IMF Virtual Regional Community Workshop (RCW) - South Atlantic by International Myeloma Foundation

Welcome and Announcements Kelly Cox

Director Support Groups & Senior Director Regional Community Workshops 1

Thank you to our sponsors!

IMF REGIONAL COMMUNITY WORKSHOP Saturday July 16, 2022- Agenda

10:00 AM - Welcome and Announcements Kelly Cox, Director Support Groups & Senior Director of Regional Community Workshops 10:05 AM - Myeloma 101 and Frontline Therapy Craig Hofmeister, MD, MPH, Winship Cancer Institute, Atlanta, GA 10:40 AM - Q & A with Panel 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials Ciara Freeman, MD, PhD, Moffitt Cancer Center, Tampa, FL 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Charise Gleason, MSN, NP-C, AOCNP 12:05 PM - Q&A with Panel

Myeloma 101 and Frontline Therapy Craig Hofmeister, MD, MPH Winship Cancer Institute, Atlanta, GA 4

Myeloma 101 & Frontline treatment Craig Hofmeister MD MPH Associate Professor Winship Cancer Institute of Emory University Emory University School of Medicine

Winship Cancer Institute | Emory University

Myeloma cells The Termites

Bone Marrow The skeleton of a house

Chemotherapy 2 treatment regimens

We don’t cure the vast majority of patients with myeloma because we don’t kill the myeloma initiating cells.

Myeloma Stem Cell, the Queen

How is myeloma different than leukemia Lymphoid progenitor

Stem Cells

Lymphocyte

Plasma cells

Lymphoma Multiple Myeloma

Myeloid progenitor

Leukemia Left: courtesy of National Cancer Institute Middle: courtesy of My Life Stages Right: courtesy of UF Health

Clogs the kidneys causing kidney failure Monoclonal protein Fractures Hypercalcemia

Infections Anemia Marrow growth

Diagnosis requires showing plasma cells trying to kill the patient

Patient presents with worsening back pain

Obtain a bone biopsy at this vertebra showing the cells shown on the right panel

Pathologist reviews slides and documents clonal plasma cells

The most common signs are fractures, anemia, and kidney failure

Precancerous state to cancer: A slippery slope CRAB CRITERIA Calcium Renal Anemia Bone

MGUS

Monoclonal Gammopathy Undetermined Significance

→ High calcium → Kidney failure → Fewer red blood cells → Holes in bones causing spontaneous fractures

Smoldering Myeloma

Pre-cancer

Multiple Myeloma

SLiM - CRAB criteria - avoiding fractures Likelihood of multiple myeloma

S-LI-M CRAB criteria

95% in 2 years

Sixty percent plasma cells on bone marrow biopsy

70% in 2 years

LIght chain ratio ≥ 100

75% in 2 years

MRI abnormalities (≥ 5 mm) in 2+ sites

100%

CRAB Calcium elevation Renal damage Anemia Bone holes

These patients have not yet proven they have cancer, so avoid or embrace treatment at your own risk

Revised IMWG Diagnostic Criteria MGUS ▪

▪ ▪

Smoldering Myeloma

Small monoclonal or abnormal serum free light chain ratio Clonal plasma cells in marrow < 10% No SLiM-CRAB criteria

▪ ▪ ▪

M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine) Clonal plasma cells in marrow 10-60% No SLiM-CRAB criteria

AL Amyloidosis

Multiple Myeloma ▪

▪

Clonal marrow plasma cells ≥ 10% or ≥ 1 biopsy-proven plasmacytoma 1+ SLiM-CRAB criteria

▪

Pre-cancerous

Amyloid-related systemic syndrome (renal, liver, heart, GI, PNS) Congo red in any tissue established to be light-chain related Circulating monoclonal protein or clonal marrow plasma cells

Needs cancer treatment

Who develops myeloma

1 in 125

over a lifetime

https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html

1.8%

of all new cancer cases in the U.S.

32,110 new cases in the U.S. in 2019

What is the risk of developing multiple myeloma? 01

More than one first degree relative of a myeloma patient

Gaucher’s disease

Increased risk of myeloma or lymphoma 30-fold

Age

Average age of myeloma patient is 70 y.o.

African-Americans

African Americans are twice as likely to develop myeloma as caucasians, who are twice as likely as pacific islanders

● ●

Two first degree relatives >100x the risk One first degree relative is 4x as likely to develop myeloma

The meaning of “risk” depends on the context. 😞😞 What the doctor says

What is meant by the word “risk”

“You have high risk monoclonal gammopathy of undetermined significance (MGUS), so please come back in 3 months for a blood test.”

Risk means the odds of developing multiple myeloma.

Because of your high risk disease, we will always need to treat you with 3- or even 4drug cocktails.

High risk means less likely to respond to drugs and for a shorter time is more treatment resistant. Low risk is easier to treat and patients on average live longer.

“Your only lytic lesion is in your skull, so your myeloma bone disease is low risk.”

