and : A Primer to an Evolving Landscape

Authors: *Rebecca Gonzalez,1,2 Hanna Bailey,1,2 Omar Castaneda Puglianini3

1. Department of Pharmacy, Moffitt Cancer Center, Tampa, Florida, USA 2. Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA 3. Cellular Immunotherapies and Transplant Program, Division of Hematology/ Oncology and Palliative Care, Virginia Commonwealth University, Massey Cancer Center, Richmond, Virginia, USA *Correspondence to [email protected]

Disclosure: The authors have declared no conflicts of interest.

Received: 09.09.20

Accepted: 09.11.20

Keywords: B-cell maturation (BCMA), Belantamab mafodotin, CD38, immunotherapy, isatuximab, monoclonal antibodies, multiple myeloma (MM).

Citation: EMJ Hematol. 2021; DOI/10.33590/emjhematol/20-00231.

Abstract Multiple myeloma (MM) continues to be an incurable disease impacting mainly an ageing population. Comorbidities, disease characteristics, and drug toxicity profiles heavily influence treatment selections. Despite single agent activity of many anti-MM agents, opportunities to maintain responses most often include combination therapy with immunomodulator and/ or therapies. Monoclonal antibodies (moAb) have become an additional backbone to both newly diagnosed and relapsed or refractory transplant eligible and ineligible patients. Tolerability of these agents offers an additional benefit particularly to an ageing population. Two newly approved moAb targeting CD38 and B-cell maturation antigen have been added to the anti-MM arsenal. Isatuximab, a chimeric anti-CD38 moAb, is the second U.S. Food and Drug Administration (FDA)-approved CD38 offering unique mechanisms of action owing to differences in binding and favourable side effect profiles. Belantamab mafodotin, a B-cell maturation antigen drug-antibody conjugate, is a first- in-class humanised moAb containing a distinct microtubule-disrupting agent: monomethyl auristatin-F. Its distinctive anti-MM activity includes antibody-dependent cellular cytotoxicity and phagocytosis, as well as direct cytotoxicity caused by internalisation of monomethyl auristatin-F. This review focusses primarily on the mechanisms of action, resistance patterns, and clinical utility of two recently FDA-approved agents; isatuximab in combination with pomalidomide and for relapsed or refractory MM exposed to at least two or more lines of therapy, and belantamab mafodotin monotherapy in relapsed or refractory MM exposed to four or more lines of therapy.

HEMATOLOGY • April 2021 EMJ INTRODUCTION This review specifically focusses on isatuximab and belantamab mafodotin including discussion of the mechanisms of action, As the second most common haematological development leading to FDA approval, clinical malignancy, multiple myeloma (MM), a plasma cell activity, relevant adverse events (AE), as well as disorder, continues to affect a significant portion of the manner in which these two agents are used patients with increasing incidence over the past 25 within the MM treatment landscape. There is years.1–3 MM remains an incurable disease despite also a brief discussion of emerging moAb for the the continued improvement of outcomes over management of MM. the past decades with immunomodulatory (IMID) and proteosome inhibitor (PI) therapies. Targeted immunotherapy with monoclonal antibodies CD38 MONOCLONAL ANTIBODIES: (moAb) is critical for the successful treatment ONE TARGET, MANY ACTIONS of different malignancies and is no different in MM. The first-in-class, humanised IgG1-κ moAb Immunotherapy for the treatment of MM has targets the CD38 epitope and has become a significant addition to the anti-myeloma rapidly changed the treatment landscape of MM, repertoire. CD38, a Type II transmembrane moving quickly from the relapsed or refractory to glycoprotein with ectoenzyme properties, has the upfront setting with unparalleled results.4-6 a prominent role in proliferation and growth of MM cells.10,11 CD38 directed moAb offer a unique Several anti-CD38 and B-cell maturation antigen target because of its higher presence on MM and (BCMA) therapies are being developed for the plasma cells, while having low expression on other treatment of MM.7 Reflecting this rapid progress myeloid and lymphoid cells, making it an ideal of MM drug development, two new agents anti-MM therapy candidate.2 Several mechanisms received approval from the U.S. Food and Drug of anti-CD38 activity have been shown and are Administration (FDA): belantamab mafodotin, dependent on fragment crystallisable (Fc)-based a monotherapy BCMA-directed antibody and immune activation. These include complement- microtubule inhibitor conjugate, and isatuximab, a dependent cytotoxicity (CDC), antibody- CD38-directed cytolytic antibody, in combination dependent cellular cytotoxicity (ADCC), and with pomalidomide and dexamethasone. Studies antibody-dependent cellular phagocytosis have shown that these therapies are effective (ADCP), as well as direct apoptosis. CD38 moAb in the treatment of relapsed or refractory MM additionally offer immunomodulatory effects by (RRMM) and are well tolerated with manageable way of regulatory and suppressor cell reduction .8,9 and improved antitumour activity (Figure 1A).12-14

