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A New Horizon for the Treatment of Multiple Myeloma

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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 + 2018 John Wiley & Sons Ltd, 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 British Journal of Haematology (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 2018 John Wiley & Sons Ltd, 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 British Journal of Haematology 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.
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