of the participants cules found on lymphocytes and natural killer cells (Funaro (grade 1/2 in 84% of patients), of which 88% occurred dur- et al, 1993; Dianzani et al, 1994). CD38 is overexpressed on ing the first infusion. Besides infusion-related reactions the surface of clonal plasma cells (Lin et al, 2004). The role (IRR), the most common treatment-emergent AEs (TEAEs, of CD38 and its high expression on myeloma cells have all grades) were diarrhoea (53%), fatigue (49%), upper respi- made it an attractive target for treatment. ratory infections (40%) and nausea (35%). The overall response rate (ORR) was 56%, similar between the 10 mg/kg every other week and the 10 and 20 mg/kg weekly/every Isatuximab (SAR650984) other week cohorts. The ORR did not differ, even among Similar to daratumumab (DARA), SAR650984 is a new gen- lenalidomide-refractory patients (ORR 51%) and the median eration humanized IgG1 mAb capable of targeting the CD38 progression-free survival (mPFS) was 8Á5 months (Martin receptor of clonal plasma cells. What differentiates isatux- et al, 2017). imab from DARA is its ability to specifically target a unique An open label, phase Ib study, combining isatuximab with epitope on the CD38 surface protein. In preclinical studies, pomalidomide and dexamethasone in patients with RRMM, Deckert et al (2014) examined the activity of SAR650984 on is currently recruiting patients (NCT02283775). Preliminary lymphoma, leukaemia and MM cell lines and MM xenograft results are available on 14 patients: 8 patients treated at models in immune-deficient mice. This agent demonstrated 5 mg/kg and 6 patients treated at 10 mg/kg (Richardson strong pro-apoptotic activity in addition to complement- et al, 2016). The most frequent treatment-related AEs were dependent cytotoxicity (CDC), antibody-dependent fatigue (64%), upper respiratory tract infection, tremor, dys- cell-mediated cytotoxicity (ADCC) and antibody-dependent pnoea and cough (29% each). IRRs occurred in 8 (57%) cellular phagocytosis (ADCP). As CD38 can be expressed on patients; all cases were minor (grade 1/2). Of the 13 evalu- a wide range of haematopoietic cells, Feng et al (2017) able patients, 8/13 (62%) achieved at least a partial response wanted to study the effects of isatuximab on immune cells (PR) and 10/13 (77%) at least a minimal response (MR). by examining CD38 levels in regulatory T cells (Tregs) from Given these encouraging results, a phase III trial to evaluate normal donors and from MM patients. Peripheral blood isatuximab with pomalidomide and dexamethasone is now mononuclear cells were then treated with isatuximab with or underway (NCT02990338) (Table I). without an IMiD (lenalidomide or pomalidomide) in order In a phase Ib dose escalation-trial (NCT02332850), com- to determine the impact on the percentage and immunosup- bining isatuximab with carfilzomib in the RRMM popula- pressive activity of Tregs on conventional T cells. CD38 tion, preliminary data was available for 10 patients for expression was higher on Tregs than on conventional T cells presentation at the ASH Annual Meeting in 2016 (Martin from MM patients versus normal donors. The expression of et al, 2016). Isatuximab was given weekly or every 2 weeks in CD38 on Tregs was increased by lenalidomide and poma- combination with carfilzomib at standard doses. The ORR lidomide. Not only did isatuximab preferentially decrease was 80%, with 2 very good partial responses (VGPRs) and 6 Tregs and increase conventional T cell levels, but it also aug- PRs for a clinical benefit rate of 90%. Haematological toxic- mented MM cell lysis by CD8+ T cells and Natural Killer ity was mild with grade 3/4 anaemia (9%), grade 3/4 neu- (NK) cells, thus restoring immune effector function against tropenia (9%) and grade 3/4 lymphopenia (64%). The most MM (Feng et al, 2017). Overall, SAR650984 was validated as serious adverse event was a grade 3 pneumonia (18%). a functional CD38-targeting antibody (Deckert et al, 2014). About half the patients experienced mild (grade 1 or 2) infusion reactions. Expanded accrual is ongoing for this study (Martin et al, 2016). Phase I/II Other ongoing studies include isatuximab in high-risk NCT01749969 was a phase 1b, open-label, dose escalation smouldering MM (NCT02960555), and isatuximab combined study examining the safety and efficacy of isatuximab admin- with various backbone regimens [RVD (lenalidomide-borte- istered in 2 dosing schedules (3, 5, 10 mg/kg every other zomib-dexamethasone) and CYBORD (cyclophosphamide- week or 10, 20 mg/kg weekly for 4 weeks then every other bortezomib-dexamethasone)] in newly diagnosed patients week thereafter) in combination with lenalidomide 25 mg who are ineligible for SCT (NCT02513186). days 1-21 and dexamethasone 40 mg weekly in a relapsed- refractory MM (RRMM) population. Eighty-two per cent of MOR202 patients were refractory to previous lenalidomide therapy and 68% had received pomalidomide or carfilzomib. Patients MOR202 is a human anti-CD38 mAb that exerts its anti- were continued on study drug until disease progression, tumour effect via ADCC and ADCP. In vitro studies have unacceptable adverse events (AEs) or physician/patient pref- compared the ADCC profile of MOR202 on MM cells and erence. Bilateral pneumonia in the 20 mg/kg cohort was the normal haematopoietic cells with respect to daratumumab only grade 3 dose-limiting toxicity (DLT) to be reported. and isatuximab (Boxhammer et al, 2015). Overall, the The maximum tolerated dose (MTD) was not reached. in vitro studies demonstrated equivalent killing compared to

