Relapsed/refractory multiple myeloma: what can we target next?

• CD38 is a surface antigen and ectoenzyme expressed at high levels by MM cells and at lower levels by immune cells. Not expressed by early stem cells

• Appears to be downregulated by plasma cells (PCs) by the administration of specific mAbs

• Anti-CD38 mAbs: designed to kill MM cells via Fc-dependent immune effector mechanism

• CAR T-cells targeting CD38-expressing cells

• Main mechanisms of action (MOA): complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct apoptosis after secondary cross-linking

• Increasing NK cell number creates a synergistic effect with IMiDs and other anti-CD38 mAbs·       Anti-CD47 mAbs potentiate the effects of anti-CD38 mAbs

• Daratumumab eliminates CD38⁺ immune-suppressor cells

• Treatment with daratumumab and lenalidomide leads to increased expansion of CD4 and CD8 T cells

• Clinical trials in patients with RRMM:

• Single-agent daratumumab: phase II GEN501 and SIRIUS

  • Overall response rate (ORR): 31%

  • The median duration of response (DOR): 7.6 months

  • Median progression-free survival (PFS): 4 months

  • Overall survival (OS): 20 months 

• Combination of daratumumab + lenalidomide + dexamethasone (dara-Rd) vs Rd tested in phase III POLLUX trial

  • Median follow-up: 25.4 months

  • PFS: not reached vs 17.5 months

  • ORR: 92.9% vs 76.4%

  • Minimal residual disease (MRD) negativity: 26.2% vs 6.4%

• Combination of daratumumab + bortezomib + dexamethasone (dara-Vd) versus Vd tested in phase III CASTOR trial

  • Median follow-up: 19.4 months

  • PFS: 16.7 vs 7.1 months

  • ORR: 83.8% vs 63.2%

  • MRD-negative rates: >2.5x higher with daratumumab in all subgroup analyses

• Isatuximab binding to CD38 has a strong direct pro-apoptotic effect, independent of cross-linking by activating caspase 3 and 7 pathways

• Immunomodulatory effect: decreasing CD38⁺ T_reg cells and increasing NK cells with a T-cell mediated immune response

• Phase I-II clinical trial: Isatuximab monotherapy in patients with hematological malignancies, including MM

  • N= 97 patients

  • ORR: 24%

  • DOR: 6.6 months

• Phase Ib clinical trial: Isatuximab combination with lenalidomide + dexamethasone for RRMM

  • N= 57 patients

  • ORR: 51%

  • Median PFS: 8.5 months

• Moderate CDC potential

• CAR T and bispecific mAbs may be challenging due to the expression of CD38 on activated T cells

What is it and why target it?

• Cell-surface glycoprotein receptor also called CS1

• Interacts with an adaptor protein (EAT2) which is expressed by NK cells and regulates the activation signaling of SLAMF7. Acts as an adhesion molecule in the absence of EAT2

• Highly and uniformly expressed by MM cells

What are the therapeutic options?

• Antibodies

• Immunotherapy e.g. CAR T-cells

Elotuzumab (mAb)

• Humanized antibody

• Binds to the membrane-proximal motif of SLAMF7 on MM and NK cells

  • Activates NK cells with production of IFN-γ

  • Increase of ADCC-mediating killing of tagged MM cells

• Effect potentiated by lenalidomide

• Phase III trial in RRMM (ELOQUENT-2): Elotuzumab + Rd versus Rd

  • ORR 79% vs 67%, PFS 19.4 vs 14.9 months

  • Elotuzumab reduced risk of disease progression/death by 29%

• Phase III trial in RRMM (ELOQUENT-3): Elotuzumab + pomalidomide + dexamethasone (elo-Pd) vs Pd alone

  • PFS: 10.3 vs  4.7 months

  • ORR: 53% vs  26%

Limitations of target

• SLAMF7 CAR T-cells can target and destroy healthy T and B cells with high SLAMF7 expression

What is it and why target it?

• It is a tumor necrosis factor (TNF) receptor (TNFR) family, also known as TNFRSF-17

• Selectively expressed by plasmablasts and differentiated PCs

• Not expressed by B lymphocytes, hemopoietic stem cells, and normal tissue cells

What are the therapeutic options?