If you only have a few bones known to be affected by myeloma, and they are not weight-bearing, you have a lower risk for fracture. 15

Risk in the setting of multiple myeloma describes how quickly the disease will become resistant to treatment LOW RISK (easier to control) 8-12 year average overall survival

High Risk

(difficult to control) 2-5 year average overall survival

Know the risk of your multiple myeloma

Introducing the SECOND staging system - International Staging System (ISS) Stage

Criteria

Survival (yrs) when published

ß2-M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL

Not stage I or III

3.5

ß2-M ≥ 5.5 mg/L

ß2-M = Beta 2 microglobulin. It and albumin are both standard blood tests.

Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

Know the risk of your multiple myeloma

Introducing the THIRD staging system - Revised Intl Staging System (R-ISS) Stage

Criteria

Genetics

Survival (yrs)

ß2-M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL

No del(17p) Normal LDH No t(4;14) No t(14;16)

8-12

2 3

Not stage 1 or 3

ß2-M ≥ 5.5 mg/L

Palumbo A, et al. J Clin Oncol. 2015;33(26):2863-2869.

t(4;14) or t(14;16) or Del(17p) or High LDH

2-5

The meaning of “stage” depends on the context. 😞😞 When a patient with lung, colon, breast, or prostate cancer hears

Then that means

“You have early stage cancer.”

You likely have stage 1 or 2 cancer, it is isolated to a small part of the affected organ, and there is a better than 50% chance of cure.

“Your cancer is metastatic.”

Your cancer is spread throughout your body, and curative surgery is not an option. We found this cancer late in its course after it spread. Your survival is shorter than if we had found this cancer significantly earlier.

In most cancers, stage is a synonym for control.

The meaning of “stage” depends on the context. 😞😞 When I say ‘stage’ to a myeloma patient

What does that mean

“We expect you to have easier to treat myeloma”

You have stage 1 myeloma

“Just like 60% of my myeloma patients, I don’t know whether you have easier or harder to treat myeloma.”

You have stage 2 myeloma

“We expect you to have harder to treat myeloma.”

You have stage 3 myeloma.

In myeloma, stage is a synonym for risk.

How are ‘stage’ and ‘risk’ different than ‘control’? IN CONTROL No New Cells

Kidney output, bone marrow health, and bone disease as good as it’s going to get

OUT OF CONTROL Some New Cells

More New Cells

Kidneys may worsen and hemoglobin may drop. New holes in the bones are unlikely to develop. Calcium is may slowly rise

Many New Cells

Expect new fractures, anemia, and kidney failure

And control is usually measured by monoclonal protein and light chains

Can we enumerate ‘control’? Yes! Numbers rule. Patient is asymptomatic IgG or IgA or Kappa or lambda light chains or SPEP (aka M-spike)

Symptoms

2 Years

Do you relapse differently if you are low risk?

Your best myeloma indicator

Asymptomatic

Symptoms

In low risk patients, this period can last for years

Great time for a clinical trial

Do you relapse differently if you are high risk?

In high risk patients, this period is short

Symptomatic

Your best myeloma indicator

Asymptomatic

In these patients, a clinical trial is often ideal whenever they are eligible

New treatments have improved survival 100%

2006-2010

80% 60%

2001-2006

40% 20% 0

1.6

3.3

6.6

Years

8.3

1971-2000 10

Myeloma drugs

1 2

Steroids

Decadron (Dexamethasone)

Proteasome Inhibitors Velcade (Bortezomib) Kyprolis (Carfilzomib) Ninlaro (Ixazomib) NPI-0052 (Marizomib)

IMiDs / CELMODs

Revlimid (Lenalidomide) Pomalyst (Pomalidomide) cc-220 (Iberdomide)

CD38 Antibodies

Darzalex (Daratumumab) Isatuximab

This is how it is for FIT patients 1

Treatment until your damaged organs are as good as they are going to get

Drug

Decadron

Type

Mode

Steroid

Pill 1-2x

2-4 months on average

Side effects

Insomnia, rage, talkative,

weekly

weight gain

(lenalidomide)

modulating

(IMiD)

Pill daily

Blood clots, diarrhea, taste

Velcade

Proteasome Inhibitor

Shot 2x / wk subcutaneous

hands or feet

Darzalex

CD38 antibody

Shot 1x/wk

Fatigue, infections

(dexamethasone)

Revlimid

(bortezomib)

(daratumumab)

Immune

changes

Tingling & numbness in

This is how it is for FIT patients 2

Autologous transplant – – –

High dose IV melphalan 6 weeks of drug prep prior to transplant 14-16 day hospital stay

Revlimid maintenance

Yields 30 months of remission on average In low risk patients, this adds 20 months of remission on average

ABCDs of myeloma treatment 3-Drugs

2-Drugs

For New Patients

Velcade Dexamethasone

Revlimid Dexamethasone

Ixazomib Dexamethas one

VRd

KRd

Velcade Revlimid Dexamethasone

Kyprolis Revlimid

4-Drugs Darzalex Revlimid Dara-RVd Velcade Dexamethaso ne

Dexamethasone

Cytoxan Velcade [Bortezomib CyBorD ] Dexametha sone Darzalex

Kyprolis Pomalyst

Disease risk

Initial treatment

Monoclonal Gammopathy Undetermined Significance (MGUS)