ª 2018 John Wiley & Sons Ltd, British Journal of Haematology 5 Review other anti-CD38 antibodies except in normal haematopoietic A dose-escalation, open-label, multicentre, Phase I clinical cells (expressing low levels of CD38), where the ability trial was conducted; 32 patients previously treated with an MOR202 to do so was significantly reduced. The combina- IMiD and PI received one of 7 dose levels ranging from tion of MOR202 with lenalidomide, bortezomib or melpha- 10 mg/m2 to 200 mg/m2. The MTD was defined at 200 mg/ lan was able to drastically reduce bone lysis as well as m2, with mucositis as the DLT. Among the 27 evaluable significantly reduce (>90%) the M protein levels. All mice patients, 1 patient had a PR and 2 patients had MRs. Stable that received MOR202 alone eventually died from disease disease (SD) was noted in an additional 11 patients. Most progression. Conversely, when MOR202 was combined with patients came off study due to disease progression (Jagannath bortezomib or lenalidomide, approximately 40% of mice et al, 2011). In another Phase I/II study, BT062 was adminis- were free of MM at day 98 (study termination) (Boxhammer tered for 3 weeks out of a 4-week cycle. Fifty-two per cent of et al, 2015). patients experienced at least SD with an acceptable toxicity In an ongoing Phase I/IIa, multicentre study, MOR202 is profile (90% of the AEs were grade 1-2) (Table I) (Heffner being administered as monotherapy or in combination with et al, 2012). dexamethasone, pomalidomide-dexamethasone and lenalido- A phase I/IIa, open-label, multicentre study evaluating the mide-dexamethasone to patients with RRMM (Raab et al, safety and efficacy of BT062 combined with lenalidomide 2016). Preliminary data were presented at the American Soci- and dexamethasone was initiated. Increasing doses of BT062 ety of Hematology conference in 2016. Sixty-six patients have (days 1, 8 and 15, every 4 weeks) in combination with been treated with MOR202 (Raab et al, 2016): 18 patients lenalidomide (25 mg on days 1-21) and low dose dexametha- receiving MOR202 alone, 8 receiving MOR202 and lenalido- sone (40 mg weekly) were administered to patients with mide, and 5 receiving MOR202 and pomalidomide. The RRMM. A total of 45 patients were included in the analysis treatment-emergent AEs were similar to those reported with and had received BT062 at doses of 80 mg/m2 (n = 3), other CD38 mAbs, which include: anaemia, fatigue, IRRs 100 mg/m2 (n = 36) or 120 mg/m2 (n = 6) at the cut-off and leucopenia. Grade 3 or greater AEs were reported in date. At the highest dose level, grade 3 mucositis in one 64% of patients. IRRs occurred in only 3/31 (10%) patients, patient and grade 3 anaemia in another patient were all low grade (≤2) and during the first infusion. In this trial, observed and considered as DLTs. The MTD was defined as the MTD has not been reached. There have not been any 100 mg/m2 and was selected for the recommended phase II treatment-related deaths. Of the 16 evaluable patients in the dosing. Eighty-nine per cent of the reported AEs were grade MOR202 alone arm, there were 3 PRs (19%) and 2 VGPRs 1 or 2 and they included fatigue, hypokalaemia, and diar- (13%). Three of5 patients responded to the MOR202 and rhoea. Among the 36 evaluable patients, the ORR was 78% pomalidomide, including 2 complete responses (CRs) with a across all doses: stringent CR (sCR, n = 1), CR (n = 2), median time to response of 4 weeks, indicating encouraging VGPR (n = 10) and PR (n = 15). Two patients achieved a preliminary activity, although the data remain early and MR while 6 patients had SD, resulting in a clinical benefit require further follow up, with efficacy analysis ongoing rate of 100%. The ORR was 70% among the 23 patients with (Table I). previous exposure to lenalidomide and bortezomib, and among the 10 patients who were considered refractory to lenalidomide (Kelly et al, 2014). Anti-CD138 Based on these encouraging data, BT-062 in combination CD138 is a protein expressed on the surface of myeloma cells with lenalidomide or pomalidomide and dexamethasone as well as on normal plasma cells but at lower levels (Wijde- (NCT01638936) was investigated in an ongoing, prospective, nes et al, 1996). CD138 acts as a co-receptor for MM growth open-label, multicentre, phase I/IIa study in patients with factors and also mediates cell adhesion (Dhodapkar et al, RRMM. BT062 100 mg/m2 was