• mAbs

• Antibody-drug conjugates

• Bispecific antibodies (BsAbs)

• CAR T-cells

GSK2857916

• Humanized IgG1 anti-BCMA antibody conjugated with toxin monomethyl auristatin F (MMAF) via non-cleavable linker with high affinity for BCMA

• Phase I trial as monotherapy:

  • ORR: 60%

  • Median PFS: 7.9 months

  • Toxicity: keratitis, thrombocytopenia, and infections

• United States (US) Food and Drug Administration granted breakthrough therapy designation

• European Medicines Agency granted priority medicine designation

AMG 420

(BI 836909)

• Bispecific T-cell engager (BiTE®)

  • Two linked single-chain variable fragments specific for BCMA and CD3ε

• Phase I dose-escalation study is ongoing

  • Administered as a continuous infusion for 4 weeks every 6 weeks

  • ORR: 83% at 400µg/day

• Read more about the phase I results of AMG 420 presented at the American Society of Clinical Oncology (ASCO) meeting here

EM801

• BsAb

  • Asymmetric two-arm IgG1-based human antibody

  • One arm has low affinity for CD3 with monovalent binding

  • The other has a high affinity for BCMA via divalent binding

  • Engineered Fc region to increase plasma half-life

  • Aim: reduce cytokine release syndrome (CRS) and excessive T-cell activation

Anti-BCMA CAR T-cell trials in RRMM

• National Cancer Institute (NCI)

  • Phase I trial

  • N= 24

  • CAR T-cells: murine scFv and CD28 costimulatory domain, transduced with a γ-retroviral vector

  • Given after lymphodepleting chemotherapy

  • In patients (n= 16) treated with 9 x 10⁶ CAR T cells/kg

  • ORR: 81%

  • Median event-free survival (EFS): 31 weeks

• University of Pennsylvania

  • Phase I trial

  • CAR T: fully human anti-BCMA scFv and 4-1BB as costimulatory domain, transduced with a lentiviral vector

  • Group 1 (n= 9) received 1–5 x 10⁷ cells

  • Group 2 (n= 5) received cyclophosphamide then 1–5 x 10⁷ cells

  • Group 3 (n= 11) received cyclophosphamide then 1–5 x 10⁸ cells

  • ORR (group 1 vs 2 vs 3): 44% vs 20% vs 64%

  • Median DOR (group 3): 125 days

• bb2121

  • Phase I, multicenter trial

  • N= 33

  • CAR T: murine anti-BCMA scFv and 4-1BB costimulatory domain transduced with a lentiviral vector

  • ORR: 85%

  • Median PFS: 11.8 months

  • Read more here

• LCAR-B38M

  • CAR T: binding domain for two separate BCMA epitopes and 4-1BB costimulatory domain

  • Cyclophosphamide conditioning

  • N= 57

  • Dose: 0.07–2.1 x10⁶ cells/kg:

  • ORR: 88%

  • Median PFS: 15 months

• Read more about when to use CAR T in MM here and the latest data here

Limitations

• CAR-T-related toxicities

What is it and why target it?

• Inhibitory checkpoints include the PD-1 receptor and its ligands, PD-L1 and PD-L2 

• PD-1 receptor is expressed by activated and exhausted T and B cells

• PD-L1 and PD-L2 are expressed by MM cells to escape T-cell killing

What are the therapeutic options?

• mAbs against PD-L1 (durvalumab, atezolizumab) on MM cells and mAbs against the PD-1 receptor (nivolumab, pembrolizumab) restore immune activation and help in tumor destruction

Pembrolizumab (mAb)

• mAb against the PD-1 receptor

• Phase III trial (KEYNOTE-183): Pembrolizumab in combination with dexamethasone + pomalidomide vs dexamethasone + pomalidomide

  • N= 249 RRMM patients

  • ORR: 34% vs 40%

  • Median PFS: 5.6 vs 8.4 months

  • Trial was prematurely halted by the FDA due to high toxicity

  • Read more about the trial here

• Phase III trial (KEYNOTE-185): Pembrolizumab in combination with lenalidomide + dexamethasone vs lenalidomide + dexamethasone

  • N= 301 newly-diagnosed MM patients

  • ORR: 64% vs 62%

  • Median PFS: not reached vs not reached

  • Trial was prematurely halted by the FDA due to the high incidence of death

  • Read more about the trial here

Nivolumab (mAb)

• mAb against the PD-1 receptor

• Clinical trial: Nivolumab + daratumumab with or without dexamethasone + pomalidomide

  • RRMM patients

  • Trial was placed on hold due to toxicity but has now resumed recruitment

Atezolizumab or durvalumab (mAbs)

• mAbs against PD-L1

• Clinical trials:

  • Atezolizumab or durvalumab in combination with IMiDs for MM patients

  • All trials were placed on hold due to toxicity

Limitations

• High toxicity rates with IMiD co-administration

What is it and why target it?

• Inhibitors of histone deacetylases

• In general, HDAC inhibitors lead to DNA damage-mediated apoptosis by downregulating the anti-apoptotic Bcl-2 proteins and upregulating pro-apoptotic targets

• HDAC inhibitors also reduce proteasome-related activities

• High expression of HDACs has been associated with poor prognosis in MM

• Aim: inhibition of tumor proliferation as well as tumor cell apoptosis

What are the therapeutic options?