Observation

Low and low-intermediate smoldering myeloma (SMM)

Observation

Intermediate- and intermediate-high SMM

Revlimid ± dexamethasone

Multiple myeloma & High risk SMM

High risk

PI + IMiD + Steroid ± Darzalex initially

Intermediate risk

PI + IMiD + Steroid

Low risk

Darzalex + PI + IMiD + Steroid

Frail patients

Darzalex + IMiD + Steroid

Zometa slows cells that normally remove bone XGeva subcutaneous monthly Zometa monthly

Bone stabilizing effect

Xgeva subcutaneous twice yearly Zometa given IV yearly Oral bisphosphonates (Fosamax, Boniva, etc) Calcium and Vitamin D Supplements

Osteoporosis

Calcium and Vitamin D Supplements

Myeloma

Limits of Zometa and XGeva Zometa & XGeva decrease risk of fracture Don’t prevent all fractures in myeloma patients Don’t build new bone in myeloma patients Don’t allow patients to heal holes in bones (lytic lesions)

Bisphosphonates and Osteonecrosis ●

●

Uncommon complication causing avascular necrosis of maxilla or mandible Biggest risk factor is pulling a tooth after receiving bone directed drugs (Zometa or XGeva)

●

Suspect with tooth or jaw pain +/- exposed bone

●

Related to duration of treatment

MOST CURRENT MYELOMA THERAPIES HAVE IMMUNE ACTIVITIES 1. Steroids Dexamethasone Prednisone 2. Proteasome Inhibitors Bortezomib Carfilzomib Ixazomib 3. IMiDs / CelMods Lenalidomide Pomalidomide cc-220 cc-92480 4. Add-on’s Elotuzumab Panobinostat

9. Bispecific T-cell engagers Teclistamab Talquetamab 8. Chimeric antigen Receptor T-cells (CAR-T) ABECMA (Ide-cel) Carvykti (Cilta-cel)

5. CD38 Ab 6. Nuclear export Daratumumab inhibitors Isatuximab Selinexor

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

7. Ab Drug Conjugate Belantamab (BCMA)

NCI Designated Comprehensive Cancer Center

DARATUMUMAB – THE FIRST REAL IMMUNOTHERAPEUTIC IN MM Approved after monotherapy (2015) & SIRIUS (2016) published.

Phase 3 Trials

RRMM • D-Rd (POLLUX) • D-Vd (CASTOR) • D-Pd (APOLLO) • D-Kd (CANDOR) NDMM non-transplant • D-Rd (MAIA) • D-VMP (ALCYONE) • D-VRd (CEPHEUS) NDMM transplant • D-VTd Part 1 (CASSIOPEIA) – D maintenance Part 2

• D-VRd (PERSEUS)

– R ± D SC maintenancea

• D-R maintenance (AURIGA)

*Pending results. aDiscontinue D SC if MRD negative. Blue indicates study uses subcutaneous DARA.

CDC, complement-dependent cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ADCC, antibody-dependent cell-mediated cytotoxicity; NK, natural killer; RRMM, relapsed/refractory multiple myeloma; D, daratumumab; R, lenalidomide; d, dexamethasone; V, bortezomib; P, pomalidomide; K, carfilzomib; NDMM, newly diagnosed multiple myeloma; MP, melphalan and prednisone; T, thalidomide; SC, subcutaneous; MRD, minimal residual disease. 1. DARZALEX® (daratumumab) injection, for intravenous use [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2020. 2. Liszewski MK, et al. Adv Immunol. 1996;61:201-283. 3. Debets JM, et al. J Immunol. 1988;141(4):1197-1201. 4. Overdijk MB, et al. MAbs. 2015;7(2):311-321. 5. Lokhorst HM, et al. N Engl J Med. 2015;373(13):1207-1219. 6. Plesner T, et al. Oral presentation at: ASH; December 8-12, 2012; Atlanta, GA. Abstract 73. 7. Krejcik J, et al. Blood. 2016;128(3):384-394. 8. Adams HC 3rd, et al. Cytometry A. 2019;95(3):279-289. 9. Casneuf T, et al. Leukemia. May 26, 2020; doi: 10.1038/s41375-020-0855-4; [E-pub ahead of print].

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

WHAT IS A CHIMERIC ANTIGEN RECEPTOR T-CELL (CART) Virus containing instructions in its DNA to create a target on the cell surface to myeloma cells

Chimeric antigen receptor enabled cell targeting the patient’s myeloma cell T Cells (Immune cells) from the myeloma patient Myeloma cell WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

WHAT IS A BISPECIFIC ANTIBODY? A bispecific antibody is a drug that has been designed to simultaneously target two different proteins, often on two different cells. Bispecific T-cell Engager (BiTe)

Bispecific Killer Engager (BiKE) Trispecific Killer Engager (TriKE)

• BiTEs are fusion proteins consisting of two single-chain variable fragments (scFvs) of different antibodies • One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule, leading the T-cell to secrete cellular poisons that kill the tumor cell. BiTE is a registered trademark of Amgen, so other companies avoid using the word and say bispecifics WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

WHAT IS AN ANTIBODY DRUG CONJUGATE (ADC)? ADCs are targeting antibodies (green) linked to a poison (yellow balls in the figure to the right) that bind to tumor cells and are internalized. Once inside, the linker is cleaved, and the poison is released inside the cancer cell.