administered on days 1, 8 1998). and 15 in a 4-week cycle in combination with dexamethasone (20–40 mg on days 1, 8, 15 and 22) and lenalidomide (25 mg, daily on days 1–21) or pomalidomide (4 mg, daily Indatuximab Ravtansine (BT062) on days 1–21). Overall, 38 patients received BT062/lenalido- BT062 is composed of a chimerized anti-CD138 mAb conju- mide/dexamethasone and an additional 17 patients were trea- gated to a cytotoxic agent in the form of maytansinoid ted with BT062/pomalidomide/dexamethasone. Similar to (DM4). Once BT062 is bound to its ligand, the conjugate is the prior studies, 90% of AEs were grade 1 or 2, the most internalized by the target cell and DM4 is released, resulting common being diarrhoea, fatigue and nausea. Of the 43 in cell death. In vitro studies have demonstrated significant evaluable patients, the ORR was 77%. The median duration inhibition of cell growth and adhesion of MM cells to bone of response (DOR) was 21Á0 months. The ORR among the marrow stromal cells (Ikeda et al, 2009). Other preclinical 17 patients who were treated with BT062/pomalidomide/dex- studies have demonstrated synergy when lenalidomide or amethasone was 79% (VGPR: 4, PR: 7), all of which had bortezomib were combined with BT062 resulting in prior exposures to both lenalidomide and bortezomib and enhanced cytotoxicity (Zuber et al, 2010). progressed on their last therapy (Kelly et al, 2016).

6 ª 2018 John Wiley & Sons Ltd, British Journal of Haematology Review

A Phase I trial investigating the safety of tabalumab in Anti-IL6 combination with bortezomib and dexamethasone in RRMM IL6 is produced by the stromal cells within the bone marrow patients was recently published (Raje et al, 2016a). Forty- and plays a crucial role in the proliferation and survival of eight patients were enrolled: 20 to the dose-escalation arm MM cells (Klein et al, 1989). IL6 is implicated in chemother- and 28 to the expansion arm, in which 100 mg of tabalumab apy-resistance by its ability to protect against cell death by (once every 3 weeks) in combination with 1Á3 mg/m2 of regulating the activity of anti-apoptotic heat shock proteins bortezomib (days 1, 4, 8 and 11) was evaluated. All 48 (Voorhees et al, 2007). patients had received at least one prior therapy with either bortezomib (77%) or an IMiD (88%). The ORR was 42%; 3 patients achieved a CR, 2 achieved a VGPR and 15 achieved Siltuximab a PR. Responses were more frequent in patients with baseline Siltuxmab is a chimeric mAb targeting IL6. Preclinical studies BAFF levels < 1500 pg/ml. The common grade 3–4 AE’s were encouraging with synergistic cytotoxic activity when sil- were thrombocytopenia, pneumonia and neuropathy. Most tuximab was combined with other agents such as bortezomib patients discontinued treatment for progressive disease (Voorhees et al, 2007, 2009). (n = 35, 73%). Median DOR and median time to progres- A Phase I, dose-escalating study was conducted using sil- sion were 7Á2 and 4Á8 months, respectively. Overall, the tuximab as a single agent in RRMM patients. Although the response rate of 42% is somewhat lower than one might drug was well tolerated, no responses were recorded (van expect compared to other combination regimens among Zaanen et al, 1998). A Phase II trial evaluated siltuximab as patients with RRMM (Table I) (Raje et al, 2016a). a single agent as well as in combination with dexamethasone In a Phase II, double-blinded study, 220 patients with (Voorhees et al, 2013). As monotherapy, 62% of patients RRMM were randomly assigned to dexamethasone 20 mg achieved SD but when administered with dexamethasone, the and bortezomib 1Á3 mg/m2 in combination with placebo PR rate was 19% and MR rate was 28% in this heavily pre- (n = 72), tabalumab 100 mg (n = 74), or tabalumab 300 mg treated population. Infections of any grade were seen in 57% (n = 74). There were no significant differences in median of patients; grade 3 and 4 in 12% and 6% of patients, respec- PFS among the three cohorts. When stratified for BAFF tively (Table I) (Voorhees et al, 2013). expression, patients with low baseline levels (n = 162) had A Phase II, randomized study of bortezomib, melphalan significantly longer median PFS than those with high BAFF and prednisone (VMP) with or without siltuximab was com- expression (n = 55) (8Á3 versus 5Á8 months, P = 0Á015). The pleted. One-hundred-and-six patients were randomized to treatment-emergent AEs were thrombocytopenia (37%), fati- receive either VMP alone or VMP combined with siltuximab gue (37%), diarrhoea (35%) and constipation (32%). Over- (11 mg/kg every 3 weeks) followed by siltuximab mainte- all, PFS was not improved with the addition of tabalumab nance. The ORR for the siltuximab group was 88% versus compared to placebo, even at higher doses (Raje et al, 80% in the VMP alone group. The CR rate was 27% and 2017a). 