Living Well with Myeloma Webinar - New Drugs in Myeloma – What, How and When?

New Drugs in Myeloma – What, How and When?

What Patients and Care Partners Need to Know

Joseph Mikhael, MD, MEd Chief Medical Officer, International Myeloma Foundation

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Living Well with Myeloma: What, How

and When?

What Patients and Care Partners Need to Know

Dr. Joseph Mikhael Chief Medical Officer International Myeloma Foundation

Objectives

• Review the key classes of drugs we use in myeloma

• Provide an overview of how myeloma drugs work in simple terms

• Discuss the concept of immunotherapy and what it means in myeloma

• Outline the process of drug development where clinical trials start in the relapsed setting and then move up to the frontline

Introduce the newest drugs in myeloma and how they will be used

What is Multiple Myeloma?

Multiple Myeloma* is a blood cancer that starts in plasma cells of the spongy center of bones (bone marrow).

–

This is where stem cells mature into red blood cells, white blood cells, and platelets.

– Myeloma cells are abnormal plasma cells that make an abnormal antibody called “M protein”.

* Myeloma is NOT a bone cancer or skin cancer (melanoma), it is a type of blood cancer.

VEGF

A disease with many targets!

Myeloma Cell

Myeloma Cell

Increase in cytokine production and adhesion molecules

Block of programmed cell death FAS (CD95)

Pro-caspase B FAS ligand

fibers

NFkB Binding Site

BM Stromal Cells

Angiogenesis Migration Growth

Natural-Killer Cells TNFα

Inhibition of Anti-Myeloma Immunity Dendritic Cells

Monocytes

The Importance of the Myeloma Cell Surface and Surrounding Cells

An Overview of Drug Classes in Myeloma

Daratumumab (Darzalex)

An Overview of New Drug Classes in Myeloma

Drug Classes

Classic Chemotherapy

These drugs work by generally destroying cancer cells and are often very effective at reducing the burden of myeloma cells.

Melphalan is one of the most effective drugs in myeloma and has been for over 60 years!

They can often be given at lower doses (often orally) or at higher doses intravenously (high dose melphalan is the drug we give for stem cell transplant)

The Process of an Autologous Stem Cell Transplant

“Eligible” Patient

Induction Therapy

Collect PBSCs

Freeze

High-dose

Chemotherapy

Reinfuse PBSCs +/- Post-ASCT therapy

Drug Classes

Steroids – Dexamethasone (Dex)

These drugs interefere with the communication between myeloma cells and can be effective on their own. They tend to be used to “boost” the effect of nearly all other myeloma drugs. I think of them like booster rockets…

#downwithdex

Immunomodulatory Drugs (IMiDs)

Proteasome Inhibitors (Pis)

Proteasome inhibitor Velcade (bortezomib) V or Vel or

Intravenous (IV) or

subcutaneous injection (under the skin) Kyprolis (carfilzomib)

(ixazomib)

Immunotherapy – Using Your Immune System to Fight MM

Monoclonal Antibodies

Monoclonal Antibodies

Daratumumab (Darzalex)

Dara or D

Subcutaneous or Intravenous (IV)

Empliciti (Elotuzumab)

Elo or E

Intravenous (IV)

Isatuximab (Sarclisa) Isa Intravenous (IV)

CD38-Targeted mAb

dependent cytotoxicity; MAC = membrane attack complex; ADCC = antibody

SLAMF7-Targeted mAb

Image Source: Sanchez L, et al. J Hematol Oncol. 2016;9(1):51. Creative Commons License: CC BY 4.0; Magen H, Muchtar, E. Ther Adv Hematol. 2016;7(4):187-195. Creative Commons License. Sanchez L, et al. J Hematol Oncol. 2016;9(1):51; Magen H, Muchtar, E. Ther Adv Hematol. 2016;7(4):187-195.

Daratumuma b Isatuximab

Elotuzumab

Melphalan Flufenamide – A Peptide-Drug Conjugate

Melflufen

Amino-peptidase

Alkylating moiety

4. Hydrophilic alkylating moieties trapped inside the cell

2. Lipophilic melflufen rapidly traverses cell membranes

1. Amino-peptidases highly over expressed in multiple myeloma (MM) cells

3. Amino-peptidase potentiated release of hydrophilic alkylating moieties

5. Melflufen and hydrophilic alkylating moieties binds directly to DNA

Antibody-Drug Conjugate

The Process of CAR T Cell Therapy

CAR T Cell Therapy

• Incorporates 2 antibody fragments to target and bind both tumor cells and T cells

• Brings target-expressing MM cells and T cells into close proximity, enabling T cells to induce tumor-cell death

• BCMA = B Cell Maturation Antigen

Bispecific Antibodies

(Talquetamab)