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

Craig.Hofmeister@emory.edu Clinic voice 404-778-1900

Do you want to see all my patient oriented slides?

https://tinyurl.com/y5r4tjkd

Audience Q&A with Panel

• Open the Q&A window, allowing you to ask questions to the host and panelists. They can either reply to you via text in the Q&A window or answer your question live. • If the host answers live, you may see a notification in the Q&A window. • If the host replies via the Q&A box – you will see a reply in the Q&A window.

IMF REGIONAL COMMUNITY WORKSHOP – July 16, 2022 Agenda After Break

11:05 AM - Relapsed Therapy and Clinical Trials Ciara Freeman, MD, PhD, Moffitt Cancer Center, Tampa, FL 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Charise Gleason, MSN, NP-C, AOCNP 12:05 PM - Q&A with Panel

Relapsed Therapy and Clinical Trials Ciara Freeman, MD, PhD Moffitt Cancer Center, Tampa, FL 43

IMF Regional Community Workshop July 16th 2022 Management of relapsed Multiple Myeloma & Clinical Trials: The Future is BRIGHT!

Dr Ciara Freeman, MD PhD MSc Moffitt Cancer Center Tampa. FL

MMWG Moffitt Myeloma Working Group

What I aim to cover • An understanding of the treatment options available for patients when their myeloma comes back • How to navigate/understand the decision-making process on what that next treatment should be • What is new - but in our hands ready to use now • What the future holds – new therapies and trials open here in Tampa MMWG Moffitt Myeloma Working Group

What is relapsed/refractory disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy

MMWG Moffitt Myeloma Working Group

Multiple myeloma treatments—timeline of drug discovery and five year relative survival (using data from the Surveillance, Epidemiology, and Ends Results program)

Available Anti-Myeloma Agents: So Many Choices! IMiDs Thalomid (thalidomide)

Chemotherapy AnthraChemotherapy Proteasome cyclines Alkylators Inhibitors Velcade (bortezomib)

Revlimid (lenalidomide)

Kyprolis (carfilzomib)

Pomalyst (pomalidomide)

Ninlaro (ixazomib)

Adriamycin

Doxil (liposomal doxorubicin)

Steroids

Cytoxan (cyclophosphamide Dexamethasone ) Bendamustine

Melphalan

MMWG Moffitt Myeloma Working Group

Prednisone

mAbs Empliciti (elotuzumab) Darzalex (daratumumab) Sarclisa (isatuximab)

HDAC Inhibitors

Newer

XPO1 inhibitor Farydak (Xpovio/Selinex (panobinostat) or) Zolinza (vorinostat)

BCMA-targeting antibody drug conjugate (Belanatamab mafodotin) BCMA CAR-T cells (ide-cel

How do these drugs work? • Tell them to die  steroids • Interfere with DNA replication  chemo • Interfere with cellular dustbin PIs • Interfere with protein pathway  IMIDs • Flag for destruction  Mabs

MMWG Moffitt Myeloma Working Group

Why do we care about what you had before? Darwinian evolution and in multiple myeloma – this is why combinations have been the key to success

Multiple combinations possible So Many Choices! Pomalidomide

Carfilzomib

Daratumumab

Elotuzumab

Ixazomib

Panobinostat

Dara Pom D

Dara

Elo RD

Ixa

Pano VD

Car Pom D

KRD

Dara Pom

Elo PomD

Ixa Dex

Car Pano Dex

Ixa Pom Dex

K Cy Dex

Dara Len

Elo BortD

IRD

Len Pano

Bort Pom Dex

K Dara Dex

Dara Bort

Elo Pom Dex

Car Pano

Dara Carfil

Ixa Pom Dex

Pom Cy Dex

MMWG Moffitt Myeloma Working Group

Multiple factors drive treatment choice in relapsed/refractory MM Tolerance to prior therapies

Prior therapies received†

Time interval since last therapy

Side effects

Influential factors

Comorbidity e.g. renal impairment* Treatment availability

*Occurs in up to 50% MM patients. †Can repeat induction therapy where relapse occurs >6 months after treatment. PN, peripheral neuropathy; SCT, stem cell transplant.

Subtype e.g. t(4;14) Age

Previous SCT Pre-existing toxicities e.g. PN

Performance status

Moreau P, et al. Ann Oncol 2013;24 (Suppl 6):vi133–7; Lonial S. Hematology Am Soc Hematol Educ Program 2010;2010:303–9.

Patterns of Relapse / Implications • Indolent (=slow growth) – 1st – Slow and asymptomatic – Low /standard risk

Treatment implications Single agent / doublet Sequential versus combination therapies Emphasis on patient preference and convenience

• Aggressive (=FAST growth) – Multiple – Fast or symptomatic – High risk

Treatment implications Triplet or combination therapies Emphasis on efficacy

Frailty as a dynamic/modifiable risk factor FIT

Cycle 1

Cycle 2

Cycle 3

Cycle 4

Less FIT

Cycle 1

Cycle 2

Cycle 3

Cycle 4

FRAIL

Cycle 1

Cycle 2

Cycle 3

Cycle 4

MMWG Moffitt Myeloma Working Group

OR- a more personalized approach – EMMA Translating Ex vivo drug screening to direct clinical utility.