22%, respectively. Median PFS and OS at 1 year were identical in both arms. The authors concluded that the addition of Anti-receptor activator of nuclear factor (NF)-jB siltuximab to VMP did not significantly improve outcomes ligand (RANKL) or response rates (San-Miguel et al, 2014). Receptor activator of NF-jB ligand (RANKL, also termed TNFSF11) plays a key role in the pathophysiology of bone Anti-B cell activating factor (BAFF) disease in MM by activating osteoclasts and promoting B cell activating factor (BAFF, also termed TNFSF13B) is osteoclastogenesis (Yaccoby et al, 2002, 2004). part of the bone marrow microenvironment; it is produced by monocytes, osteoclasts and neutrophils (Moreaux et al, Denosumab 2005). BAFF binds to tumour necrosis-factor (TNF)-related receptors, which activate several pathways that contribute to Denosumab is a humanized mAb that targets RANKL. the survival of MM cells and play a role in dexamethasone Although none of the trials looking at single agent deno- resistance (Moreaux et al, 2004; Tai et al, 2006; Neri et al, sumab demonstrated any reduction in monoclonal protein, 2007). there was a decrease in bone resorption that persisted up to 84 days after a single dose (Body et al, 2006). In a randomized, double-blind, international Phase III study (Henry et al, Tabalumab 2011) comparing denosumab with zoledronic acid (ZA) in Tabalumab is a humanized mAb targeting serum and mem- patients with advanced solids cancers or MM, denosumab brane-bound BAFF. In vitro studies demonstrated anti- was non-inferior to ZA in delaying time to first skeletal tumoural activity (Neri et al, 2007). event. Although OS and disease progression were similar in

ª 2018 John Wiley & Sons Ltd, British Journal of Haematology 7 Review both arms, an ad hoc OS analysis of the MM subset of patients A study looking at BHQ880 as a single agent in patients (n = 180) favoured the ZA cohort (95% confidence interval with smouldering MM has been completed (Munshi et al, (CI) 1Á13–4Á50, P = 0Á014). Hypocalcaemia was seen more 2012). Twenty-five patients were enrolled. No grade 3/4 AEs often in the denosumab group. Although rates of AEs and or serious AEs were observed. The most common AEs, were serious AEs (including osteonecrosis of the jaw) were not dif- arthralgia (16%), fatigue (12%), pyrexia (12%), extremity ferent between the two compounds, ZA lead to more renal pain (12%) and upper respiratory tract infection (12%). events. Unfortunately, this study suffered from imbalances There was preliminary evidence of anabolic bone activity with respect to baseline characteristics between groups, as well among 4 of the 5 patients evaluated based on quantitative as a large number of patients who were lost to follow-up (Raje computed tomography (qCT) and finite element analysis et al, 2016b). Survival analysis will be better assessed in an (FEA). Of note, BHQ880 did not demonstrate any anti-MM ongoing, phase III, randomized, double-blinded, multicentre activity (Munshi et al, 2012). study comparing denosumab to ZA in subjects with newly diagnosed MM (NCT01345019). Preliminary data was pre- PD-1/PD-L1 antibodies and check point sented at the American Society of Clinical Oncology (ASCO) inhibition in June 2017, demonstrating that denosumab was non-inferior to ZA in delaying the time to first on-study skeletal-related PD-1 (also termed PDCD1) is a member of the CD28 family event (HR = 0Á98, P = 0Á01) (Raje et al, 2017b). The study of receptors (Ishida et al, 1992) and is expressed on the sur- demonstrated that patients randomized to receive denosumab face of antigen-activated T cells (Keir et al, 2007). PD-1 has had a significantly lower rate of renal adverse events compared two ligands: PD-L1(CD274) and PD-L2 (PDCD1LG2). PD- to ZA (10% vs. 17Á1%, P < 0Á001). Denosumab, which is not L1 is expressed on antigen presenting cells and on various cleared by the kidney, may offer a safe alternative for patients non-haematopoietic cells (Yamazaki et al, 2002). PD-1 acts with MM (Raje et al, 2017b). by limiting T cell activation and thus, when bound to PD-L1, it delivers an inhibitory signal resulting in the reduced production of cytokines and T cell proliferation (Freeman Dickkopf 1 (DKK1) et al, 2000). Ultimately, PD-1 plays a role in the maintenance DKK1 is a soluble antagonist of the WNT pathway that is of self-tolerance by suppressing the activation of auto- overexpressed by plasma cells in patients with osteolytic reactive T cells (Keir et al, 2008). lesions. The overexpression of DKK1 blocks the differentia- PD-L1 is aberrantly expressed on a wide array of solid tion of osteoblasts and thus, inhibits the formation of bone tumours (Dong et al, 2002) but not present on normal (Tian et al, 2003). epithelial cells. Various studies have shown that PD-L1 is absent on normal plasma cells (Liu et al, 2007) but expressed on tumour cells from patients with MM (Benson BHQ880 et al, 2010; Kuranda et al, 2010). Studies demonstrated that BHQ880 is a fully human neutralizing antibody targeting the PD-1/PD L1 interaction promotes progression of MM DKK1. Preclinical studies have demonstrated that BHQ880 