A B

Figure 1: A) Anti-CD38 tumour kill mechanisms; B) belantamab mafodotin anti-multiple myeloma targets.

ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; BCMA: B-cell maturation antigen; CDC: complement-dependent cytotoxicity; MMAF: monomethyl auristatin-F; moAB: ; NK: natural killer.

Creative Commons Attribution-Non Commercial 4.0 April 2021 • HEMATOLOGY Differences among anti-CD38 moAb are highly Single-agent activity of anti-CD38 therapies dependent on the Fc-directed activity driven by is evident; however, durability of response is location of epitope binding and subsequent anti- limited. Combination of anti-MM therapy (PI MM potency of the many immune mechanisms. or IMID) is one possible mechanism to boost There are currently four CD38 moAb therapies activity and potentially overcome resistance. with Phase II or more clinical data (daratumumab, Synergistic activity of IMID therapy to augment isatuximab, MOR,15 and TAK-07916).10,17 immune effector cell activity and enhance anti- CD38 therapy has been shown in patients Mechanisms and Resistance Methods who were previously refractory to one or both 20-23 Effector cells, particularly natural killer (NK) cells therapies. Additionally, high-risk cytogenetic are a crucial player in ADCC, whereas monocytes features such as t(4;14), t(4;16), and del17p and macrophages are integral in ADCP-mediated continue to negatively impact overall response cell killing and are the drivers at the forefront of and survival of patients with MM. Anti-CD38 anti-CD 38 moAb activity. Complement-driven moAb therapy unfortunately does not abrogate 12,21,24 activation increases recruitment of other immune inferior responses in high-risk patients. cells and phagocytosis, while reducing inhibitory Additional resistance to CD38 moAb therapy immune effector cells. Unlike other anti-CD38 may develop as a result of loss of CD38 cell moAb, daratumumab exhibits stronger CDC- surface density expression and/or increase in driven activity over all other anti-MM mechanisms.13 soluble CD38, leading to reduced ADCC, ADCP, Direct anti-MM properties are highly variable and CDC capabilities.10,13 Susceptibility to these among CD38 moAb and are dependent upon killing methods is heavily driven by cell surface the ability to trigger apoptosis without Fc-driven expression; methods to increase surface density binding. Daratumumab, unlike isatuximab, requires with all-trans retinoic acid,18 panobinostat,25 and secondary cross-linking to induce programmed IMID therapies have been proven to upregulate cell death, whereas isatuximab independently CD38 expression.12 Upon administration of induces reactive oxygen species and liposomal- daratumumab, a significant reduction in CD38 mediated death.10,13 Suppression of regulatory density expression from direct cell surface loss has cells, including T and B cells, leads to improved been previously noted, regardless of treatment effector (T and NK) cell numbers and activity response.11,13 This reduction can be transient as while promoting an anti-MM microenvironment.12,13 baseline levels have been restored up to 6 months postexposure.18 This phenomenon is not noted with Eventually patients with MM exposed to CD38 isatuximab therapy, although an increase in CD38 directed therapy will progress; however, several internalisation has been reported, this property is resistance mechanisms, both primary and potentially driven by a different epitope binding acquired, are known and strategies to overcome site.10 Other drivers of resistance may include this barrier are expanding.12 Concerns over prior complement inhibitory proteins, anti-apoptotic therapy exposure, disease cytogenetics, and proteins such as survivin, reduction in NK-cell reintroduction of prior refractory agents are numbers, and Fc-receptor polymorphisms.13 some patient-specific factors to consider.12 In a study conducted by Nijhof et al.,18 evaluation of Fc-dependent mechanisms of daratumumab ISATUXIMAB: EXPANSION OF CD38 showed heterogeneous CD38 expression, but TARGETING similar activity of ADCC and CDC among newly diagnosed MM (NDMM) and RRMM patients, Unlike other CD38 moAb therapies, isatuximab’s indicated that refractoriness to other anti-MM epitope binding on CD38 is located away from agents did not confer similar refractory response catalytic activity site, uniquely increasing its with CD38 moAb.18 Utilisation of anti-CD38 inhibition of enzymatic activity and contributing therapy in smouldering MM (SMM) showed to its variances in mechanism of action.10 higher single-agent daratumumab response- Isatuximab’s main anti-MM kill mechanism is rates compared to heavily pretreated MM through ADCC, which can be enhanced through patients, leading the authors to note potential concurrent use of both PI and IMID therapies. variations in the tumour microenvironment and Demonstrations of enhancement in direct immune impairment with disease progression.19 cytotoxicity and cell lysis have been shown