0.5-2 million CD138Selected cells

31-127 drugs simultaneously

31-127 in silico clinical trials -simultaneously

Figure X. Ex vivo Mathematical Malignancy Advisor (EMMA) facilitates testing of 31-127 drugs or drug combinations in myeloma patient specimens in the context of the tumor microenvironment.

Khin et al Cancer Res 2015; Silva et al Cancer Res 2017; Zhao et al Nat Comm 2017

MMWG Moffitt Myeloma Working Group

Options at First Relapse

MMWG Moffitt Myeloma Working Group

Some commonly used players Proteosome inhibitor • Kyprolis (carfilzomib) • Ninlaro (ixazomib) • Return to Velcade (bortezomib)

IMiD

Antibodies

• Pomalyst (pomalidoide) • Revlamid (lenalidomide) – if not used already

• Darzalex (daratumumab) – if not used already • Sarclisa (isatuximab) • Empliciti (elotuzumab)

• And probably some dexamethasone. • It’s like parsley.

Beyond the treatment itself… Proteasome Inhibitors

Monoclonal Antibodies

IMiDs

HDAC Inhibitors

• Peripheral neuropathy occurs less often when subcutaneous or once-weekly dosing is used for Velcade • Other peripheral neuropathy prevention: − Vitamins and other supplements* − Certain medications such as gabapentin, pregabalin, duloxetine, opioids (methadone) − Acupuncture − Physical therapy − Shingles-prevention pills − Blood thinners

• Blood thinners • L-glutamine for cramps • GI toxicity: avoid dairy; fibers (Metamucil); Imodium; colestipol; cholestyramine; dose reduction • Sleep hygiene, regular exercise, dose reduction for fatigue

• Pre- and post-medication for infusion reactions • Antibiotic prophylaxis (levoflox or septra) for some

• Anti-diarrheal medication • Baseline EKG prior to starting medication

How Do We Define & Measure Success? • Goals of therapy 1. 2. 3. 4.

Improve symptoms Prevent complications Improve survival ? Functional cure

MMWG Moffitt Myeloma Working Group

Depth of Response and Outcome in MM

MMWG Moffitt Myeloma Working Group

Options at Second Relapse and Beyond

MMWG Moffitt Myeloma Working Group

Relapsed MM Management. Phase III (& II†) trials have helped to define salvage therapy for RRMM: -1-3 prior lines:         

ASPIRE: TOURMALINE: ELOQUENT-2: CASTOR: POLLUX: OPTIMISMM: CANDOR: Bellini: LYNX:

- “>3” prior lines: KRd vs Rd IRd vs Rd ERd vs Rd DVd vs Vd DRd vs Rd PVd vs Vd DKd56 vs Kd56 VenVd vs Vd D(sq)Kd vs Kd* (*prior IV Dara)

 ENDEAVOR:  ARROW:

 ELOQUENT-3†:  ICARIA:

EPd vs Pd IsaPd vs Pd

 DREAMM-1:

BM**

 DREAMM-3:  STORM†:  STOMP†:  CC-220†:  Melflufen:

(**Belantamab mafodotin)

BM** vs Pd XpD (Seli) PXpD, DXpD Iber/dex

Kd56 vs Vd Kd qw vs Kd 2x/wkz

What about the newer kids on the block? ADCs/Seli/CARs

Antibody-Drug Conjugates (ADCs) in MM ADCs can selectively target and deliver drugs to myeloma cells – Belantamab Mafodotin

2 Endocytosis

Components • Antibody • Stable linker • Toxin

1 Binding

MMWG Moffitt Myeloma Working Group

BCMA 3 Lysosomal degradation

BCMA ADC conjugate

Myeloma cell 4 Toxin activation  cell death

Myeloma cell dying

Small molecule inhibitors of nuclear export (SINE) • Selinexor (XPOVIO) --> XPO1 inhibitor • Theodoropoulos et al Oncology, 2020. 15(6): p. 697-708.

MMWG Moffitt Myeloma Working Group

So – What about CAR T-Cell Therapy? Genetically modified T cells designed to recognize specific proteins on MM cells CAR T cells are activated once in contact with the MM cell and can destroy the MM cell

Chimeric antigen receptor

CAR T cell

CAR T cells can persist for long periods of time in the body CAR T cells are created from a patient’s own blood cells, but the technology is evolving to develop “off-the-shelf” varieties CAR, chimeric antigen receptor; MM, multiple myeloma CAR T-cell therapy is not yet FDA-approved for patients with MM.

Chimeric antigen receptor

Myeloma cell

Previous expectations for triple refractory patients Selixenor/ Dex* Belantamab mafodotin

ORR

mPFS (mo)

mOS (mo)

26%

3.7

8.6

2.8

13.5

31%

• Initial visit ?eligible • Waitlisted • Once spot available 

Process and samples

MMWG Moffitt Myeloma Working Group

Ide-cel: transfect bulk, unselected cells Cilta-cel: positive selection CD3+ T-cells D1

Two approved – more to come! Common Observations of CAR T-Cell Therapy Studies

All patients were very heavily pretreated, with some having received on average at least 6 prior therapies. Many patients on the trials were considered tripleclass refractory.