by inhibiting the immune system’s ability to control the dis- reduces IL6 secretion and tumour growth, as well as promot- ease (immune escape) (Rosenblatt et al, 2011; Tamura et al, ing osteoblastogenesis in both in vitro and mouse models 2013). In addition, the degree of PD-L1 expression was (Fulciniti et al, 2009). A Phase Ib open-label, multicentre, associated with disease progression. It has also been demon- single-arm study was designed to determine the MTD and strated that T cells isolated from patients with MM demon- the DLT of escalating doses of BHQ880 in combination with strate PD-1 expression (Rosenblatt et al, 2011). Ray et al anti-myeloma therapy and ZA in patients with RRMM (Iyer (2015) confirmed that PD-L1 is not only highly expressed et al, 2014). Twenty-eight patients were administered on MM cells, but also on MM patient-derived plasmacytoid BHQ880 at doses of 3–40 mg/kg. Although no DLTs were dendritic cells (pDCs) within the bone marrow, both of reported and thus no MTD determined, the recommended which suppress PD-1-expressing T cell and NK cell immune Phase II dose was declared to be 10 mg/kg. There was a function. The blockade of the PD-L1-PD-1 signalling axis trend towards increased bone density over time; specifically, via an anti-PD-L1 antibody enhanced CD8+ cytotoxic T in the spine from cycle 12 and onwards in some patients lymphocyte and NK cell-mediated cytolytic activity (Ray (Iyer et al, 2014). Only a small number of patients experi- et al, 2015). Benson et al (2010) also established that NK enced an increase in the number or size of lytic bone lesions. cells from myeloma patients expressed PD-1 as opposed to Five new skeletal-related events (SREs) occurred in four NK cells from healthy individuals. When a PD-1 mAb was patients, but it is believed that three of these were considered applied, there was observed enhancement of the cytolytic to be a progression of baseline SREs. The main limitation of activity of NK cells against MM cells. Iwai et al (2002) this study is the difficulty in interpreting the cause and effect demonstrated that the administration of an anti-PD-L1 anti- because of the concomitant use of ZA and anti-MM therapy body managed to suppress myeloma progression in mice. In in conjunction with BHQ880. another study evaluated the impact of single and dual

8 ª 2018 John Wiley & Sons Ltd, British Journal of Haematology Review blockade of PD-1/PD-L1, alone or in combination with (4%). There was a 42% incidence of grade 3 neutropenia lenalidomide, on immune cell function and the growth of associated with increased risk of infection. One patient died MM cell growth in the bone marrow milieu (Gorgun et al, of neutropenia and sepsis. Although the combination of 2015). This study demonstrated that the anti-MM immune pembrolizumab and pomalidomide resulted in significant response was enhanced by the addition of lenalidomide pro- clinical activity, there were higher-than-expected rates of viding rationale for the combination of PD-1/PD-L1 block- infection and autoimmunity (Table I) (Badros et al, 2017). ade agents with an immunomodulator in future clinical These promising results have led to KEYNOTE-185 studies (Gorgun et al, 2015). (NCT02579863) and KEYNOTE-183 (NCT02576977), both phase III studies administering pembrolizumab (200 mg every 3 weeks) or placebo in combination with lenalidomide MK-3475 (KEYNOTE-185) or pomalidomide (KEYNOTE-183) and low dose dexamethasone (40 mg weekly) in newly diagnosed Pembrolizumab (MK-3475) MM and RRMM, respectively. In KEYNOTE-183 (n = 249), MK-3475 is a potent, selective, humanized IgG4 anti-PD-1 29 deaths were reported in the pembrolizumab arm versus mAb aimed at blocking the interaction between PD-1 with 21 deaths in the control arm. The hazard ratio for OS was PD-L1 and PD-L2 with the hope of attaining tumour regres- 1Á61 (95% CI, 0Á91–2Á85), translating into more than a 50% sion. KEYNOTE-023 (NCT02036502) is an open-label, Phase increase in the relative risk of death in the pembrolizumab I, multicentre, non-randomized, dose-escalation trial looking arm. In KEYNOTE-185 (N = 301), at a median follow-up of to evaluate the safety and tolerability of MK-3475 when com- 6Á6 months, there were 19 deaths in the pembrolizumab bined with lenalidomide and dexamethasone in patients with group compared with 9 in the control arm. RRMM (at least 2 prior lines of therapy including PI and As of June 2017, the FDA placed a full clinical hold on IMiD). Preliminary data was presented at the American Soci- these three studies (KEYNOTE-183, KEYNOTE-185 and ety of Clinical Oncology annual meeting in 2016 (Mateos KEYNOTE-023) based upon an increased risk of death et al, 2016). Enrolled patients received 2 mg/kg of pem- among patients treated with pembrolizumab in 2 of these 3 brolizumab every 2 weeks in combination with 10 mg or trials. The reason for death rate imbalance in the pem- 25 mg of lenalidomide on days 1-21 (out of a 28-day cycle) brolizumab arms can only