HEMATOLOGY • April 2021 EMJ with combined therapies versus single-agent patients versus none in doublet combination isatuximab; although, isatuximab does exhibit patients. Neutropenia and infections remained the a dose-dependent CD38 enzymatic inhibition most common AE among both treated groups more potent than daratumumab.10,26 During initial with approximately 40% (Grade 3–4: 2.6%) monotherapy dose-escalation trials, isatuximab experiencing isatuximab-IRR.8 Outcomes from was given intravenously to RRMM patients at the ICARIA trial8 led to FDA approval of dosages up to 20 mg/kg weekly or every 2 isatuximab34 on 2nd March 2020. Clinical discussion weeks. The maximum tolerated dose was not of the major isatuximab trials is summarised reached because of lack of significant AE. The in Table 1. 8,21,24,27,28 most common AE was infusion-related reactions Additional activity was also noted with a PI in (IRR) occurring in 49.3% patients, with mandatory a Phase Ib trial of isatuximab with carfilzomib prophylaxis given at dose levels more than 3 and dexamethasone. When given together with mg/kg. Symptoms included shortness of breath, biweekly carfilzomib, isatuximab had an ORR nausea, headache, chest discomfort, and pyrexia. of 60.6% in patients who had received prior Most often, IRR occurred within first infusion and carfilzomib (45.0%) and were dual-refractory was associated with CDC activity. Haematologic (79.0%).35 Similar to the ICARIA clinical trial, toxicity occurred in 45–98% of patients, while the IKEMA study is prospectively evaluating fatigue and nausea occurred in approximately isatuximab with and without carfilzomib and 35%.27 A Phase II dose-escalation trial28 supported dexamethasone.36 Results of this trial will isatuximab clinical and pharmacokinetic activity further add to the understanding of standard and determined the single-agent dosing strategy doublet-therapy versus triple-therapy in RRMM of 20 mg/kg weekly for four doses, followed by patients, especially amongst those with dual- 20 mg/kg every 2 weeks. When combined with refractory disease. dexamethasone 40 mg or 20 mg daily in patients aged >75 years, isatuximab combination therapy had significant improvements in overall response CLINICAL TRIALS AND FUTURE rate (ORR), median progression-free survival OPPORTUNITIES (PFS), and reduction in IRR.29 Opportunities to improve patient care Synergistic activity with other anti-MM therapies experiences with different CD38 moAb include has proven effective throughout the history of recent approval of subcutaneous daratumumab MM treatment. Due to several MM subclones and administration,37 isatuximab fixed-volume the heterogeneity of the disease, combination infusions reducing infusion duration to less than strategies with IMID and PI have been effective 2 hours,38 reduced IRR moAb MOR-202,15 and with daratumumab and now isatuximab.26 nonhyaluronidase-containing subcutaneous Isatuximab combination with other IMID, such as formulation of TAK-079.16 Due to its efficacy , established a lower dosing strategy and tolerability in the RRMM setting, there are of four weekly doses of 10 mg/kg followed by several ongoing clinical trials investigating the doses every 2 weeks because of similar outcomes efficacy of isatuximab in combination with both but higher Grade 3 toxicities noted with higher ≥ IMID and PI therapies in patients with NDMM. dosing.21 Most recently, isatuximab was studied These include both transplant eligible39 and in a Phase II trial24 combining pomalidomide transplant ineligible40-43 patients. Additionally, in patients with lenalidomide and PI refractory isatuximab is currently being investigated as a disease (82% and 84%, respectively). These results monotherapy in SMM.10,26 Utilising CD38 moAb led to a Phase III, prospective trial (ICARIA-MM)8 therapy earlier on may benefit from a more ‘fit’ of isatuximab with and without pomalidomide immune system for modulation; however, exact and dexamethasone in RRMM patients. Triple sequence of use and corresponding resistance therapy in highly refractory patients improved PFS patterns are still being questioned. regardless of age (>75 years),30 renal impairment,31 high-risk cytogenetics,32 or those with more than Concerns regarding emergence of CD38 three prior lines of therapy33 or dual-refractory moAb therapies in both SMM and NDMM disease. Minimal residual disease negativity (level patients may change these responses in of 10-5) was also obtained in 5% of triple therapy RRMM patients, however, full understanding