• HDAC inhibitors together with bortezomib lead to enhanced MM cytotoxicity

• HDAC6 specifically has been shown to kill MM cells successfully when combined with anti-PD-L1 drugs

Panobinostat

• Pan-HDAC inhibitor

• Approved by FDA and EMA for the treatment of RRMM in combination with bortezomib

• Phase III trial (PANORAMA 1): Panobinostat in combination with bortezomib + dexamethasone vs placebo + bortezomib + dexamethasone

  • N= 768 RRMM patients

  • PFS: 12.5 vs 4.7 months

  • OS: 25.5 vs 19.5 months

  • Incidence of grade 3-4 adverse events: 76.9% vs 51.2%

Ricolinostat

• HDAC6 inhibitor

• Phase I/II trial: Oral ricolinostat (³160mg) in combination with bortezomib and dexamethasone in RRMM patients

  • ORR: 37%

  • Well tolerated, low toxicity

• Phase Ib trial: Oral ricolinostat (160 mg) in combination with lenalidomide and dexamethasone

  • N= 38 RRMM patients

  • Response rate: 55%

  • Well tolerated, low toxicity

Limitations

• HDAC inhibitors as single agents are not as potent as when combined with other anti-tumor agents

What is it and why target it?

• Member proteins include Bcl-2, Bcl-xL, and MCL-1

• Critical for the survival of MM cell through prevention of apoptosis

• Pro-survival cytokines, such as IL-6, regulate the expression of Bcl-2 proteins on MM cells, which in turn maintain MM cell homeostasis

• MCL-1, a member of the Bcl-2 protein family, is overexpressed in patients with RRMM, while MCL-1 knockout induces MM cell apoptosis in vitro

What are the therapeutic options?

• Selective small inhibitors

  • Bcl-2 or Bcl-xL inhibitors (BH3 mimetics)

Venetoclax

• Bcl-2 inhibitor with an affinity for Bcl-xL but does not bind to MCL-1

• Induces MM cytotoxicity only in patients with the t(11;14) mutation that has a high Bcl-2:Bcl-xL: MCL-1 expression ratio

• Phase I trial (M13-367): Venetoclax monotherapy

  • N= 66 RRMM patients

  • ORR: 21% (total cohort); 40% (t(11;14) patients)

  • Median DOR (t(11;14) patients): 9.7 months

  • Well tolerated

• Phase Ib trial (M12-901): Venetoclax in combination with bortezomib + dexamethasone

  • N= 66 RRMM patients

  • ORR: 67% (total cohort); 78% (t(11;14) patients)

  • Median DOR (total cohort): 9.7 months

  • Read more about this trial here

  • Well tolerated

• Phase III trial (BELLINI): Venetoclax in combination with bortezomib + dexamethasone vs placebo + bortezomib + dexamethasone

  • N= 291 RRMM patients

  • ORR: 82% vs 68%

  • Median PFS: 22.4 months vs 11.5 months

  • Patients with t(11;14) benefited the most from venetoclax treatment with median PFS: not reached

  • Incidence of deaths: 21% vs 11%

  • Based on the results of this trial, the FDA issued a hold on all trials involving venetoclax in MM due to the high death rate

  • Read more about the results of the trial here

AZD5991

• Highly selective MCL-1 inhibitor

• Induces quick and potent MM cell apoptosis in vitro

• Currently under development and pre-clinical investigation

Limitations

• High incidence of death when venetoclax is co-administered with bortezomib and dexamethasone for the treatment of patients with RRMM

What is it and why target it?

• Nuclear export protein

• Critical for the regulation of MM cell survival and intracellular protein transport

• MM cells overexpress XPO1

• XPO1 blockade leads to MM cell death both in vitro and in vivo

What are the therapeutic options?

• Selective small inhibitors that bind covalently to XPO1 and block its nuclear transport

Selinexor

• First-in-class, selective, oral XPO1 inhibitor

• Aim: blockade of XPO1-mediated nuclear transport activity

• Phase IIb trial (STORM): Selinexor in combination with dexamethasone

  • N= 79 RRMM patients

  • ORR: 21%

  • Median PFS: 2.3 months

  • Median DOR: 5 months

  • Median OS: 9.3 months

• Phase Ib/II trial (STOMP): Selinexor in combination with bortezomib + dexamethasone

  • N= 42 RRMM patients

  • ORR: 63%

  • Median PFS: 9.0 months

• Phase III trial (BOSTON): Selinexor in combination with bortezomib + low-dose dexamethasone vs bortezomib+ low-dose dexamethasone

  • RRMM patients

  • Results not reported yet, anticipated by the end of 2019

• The FDA has recently delayed the approval of selinexor for RRMM until more safety data are available from the BOSTON trial. Read more about this here

Limitations

• More safety and efficacy data from phase III trials are needed to validate the potential of selinexor in RRMM