be speculated until safety data is and weekly dexamethasone. The MTD was defined as pem- publicly released. brolizumab 200 mg fixed dose in combination with lenalidomide 25 mg and dexamethasone 40 mg in the expansion BMS-936558 cohort. As of September 2015, 33 additional patients were enrolled onto the dose-expansion phase. Thirty-six patients Nivolumab (BMS-936558) (72%) experienced at least one AE of any grade, most com- monly thrombocytopenia (28%) and neutropenia (24%). PNivolumab is an anti-PD-1 mAb that has shown significant After a median follow-up of 9Á7 months, 13/17 (76%) therapeutic activity and an acceptable safety profile in patients in the dose determination phase responded to treat- patients with relapsed or refractory Hodgkin lymphoma. In ment: 4 VGPRs and 9 PRs. Of note, these responses were a Phase I open-label, dose-escalation study, patients with also observed among patients with immunomodulator-refrac- various relapsed or refractory haematological malignancies, tory and double-refractory myeloma (Table I) (Mateos et al, including B and T cell lymphomas and MM, received nivo- 2016). lumab at doses of 1 or 3 mg/kg every 2 weeks (Lesokhin In a Phase II study, pembrolizumab (200 mg IV every et al, 2016). Twenty-seven patients with RRMM took part 2 weeks), pomalidomide (4 mg on days 1-21) and dexam- in this study, 24 of whom experienced disease progression ethasone (40 mg weekly) demonstrated clinical activity in after prior IMiD and PI therapy. Because the MTD was not patients with RRMM who were pomalidomide-na€ıve (90% reached, patients in the expansion phase received nivolumab lenalidomide refractory) with a response rate of 60% [sCR at a dose of 3 mg/kg. Ninety-six percent of patients experi- (6%), CR (2%), VGPR (19%), PR (33%)]. The median PFS enced at least one AE, of which 18% were considered grade was 17 months. The ORR seemed to correlate with PD-1 3. Only one patient experienced a grade 5 AE. Immune expression on myeloma cells by immunohistochemistry. reactions due to T-cell activation were observed in 34% of TEAEs of any grade occurred in 73% of patients. The most patients (predominantly grade 1 or 2). Nine patients devel- Pcommon non-haematological AEs were fatigue, hypergly- oped pneumonitis, including one fatal case. Among the caemia, dizziness and constipation. One-third of patients patients with MM, SD was the best response in 17 out of experienced respiratory symptoms [dyspnea (31%), upper 27 patients which lasted a median of 11Á4 weeks (Table I) respiratory tract infection (URTI; 33%), pneumonia (21%) (Lesokhin et al, 2016). Overall, there was a lack of objective and influenza A (8%)]. The most common immune- tumour response in this study among RRMM patients when mediated events included pneumonitis (13%), hypothy- compared to the other participants. The reason for this poor roidism (10%), adrenal insufficiency (4%) and hepatitis response remains unclear but it has been theorized that it

ª 2018 John Wiley & Sons Ltd, British Journal of Haematology 9 Review may be related to the accompanying complex microenviron- (2016) demonstrated that overexpression or activation of ment as well as the need for combination approaches in this BCMA by a proliferation-inducing ligand (APRIL setting, which are now under evaluation as part of several [TNFSF13]) promoted augmented MM cell growth and sur- ongoing clinical trials incorporating IMIDs and Elotuzumab. vival as well as the in vivo growth of xenografted MM cells CheckMate-602 (NCT02726581) is a phase III trial evalu- harbouring a Tp53 mutation in mice. The inhibition of ating the combination of nivolumab, elotuzumab, pomalido- APRIL by an antagonistic anti-APRIL mAb successfully pre- mide and dexamethasone in patients with RRMM. vented in vivo MM cell growth (Tai et al, 2016). CheckMate-039 (NCT01592370) is a phase I study investigat- A mAb that effectively targets BCMA has yet to be discov- ing the safety of nivolumab in combination with daratu- ered. Tai et al (2014) demonstrated that BCMA was success- mumab, with or without pomalidomide and dexamethasone fully targeted by J6M0-mcMMAF (GSK2857916), a novel in the relapsed/refractory population. CA204142 humanized and afucosylated antagonistic anti-BCMA anti- (NCT02612779) is a phase II study assessing the safety and body-drug conjugate, via a non-cleavable linker. J6M0- efﬁcacy of elotuzumab with pomalidomide and dexametha- mcMMAF effectively exerted its anti-MM effect via ADCC, sone versus elotuzumab with nivolumab for lenalidomide- which was further enhanced by the addition of lenalidomide. refractory patients. The FDA has placed partial clinical holds Furthermore, J6M0-mcMMAF induced ADCP via the on these 3 clinical trials based on the safety concerns identi- recruitment of macrophages. Together, these results demon- ﬁed in clinical trials combining pembrolizumab with strate that GSK2857916 is a promising next-generation immunomodulatory agents. immunotherapeutic agent in MM (Tai et al, 2014).