Creative Commons Attribution-Non Commercial 4.0 April 2021 • HEMATOLOGY has yet to be elucidated. Additionally, with Clinical responses with anti-CD38 therapies are different mechanisms of action and epitope promising; however, due to small numbers of high- binding properties, isatuximab may be useful risk patients in clinical trials (20% approximately in previously exposed daratumumab patients. in monotherapy27 and ICARIA-MM8), it is not fully Gandhi and colleagues23 reported on the extent clear if anti-CD38 therapies can mitigate these of success of anti-CD38 therapy in 275 patients oncogenic impacts on durability of response.27 with refractory CD38 disease. This retrospective A trial45 is currently investigating the role of study (MAMMOTH) analysed triple-, quadruple-, isatuximab monotherapy in high-risk SMM and penta-refractory patients exposed to patients and may offer further insight into the daratumumab (93%) and isatuximab (7%). role of targeted therapies in modifications of Survival was significantly affected by level of patient-specific therapy based on mutations, refractoriness to anti-MM therapies. Patients who molecular characteristics, and minimal residual were penta-refractory had approximately 5.0 disease status,14 and may also offer insight into the months less survival compared with nontriple- refractory (11.2 months) and those refractory particular role of CD38 moAb therapy to obtain to CD38 moAb had an overall survival (OS) deeper and better responses. of 8.6 months. A Phase I trial44 of isatuximab monotherapy in patients with prior daratumumab exposure was ongoing at the time of writing.

Table 1: Isatuximab clinical trials in relapsed or refractory multiple myeloma patients.8,21,24,27,28