All have similar side effects, causing cytokine release syndrome (CRS), neurotoxicity, and low blood counts, but all at varying degrees.

Most patients respond very well to treatment, but also to varying degrees.

Median follow-up: 24.8 months  First cell-based gene therapies for the treatment of R/R MM Dose, x 450 (N=54) Total (N=128) CR Patients  Progression on/after > 4 lines of therapy including an immunomodulatory agent, 10^6 CAR-T cells a proteasome inhibitor, and an anti-CD38 monoclonal antibody  Median DOR: 21.5 mo

44 (81%) 94 (73%) Median  ORR Manufacturing limitations: facilities must be  cleared byPFS: FDA22.4 andmo low supply for both products,42which CR/sCR 21 (39%) (33%) have strict specifications

Responses in difficult to treat patients

Median  Moffitt DOR Median PFS

11.3 10.9 has had more manufacturing slots thantumor otherburden, centerORR: to date  High 71% 12.2

8.6

Munshi NC et al. NEJM 2021; 384 (8): 705-716 Anderson LD et al. IMW 2021. Abstract OAB27 Anderson LD et al. ASCO 2021. Abstract 8016 MMWG Moffitt Myeloma Working Group

 Extramedullary disease, ORR: 70%  R-ISS-III, ORR: 48%

Clinical Trials as an Option

• ALWAYS ask your doctor whether a clinical trial is potentially available • Promising therapies in development – Venetoclax* – BITEs – Other CAR-T cell therapies – Many, many others….

• www.clinicaltrials.gov • Myeloma Matrix 2.0 MMWG Moffitt Myeloma Working Group

Bispecific Antibodies and Bispecific T-Cell Engagers (BiTEs) Bispecific antibody

Bispecific antibodies can target two cell surface proteins at the same time

Bispecific T-cell engager (BiTE)

BCMA-bispecific antibody

BCMA-bispecific T-cell engager

T cell

CD3

BCMA Myeloma cell

T cell

T cell toxin

Adapted from Cho S-F et al. Front Immunol. 2018;9:1821.

BCMA Myeloma cell T cell toxin

Myeloma cell dying

CAR’s vs BiTE’s – Apples vs Oranges? Advantages with CAR T cells

Advantages with BiTE’s & BsA’s

Achieves deep durable responses in heavily –treated MM patients

Manageable acute toxicities (CRS & ICANS)

Single infusion – period of response OFF ALL THERAPY!

Off-the-shelf availability Amenable to flexible dosing strategies

Disadvantages with CAR T cells

Disadvantages with BiTE’s & BsA’s

Production causes treatment delays

Requires repetitive administration

Unable to stop and restart treatment Fitness of collected T cells impacts response

MMWG Moffitt Myeloma Working Group

A snapshot of MM Clinical Trials at Moffitt •

High risk smoldering myeloma: –

•

Newly Diagnosed MM –

•

ASCENT Dara+KRD for high-risk smoldering Phase 2: daratumumab based response adapted therapy for older adults with NDMM

HDM-ASCT and maintenance – –

Phase 3: Lenalidomide daratumumab vs lenalidomide maintenance IIT looking at MRD monitoring to determine duration of len maintenance

• Cellular Immunotherapy: – –

•

Phase 1-3: BCMA CAR-T – allo and auto products Cilta-cel consolidation post HSCT

Relapsed and/or Refractory MM: – – – – – –

Phase 2: Elotuzumab + Lenalidomide for patients with biochemical progression Phase 1: CB-839 a novel glutaminase inhibitor and carfilzomib Phase 1/2 : venetoclax daratumumab dex for early relapse for patients with t(11;14) MM Phase 1: A bi-specific T cell engager (Regn 5458) for RRMM Phase 1/2: CC92480 a novel cell mod (IMID) in various combination (coming soon) Phase 1: Ixazomib and pevonedistat for RRMM

MMWG Moffitt Myeloma Working Group

Can early detection and interception be adopted in MM? The PROMISE study: 1. To determine the prevalence of MGUS in a high-risk population

2. Determine clinical/genomic alterations present in these high- risk individuals

3. Determine clinical genomic and

immune predictors of progression from MGUS to MM

https://www.enroll.promisestudy.org/ Adapted from Irene Ghobrial

MMWG Moffitt Myeloma Working Group

PROMISE: Nation wide study of MM screening and prevention Genetics and Genomics

Screen 30,000 High-Risk Individuals

Viktor Adalsteinsson

Gad Getz

Develop novel biomarkers for diagnosis

Irene Ghobrial

Epidemiology

Tim Rebbeck

Screen Negative 26,100

Screen Positive 3,900

Accept Prospective Terms Follow-Up

Catherine Marinac Bone Marrow Niche

Lorelei Mucci

Ivan Borrello

Establish new risk stratification tools

Irene Ghobrial

Generate new tools to prevent Receive Schedule Imaging and Therapeutics Receive disease progression Blood Kit Blood Draw Results

Jeremiah Johnson

Irene Ghobrial

Adapted from Irene Ghobrial MMWG Moffitt Myeloma Workinghttps://www.enroll.promisestudy.org/ Group

In summary, tools are multiplying! Survival is improving

Nishida, H. Cancers, 2021. 13(11): p. 2712.