Durvalumab Chimeric antigen receptors (CAR) T cell in MM PDurvalumab is an IgG kappa1 human mAb that inhibits PChimeric antigen receptors (CAR) are synthetic fusion binding of PD-L1 to PD-1(Stewart et al, 2015); it has been proteins made up of the variable portion of an antibody granted accelerated approval for locally advanced or meta- that targets a surface antigen expressed on a tumour cell. static urothelial carcinoma and was recently granted break- The synthetic gene is genetically incorporated into the T through therapy designation for patients with locally cell using retroviral or lentiviral vectors leading to consti- advanced unresectable non-small cell lung cancer. The FDA tutive expression. CAR T cells targeting CD19 have been has placed partial clinical holds on trials assessing durval- the most successful and the most widely studied to date umab in combination with Daratumumab (NCT02807454, (Sadelain, 2015). CD19 is a surface protein expressed on NCT03000452), and in a phase 1b study alone or in com- precursor and mature B cells and thus, is a target of bination with pomalidomide with or without dexametha- interest in disease like acute B cell lymphoblastic leukaemia sone (NCT02616640) in RRMM. In newly diagnosed and non-Hodgkin lymphoma. Clonal plasma cells do not patients, a study combining durvalumab with lenalidomide routinely express CD19 on their surface. BCMA is an with or without dexamethasone (NCT02685826) has been ideal target for CAR T cells in MM as it is highly placed on a full clinical hold. Patients already enrolled in expressed on the surface of clonal plasma cells (Carpenter the partially held trials may continue treatment if they et al, 2013). have experienced a clinical benefit, but no new patients are Results from a first-in-human Phase I clinical trial at the being enrolled. Furthermore, treatment has been stopped National Cancer Institute using CAR-BCMA in RRMM completely for patients enrolled in the trial on full clinical patients (NCT02215967) was recently published (Ali et al, hold. 2016; (Table II). Participants in this study had advanced MM (median of 7 previous lines of therapy) and they had to demonstrate >50% BCMA expression by flow cytometry or T cell approaches immunohistochemistry Twelve patients were treated in this dose-escalation trial with CAR-BCMA following 3 days of B cell maturation antigen (BCMA) treatment with 300 mg/m2 of cyclophosphamide and 30 mg/ BCMA (also termed TNFRSF17) is an antigen that plays a m2 of fludarabine. One of four doses of CAR+ T cells/kg key role in the regulation and differentiation of B cells into were used: 0Á3 9 106,19 106,39 106, and 9 9 106.Of plasma cells (Carpenter et al, 2013). BCMA is expressed the 6 patients who received the two lowest doses of CAR+ T homogeneously on the surface of plasma cells in patients cells, one achieved a PR (duration of response: 2 weeks) with MM, plasma cell leukaemia and plasmacytomas. The while the rest had SD. On the 3rd dose level, one patient expression of BCMA on plasma cells was confirmed using achieved a VGPR with a negative positron emission tomogra- gene expression profiling and flow cytometry. BCMA expres- phy (PET) scan. Three patients were treated at the highest sion was observed in clonal plasma cells from 723 out of 726 dose level (9 9 106 CAR+ T cells/kg): one patient, who had (99Á5%) patients with MGUS and MM, but was absent on 90% bone marrow plasmacytosis, achieved a sCR that lasted normal bone marrow cells (Seckinger et al, 2015). Tai et al for 17 weeks before relapse and the second patient, who had

10 ª 2018 John Wiley & Sons Ltd, British Journal of Haematology Review

80% bone marrow plasma cell involvement, had undetectable Conclusion plasma cells on a repeat bone marrow biopsy 4 weeks following treatment. Twenty-eight weeks after the infusion, this With the approval of multiple new agents over the last patient’s bone marrow plasma cells were undetectable by decade together with better supportive care, there has been flow cytometry. Of note, the patients with the most impres- a dramatic increase in the proportion of myeloma patients sive anti-myeloma responses also had the highest IL6 levels living longer from time of diagnosis, but a large number following treatment. Patients who responded demonstrated still develop resistance to therapy, including IMiDs and lower BCMA levels after CART+ T cell exposure. A dose of PIs. Immune therapy incorporating mAbs provide a new 9 9 106 was associated with grade 3-4 cytokine