 Talquetamab is a novel first-in-class, off-theshelf, T-cell redirecting bispecific antibody directed against a new antigen target called GPRC5D1,2

 GPRC5D is a novel antigen target in myeloma that is highly expressed on malignant plasma cells with limited expression in normal human tissues,3-6 including hematopoietic stem cells7

 Talquetamab has shown an ORR of 64–70% with QW and Q2W dosing in the phase 1 MonumenTAL-1 study (NCT03399799)8

Bispecific Antibodies – FcRH5 (Cevostamab)

• Cevostamab has also shown activity in relapsed myeloma with a response rate around

Anti-CD3 Fab region Anti-FcRH5 Fab region

Myeloma cell

Iberdomide: CelMOD: Cereblon E Ligase Modulator in Combination with Daratumumab or Bortezomib

Median previous lines: 4-6

In Cohort E, >50% CD 38 ab refractory

In Cohort F, >60% PI refractory

Modakafusp alfa is a first-in-class, innate immunity enhancer that functions through targeted next-generation IFN signaling

The CD38-targeted attenuated IFNα fusion protein displays a 10,000-fold greater specificity than native IFNα for CD38+ vs CD38− cells2

Modakafusp alfa

Binds with high affinity to unique epitope of CD381,2

Signals through IFNAR to:2

• Activate innate and adaptive immune cells1

• Elicit direct antiproliferative/ apoptotic signals to tumor cells2,3

*hIgG4 is a poor inducer of Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity and phagocytosis.4

Fc, fragment crystallizable; hIgG4b, human immunoglobulin 4b; IFN, interferon; IFNAR, interferon α receptor; MDSC, myeloid-derived suppressor cell; MM, multiple myeloma; NK, natural killer; Treg, regulatory T cell

Attenuated IFNα

Innate immune cell activation2,4

IFNAR

hIgG4b* with limited Fc functionality2,4

Unique CD38 epitope specificity

Unique CD38 epitope

Adaptive immune cell activation

CD38 is widely expressed on innate and adaptive immune cells, MM cells, and subsets of tumor cells of other hematologic malignancies2,5

MM cell anti-tumor effects

Cytokines

MM cell death2,3

Chemokines

1. Vogl DT, et al. Blood 2020;136(Suppl. 1):3197;

2. Pogue SL, et al. PLoS One 2016;11:e0162472;

3. Anguille S, et al. Leukemia 2011;25:739–48;

4. Crescioli S, et al. Curr Allergy Asthma Rep 2016;16:7;

5. Calabretta E, Carlo-Stella C. Cells 2020;9:802

Macrophage

NK cell

CD4

Venetoclax – bcl2-inhibitor

In patient with t(11;14) the bcl2 pathway is upregulated giving the cell

Venetoclax inhibits that pathway…

“immortality”

Emerging therapies in myeloma… The Future is BRIGHT!

CAR T cell therapy – both Auto and Allo

Bispecifics and tri-specifics – including NK Cell engagers

Targeting BCMA but also: –

GPRC5D – FCRH5

CelMods – Iberdomide and Mezigdomide

Modakafusp • And many combinations of the above!

cereblon

Emerging Drugs for Multiple Myeloma

thalidomide lenalidomide pomalidomide

iberdomide

CC-92480

CFT7455

venetoclax

melphalan cyclophosphamide melflufen*

proteasome

daratumumab CD38

isatuximab

BCMA

belantamab mafodotin

idecabtagene vicleucel

ciltacabtagene autoleucel

bispecific antibodies

panobinostat†

HDAC

glucocorticoid receptor

dexamethasone

prednisone

GPRC5D

talquetamab

RG6234

FcRH5

cevostamab

*withdrawal from US market October 2021 withdrawn January 2022

†withdrawn from US market November 2021

SLAMF7 elotuzumab

XPO1

selinexor

• The importance of preliminary research – in the lab

• Animal studies • Phase 1 clinical trials – first in human

Phase 2 and 3 trials

• General principle – start in the areas of “unmet need” = late stage disease – Then agents move up earlier in the disease course – Example – Daratumumab

We are now seeing this process with many drugs like CAR T Cell therapy…

Where you can learn more!

GREAT resources at the IMF homepage – http://myeloma.org

IMF FDA approved drug page (https://www.myeloma.org/multiple-myeloma-drugs)

IMF publications page (https://www.myeloma.org/publications)

“Drugs in Current use for MM”

https://issuu.com/international-myeloma-foundation/docs/myelomadrugs-current-use?fr=sYjBiYTQzNTE1OTI

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer,

International Myeloma Foundation

Professor, Translational Genomics Research Institute (TGen)

City of Hope Cancer Center

Director of Myeloma Research and Consultant Hematologist, HonorHealth Research Institute

jmikhael@myeloma.org

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