Phase N Number of ORR (%) PFS DOR AE prior treatment (median, lines (median, months) range) Isa mono27 I (dose 84 5 (1–13) >10 mg/kg: >10 mg/kg: Low risk: 51% IRR expansion 23.8 3.7 37 W phase) High-risk: 16.7 >10 mg/kg + high-risk: high-risk: 2.9 25 W Isa mono28 II 97 5 (2–14) 10 mg/kg >10 mg/kg 10 mg/kg 51.5% IRR; · Q2/Q4W: 20 (n=18/74): 4.6 · Q2/Q4: 8.3 Grade ≥3: · Q2: 29.2 · Q2: 14.8 cytopenias; 20 mg/kg 20 mg/kg PNA · QW/Q2W: 24 QW/Q2W: 8.3 Isa-RD21 Ib 57 5 (1–12) 56 (n=26/52) 8.5 10.9 months Grade 3 PNA (n=1); 56% IRR Isa-PD24 Ib 45 3 (1–10) 62 17.6 18.7 months Grade ≥3: PNA; haematologic 42% IRR Isa-PD III 154 Isa- 3 (2–4) 60 Isa-PD 11.5 Isa-PD 13.3 months URI (28% versus PD8 PD versus versus 35 PD versus 6.5 PD Isa-PD versus Isa-PD 153 PD 11.1 months versus 17%); diarrhoea High-risk (26% Isa-PD versus versus 20% standard-risk PD); 38% IRR HR similar

AE: adverse event; D: dexamethasone; DOR: duration of response; HR: hazard ratio; IRR: infusion-related reactions; Isa: isatuximab; mono: monotherapy; ORR: overall response rate; PD: pomalidomide and dexamethasone; PFS: progression-free survival; PNA: pneumonia; Q: every; R: lenalidomide; URI: upper respiratory infection; W: weeks.

HEMATOLOGY • April 2021 EMJ B-cell Maturation Antigen: partial response (VGPR); and two patients (6%) A New Versatile Target with partial response. Median time to response was 1.2 months, with responses deepening with Despite significant advances in MM treatment, time. Median PFS was noted to be 12.0 months many patients develop resistance or intolerance with a median duration of response (DOR) of to available therapeutics including PI, IMID, and 14.3 months. Of significance, median PFS of anti-CD38 moAbs. In the last few years, BCMA has 6.2 months was much lower in patients who emerged as an appealing target in MM because had received prior daratumumab therapy and it is almost exclusively expressed on mature were refractory to PI and IMID. Grade 3 or 4 B-lymphocytes, plasma cells, and MM cells. BCMA AE were observed in 83% of patients including belongs to the TNF receptor superfamily and is thrombocytopenia (35%) and anaemia (17%). critical for bone marrow plasma cell long-term Corneal toxicity, both keratopathy and visual survival.46 Serum BCMA concentrations have been acuity changes, occurred in 69% of patients shown to be elevated in patients diagnosed with and was likely related to the direct effects of MM compared with healthy controls and patients MMAF-related toxicity. Twenty-nine percent of with more progressive disease as opposed to patients experienced IRR, the majority of them those responding to treatment.47,48 These being mild in severity and occurred with first observations have led to various treatment dose. Recently, Lonial and colleagues9 published modalities being investigated targeting BCMA, the results of the DREAMM-2 study, a two-arm including antibody drug conjugates (ADC), open-label randomised Phase II trial that chimeric antigen receptor T cells (CAR-T), evaluated belantamab mafodotin 2.5 mg/kg and T-cell engaging bispecific antibodies.49 versus 3.4 mg/kg given intravenously every For the purpose of this review, advances in 3 weeks in RRMM patients who had received ADC therapies targeting BCMA will be outlined at least three prior lines of therapy and were with a focus on the recently FDA-approved refractory to PI and IMID, and refractory or belantamab mafodotin. intolerant to anti-CD38 moAb. ORR was 31% in the 2.5 mg/kg arm versus 34% in the 3.4 mg/ Belantamab Mafodotin: kg arm with at least VGPR observed in 19% and One More Card to Play 20%, respectively. The median PFS reported was 2.9 months in the 2.5 mg/kg group versus Belantamab mafodotin has a multimodal 4.9 months in the 3.4 mg/kg arm. The median activity against MM cell lines (Figure 1B). It is a DOR and OS data are not mature to date. humanised, afucosylated IgG1 anti-BCMA moAb The most common Grade 3 or 4 AE were connected by a protease-resistant linker to keratopathy (27% in 2.5 mg/kg versus 21% in monomethyl auristatin-F (MMAF), a microtubule 3.4 mg/kg), thrombocytopenia (20% versus polymerisation inhibitor. Upon binding to BCMA, 33%, respectively), and anaemia (20% versus belantamab mafodotin is rapidly internalised, 25%, respectively). The findings of the dose- releasing its MMAF toxic payload and triggering expansion part of DREAMM-1 and DREAMM-2 cell cycle arrest in the G2/M phase that is followed trials are summarised in Table 2.9,52,53 by apoptosis.50 In addition, the afucosylation of Fc tail increases binding affinity of belantamab DREAMM-2 trial outcomes in patients with mafodotin to FcγRIIIa receptors present on high-risk cytogenetics including t(4;14), target cells leading to ADCC and ADCP.51 t(14;16), 17p13del, or 1q21+ have been reported separately.54 High-risk cytogenetics were Based on promising preclinical data, belantamab observed in 42% of patients in the 2.5 mg/ mafodotin was evaluated in a dose-escalation kg group and 47% of patients in the 3.4 mg/ and expansion Phase I DREAMM-1 study in kg group. ORR was reported in 27% (22% RRMM patients who received prior treatment with ≥VGPR) in the 2.5 mg/kg group and 40% with alkylators, PI, and IMID, and were resistant (27% with ≥VGPR) in the 3.5 mg/kg group. to the latest line of therapy.52,53 In the dose- Median PFS was 2.1 months versus 5.8 months, expansion phase, ORR was 60%, including: respectively, and median OS was 9.4 months two patients (6%) with stringent complete versus 13.8 months. response; three patients (9%) with complete response; 14 patients (40%) with very good