release syn- class of agents that offer significant promise in the treat- drome (fever, tachycardia, dyspnoea, acute kidney injury, ment of MM, and especially in the relapsed and refractory hypotension and muscle damage) in the responding patients. setting. MAbs are not only generally well-tolerated, but Most recently, four other CAR-BCMA clinical trials in they have demonstrated meaningful clinical activity, inde- RRMM have opened (Table II). The University of Pennsylva- pendent of baseline cytogenetic risk, age and SCT status. nia is conducting a phase 1, dose-escalating trial Whilst most of these antibodies exhibit single agent activ- (NCT02546167), in patients with RRMM. Patients are receiv- ity, clinical trials combining these agents with IMiDs and ing CAR-BCMA cells as split-dose infusions. In this trial, the PIs have resulted in promising outcomes across almost all expression of BCMA is not required for eligibility. The first subgroups. cohort is receiving CAR-BCMA T cells alone without condi- There are still many unanswered questions surrounding tioning chemotherapy. The other cohorts will receive the proper use of mAbs and when to incorporate them cyclophosphamide and varying doses of CAR T cells. To into the treatment algorithm. For instance, less is known date, 6 patients (all IMiD/PI-refractory with a median of 9 about the role of mAbs in the upfront setting, in the peri- prior lines of therapy) have been treated in Cohort 1. Cyto- transplant period, or in precursor states such as MGUS or kine release syndrome occurred in 5 patients; 2 with grade 3 smouldering MM. Ongoing clinical trials are designed to reactions requiring tocilizumab. There was one DLT: grade 4 address these important concerns. As we continue to develop posterior reversible encephalopathy syndrome in one patient. newer mAbs targeting independent pathways, future studies Other grade 3/4 toxicities included hypophosphataemia will be aimed at determining the best drug combinations and (n = 3), hypocalcaemia (n = 2), anaemia, neutropenia, how to incorporate these agents into current therapeutic thrombocytopenia, fatigue, infection, hypertension and pleu- paradigms with the goal of achieving better disease control ral effusion (n = 1 each). The first enrolled patient has ongo- and longer survival. ing sCR for more than 12 months with minimal residual Immune therapies provide a highly promising and disease-negative bone marrow by flow cytometry. Patient 3, unique platform for future progress. The advent of cellular who originally had pleural involvement, achieved a VGPR therapy, and CAR-T treatment in particular, offers a new with complete resolution of extramedullary disease on PET/ approach to restoring targeted host immunity. Combined computed tomography scan. The patient later progressed at with the real excitement engendered by check point inhibi- 5 months and this was associated with a significant reduction tion, recent safety concerns notwithstanding, these advances of CART-BCMA cells and loss of BCMA expression on MM altogether provide real hope for continued improvement in cells by flow cytometry (Cohen et al, 2016). patient outcomes with lasting disease control, and particular Resistance to CAR-BCMA T cells has become an area of benefit anticipated in the management of early onset interested as its mechanism is not entirely understood. It also disease. remains to be seen if extent of BCMA expression predicts degree of response. Acknowledgements

Future directions The primary authors gratefully acknowledge the contribution of Michelle Maglio and Nikhil Munshi as co-authors to this With the success of daratumumab, CAR-CD38 T cells are review. The authors also gratefully acknowledge the editorial now in pre-clinical trials. Donor-derived CAR T cells may support of Rashana Lord. also be a promising therapeutic avenue, combining the con- cept of targeted therapy with allogeneic SCT. The use of Author contributions donor-derived CAR T cells may reduce the risk of graft-versus-host disease (GVHD) by limiting the number of GVHD- CV wrote the paper and created the tables. JPL participated causing donor T cells, though it will probably lead to more in the writing of the paper. KCA participated in the writing toxicities than what has been reported with autologous CAR of the paper. PGR participated in the design and the writing T cells. of the paper.

ª 2018 John Wiley & Sons Ltd, British Journal of Haematology 11 Review

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