MMWG Moffitt Myeloma Working Group

The future is bright!!! What next? • Trials to look at optimizing therapy – deeper responses, fewer drugs, stopping treatment • How can we achieve more for less? • Remissions that LAST • Patients OFF therapy • Looking for that elusive cure….

MMWG Moffitt Myeloma Working Group

Acknowledgments: Our Patients, their families, and care-givers MMWG: Beth Finley-Oliver Melissa Alsina M.D. Christine Simonelli Rachid Baz M.D. Latoya Washington Jason Brayer M.D., Ph.D Samantha Seitzler Brandon Blue M.D. Leslie Lauersdorf Taiga Nishihori M.D. Hien Liu M.D. Doris Hansen M.D. Lionel Ochoa-Bayona M.D. Dr Kenneth Shain, M.D PhD Omar Castaneda Puglianini, M.D. Dr Frederick Locke, M.D

Elyce Turba Mark Melody Sabrina Hasan Anna Niebrzydowski Alicin Roop Ann Nelson

Gabrial De Avilla Raghu Alugubelli

Chris Cubitt Ph.D. John Koomen Ph.D. Ariosto Silva PH.D Dung-Tsa Chen Ph.D. John Cleveland Ph.D

MMWG Moffitt Myeloma Working Group

Thank you!!!

MMWG Moffitt Myeloma Working Group

How to Manage Myeloma Symptoms and Side Effects Charise Gleason MSN, NP-C, AOCNP Winship Cancer Institute, Atlanta, GA, IMF Nurse Leadership Board 85

June 16, 2022

LIFE IS A CANVAS, YOU ARE THE ARTIST Charise Gleason MSN, NP-C, AOCNP Winship Cancer Institute of Emory University Atlanta, GA

Patient Education Slides 2022

FRAMING YOUR CARE Know your care team, Shared Decision Making & Reliable Resources

You are central to the care team

Pharmacist

CARE TEAM COLLAGE General Hem/Onc Myeloma Specialist

Communicate with your team • Myeloma is a chronic disease • Understand the roles of each

team member and who to contact for your needs • Participate in support network

Be empowered • Ask questions, learn more • Participate in decisions • Know your history –

Myeloma ManagerTM Personal Care AssistantTM

Primary Care Provider (PCP)

You and Your Caregiver(s) Support Network

Subspecialists Allied Health Staff

SHARED DECISION-MAKING Be empowered to be part of the treatment decision-making • Ask for time to consider options (if needed/appropriate) • Understand options; consider priorities • Use reliable sources of information • Use caution considering stories of personal

experiences • Consider your goals/values/preferences • Get a 2nd opinion, Meet with a Myeloma expert

• Express your goals/values/preferences; create a

dialog

• My top priority is [goal/value]; additional [preferences] are also important. • I think [treatment] may be a good choice given my priorities… What do you think?

• Arrive at a treatment decision together

Data From Research

HCP Clinical Experience TREATMENT DECISION

Your Preference Philippe Moreau. ASH 2015.

CARE PARTNER SUPPORT Care partner support is essential for the entire transplant process. Phase 1: Sedated procedures; Education sessions; Phase 2: Some transplant centers allow for outpatient transplant management Phase 3: Continued support and assistance is often Care partner can be one person or a rotation of many people.

IMF HAS MANY FREE RESOURCES TO HELP YOU

www.m-power.myeloma.org/ IMF Videos

FREE Publications

www.myeloma.org

Support Groups

IMF InfoLine: 1-800-452-CURE | 9am to 4pm PST

COLOR WHEEL OF TREATMENT

Treatment options, side effects, symptom management, & supportive care

GALLERY OF GOALS MYELOMA TREATMENT • Rapid and effective disease control • Durable disease control • Minimize side effects • Allow for good quality of life

SUPPORTIVE THERAPIES • Prevent disease- and treatmentrelated side effects • Optimize symptom management • Allow for good quality of life

• Improved overall survival

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 93

MANAGING MYELOMA: THE BIG PICTURE Transplant Eligible Patients

Transplant Ineligible patients

Everyone

Transplant Consolidation

Maintenance

Initial Therapy

Treatment of Relapsed disease Consolidation/ Maintenance/ Continued therapy

Supportive Care

COLOR WHEEL OF TREATMENT OPTIONS -Mibs Frontline

Velcade® (bortezomib)

Maintenance

Velcade® (bortezomib)

Relapse

Kyprolis® (carfilzomib) Ninlaro® (ixazomib)

-MAbs

-Mides

Steroids

Darzalex® (daratumumab)

Thalomid® (thalidomide) Revlimid® (lenalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

Darzalex® (daratumumab) Empliciti® (elotuzumab) Sarclissa® (Isatuximab)