Creative Commons Attribution-Non Commercial 4.0 April 2021 • HEMATOLOGY Table 2: Belantamab mafodotin clinical trials with relapsed or refractory multiple myeloma patients.9,52,53

Trial Phase N Number ORR (%) Median PFS Median DOR AE (all of prior (months) (months) grades) treatment lines DREAMM I (dose 35 ≥5: 60 12 14.3 69% corneal -152,53 expansion 57% toxicity; phase) (1–10 range) 63% TCP; 29% IRR

DREAMM II 97 >4: 31 2.9 NR 2.5 mg/kg: -29 (2.5 mg/kg) 84% (2.5 mg/kg) (2.5 mg/kg) Both 70% corneal versus 99 (2.5 mg/kg) versus 34 versus 4.9 toxicity; 35% (3.4 mg/kg) versus 83% (3.4 mg/kg) (3.4 mg/kg) TCP; 21% IRR (3.4 mg/kg) 3.4 mg/kg: 75% corneal toxicity; 58% TCP; 16% IRR

AE: adverse event; DOR: duration of response; IRR: infusion-related; NR: not reached; ORR: overall response rate; reaction; PFS: progression-free survival; TCP: thrombocytopenia.

These results seem to suggest that Resistance Mechanisms belantamab mafodotin has similar activity in high-risk RRMM patients compared to the Anti-BCMA therapeutic efficacy as well as DOR may be contingent on the levels of soluble BCMA general RRMM population. (sBCMA). This formation occurs as a result of Following the results of DREAMM-2, belantamab BCMA shedding from the cell surface because of mafodotin received FDA approval on 5th the direct cleavage by ubiquitous γ-secretase.58 August 2020. Although it demonstrated It has been previously described that sBCMA an acceptable toxicity profile, belantamab prevent anti-BCMA antibody activity through mafodotin administration will be required competitive binding and serving as a soluble 59 through a risk evaluation and mitigation decoy for antibodies. Clinically, increased strategy programme due to the significant risk blood levels of sBCMA have been associated 47 of ocular toxicity.55 This programme requires with progression of disease and shorter OS. patients to undergo ophthalmic examinations The use of γ-secretase inhibitors to overcome (slit lamp and visual acuity) at baseline and resistance and increase anti-BCMA activity has been previously described in CAR-T therapy prior to each dose. Even though prophylactic in vivo60 and in combination with belantamab use of steroid eye drops seemed to provide no mafodotin in vitro.61 A Phase I/II trial will benefit to prevent the development of corneal evaluate the efficacy and safety of belantamab AE in DREAMM-2,9,56,57 patients were advised mafodotin in combination with a γ-secretase to use preservative-free lubricant eye drops inhibitor, nirogacestat (DREAMM-5).62 during treatment. General management of corneal toxicity consists of dose modifications Another way to combat resistance to anti-BCMA and interruptions in therapy as described in treatment is to design therapeutic agents with the DREAMM trials, with the median time to preferential binding affinity to membrane-bound keratopathy resolution being 2 months and BCMA versus sBCMA. MEDI2228 is a fully visual acuity changes at 22 days. ADC connected to a pyrrolobenzodiazepine payload, which induces DNA damage and apoptosis following internalisation. Preclinical

HEMATOLOGY • April 2021 EMJ data suggest that MEDI2228 may display weak questions will be the choice of specific anti- binding to sBCMA compared to membrane- BCMA treatment. ADC, such as belantamab bound BCMA, as well as more potent activity mafodotin, may provide an advantage due to to prevent MM cell proliferation and survival its relatively simplified manufacturing process compared with MMAF.63,64 A Phase I study and immediate availability compared to CAR-T. is currently enrolling patients with RRMM to In addition, ADC may be better suited in those evaluate the dosing and safety of MEDI2228.65 patients who are frail as it carries no risk of cytokine release syndrome seen with other anti- BCMA treatment modalities. One of the other FUTURE DIRECTIONS considerations is that BCMA expression may be preserved at disease progression allowing Due to its significant single-agent activity for different anti-BCMA therapy following in MM, belantamab mafodotin is being relapse.72 At this time, specific successive evaluated in various combination regimens treatment patterns for various BCMA-targeted as part of a series of DREAMM trials. Two therapies remains to be elucidated. Phase I/II trials will assess the combination of belantamab mafodotin with pomalidomide and dexamethasone66 or CONCLUSION (DREAMM-4).67 Early results of a Phase I/ II trial evaluating belantamab mafodotin Evolution of MM treatment has rapidly expanded in combination with dexamethasone and over the past 5 years, offering unique biologic or lenalidomide reported 78% targeting focussing on immunotherapeutic ORR and 50% at least VGPR in a bortezomib- mechanisms to control disease progression containing arm (DREAMM-6).68 Bortezomib and providing deeper and durable responses. and dexamethasone in combination with While the most effective treatment sequence for belantamab mafodotin or daratumumab will both newly diagnosed and refractory patients be studied in a Phase III trial (DREAMM-7).69 has yet to be determined, these two agents Another Phase III trial will assess belantamab offer additional therapeutic options for tailoring mafodotin, pomalidomide, and dexamethasone patient care. Strategies for selection of therapies combination versus bortezomib, pomalidomide, based upon cytogenetic risk will certainly be a and dexamethasone (DREAMM-8).70 Finally, major driver in the MM treatment landscape and belantamab mafodotin in combination with both isatuximab and belantamab mafodotin are triplet therapy consisting of bortezomib, currently being investigated in this arena. Unique lenalidomide, and dexamethasone will be triple and quadruple combinations with BCMA compared with triplet therapy alone in a Phase and CD38 moAb may offer transplant-ineligible III study of transplant ineligible NDMM patients patients desirable outcomes with a lower risk of (DREAMM-9).71 disease progression and improved OS without compromising tolerability. In transplant-eligible With multiple anti-BCMA treatment options patients, the ability to achieve a better disease being evaluated and nearing FDA approval, control may allow for improved transplant-related including CAR-T cell therapy and T-cell engaging outcomes. Finally, the approval of these agents bispecific antibodies, one of the most important has offered an additional lifeline to RRMM patients.

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