Thalomid® (thalidomide) Revlimid® (lenalidomide) Pomalyst® (pomalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

CelMods • Iberdomide • CC-92480 Neuropathy Carfilzomib: Cardiac

ImmunoTherapy

Others

Melphalan Cyclophosphamide

Cellular Therapies Melphalan + ASCT

Revlimid® (lenalidomide)

Pending FDA Approval Noted Side effects

Alkylators

Infusion reaction

DVT/PE

Melphalan Cyclophosphamide Bendamustine

”

See steroid slide

Myelosuppression

Blenrep® (Belantamab mafodotin) “Belamaf”

Xpovio® (Selinexor) Doxil (liposomal doxorubicin) Farydak® (panobinostat)

ADCs BSAs Ex: Teclistamab, Talquetamab Cevostamab

Venclexta® (venetoclax)

Infusion reaction Blenrep: Keratopathy

Myelosuppression, GI Selinexor: Low sodium

Melphalan + ASCT CAR-T • Ide-Cel • Cilta-cel

Infection risk CAR-T: CRS and neurotoxicity 95

THE BRIGHT

DARK SIDE TO STEROIDS

Steroid Synergy Steroids are a backbone and work in combination to enhance myeloma therapy

Steroid Side Effects • Irritability, mood swings, depression • Difficulty sleeping

(insomnia), fatigue

Managing Steroid Side Effects • Consistent schedule (AM vs. PM) • Take with food • Stomach discomfort: Over-the-counter or

prescription medications • Medications to prevent shingles, thrush, or other infections

Do not stop or adjust steroid doses without discussing it with your health care provider

• Increased risk of

infections, heart disease • Muscle

weakness, cramping

• Increase in blood

pressure, water retention

• Blurred vision, cataracts • Flushing/sweating • Stomach bloating,

hiccups, heartburn, ulcers, or gas

• Weight gain, hair

thinning/loss, skin rashes

• Increase in blood

sugar levels, diabetes

Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR, Eastern Cooperative Oncology Group (2010) Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11(1):29–37. King T, Faiman B. Steroid-Associated Side Effects: A Symptom Management Update on Multiple Myeloma Treatment. Clin J Oncol Nurs. 2017 Apr 1;21(2):240-249. doi: 10.1188/17.CJON.240249. PMID: 28315528.

PATIENT-REPORTED SYMPTOMS Symptoms resulted from both myeloma disease and treatment and can impact quality of life at all stages of disease. They fall into 3 categories:

Physical

Psychological

• Fatigue

• Depression

• Constipation

• Anxiety

• Pain

• Sleep Disturbance

• Neuropathy

• Decreased Cognitive Function

• Impaired Physical Functioning • Sexual Dysfunction

Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790.

Financial • Financial burden (80%) • Financial toxicity (43%)

• Decreased Role & Social Function

GI SYMPTOMS: PREVENTION & MANAGEMENT Diarrhea may be caused by medications and supplements • • • •

Laxatives, antacids with magnesium Antibiotics, antidepressants, others Milk thistle, aloe, cayenne, saw palmetto, ginseng Sugar substitutes in sugar free gum

Avoid caffeinated, carbonated, or heavily sugared beverages Take anti-diarrheal medication • Imodium®, Lomotil®, or Colestid if recommended • Fiber binding agents – Metamucil®, Citrucel®, Benefiber® • Welchol® if recommended

Physical

Constipation may be caused by • Opioid pain relievers, antidepressants, heart or blood pressure medications, others • Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency

Increase fiber • Fruits, vegetables, high fiber whole grain foods • Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

Fluid intake can help with both diarrhea and constipation, and good for kidneys. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.

Smith LC, et al. CJON.2008;12(3)suppl:37-52. Faiman B. CJON. 2016;20(4):E100-E105. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

PAIN: PREVENTION AND MANAGEMENT

Physical

Pain can significantly compromise quality of life Sources of pain include bone disease, neuropathy and medical procedures Management • Prevent pain when possible • Bone strengtheners to decrease fracture risk; anti viral to prevent shingles; sedation before procedures

• Interventions depends on source of pain • May include medications, physical therapy, surgical intervention, radiation therapy, etc

• Complementary therapies • Mind-body, meditation, yoga, supplements, acupuncture, activity, etc

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

Tell your health care provider about any new bone pain or chronic pain that is not adequately controlled

PERIPHERAL NEUROPATHY MANAGEMENT Peripheral neuropathy: damage to nerves in extremities (hands, feet, or limbs) • • • • • •

Numbness Tingling Prickling sensations Sensitivity to touch Burning and/or cold sensation Muscle weakness

Physical

Prevention / Management: • Bortezomib once-weekly or subcutaneous administration • Massage area with cocoa butter regularly • Supplements:

• B-complex vitamins (B1, B6, B12) • Folic acid, and/or amino acids but do not take on day of Velcade® (bortezomib) infusion

• Safe environment: rugs, furnishings, shoes

If PN worsens, your HCP may: Report symptoms of peripheral neuropathy early to your health care provider; nerve damage from PN can be permanent if unaddressed

• Change your treatment • Prescribe oral or topical pain medication • Suggest physical therapy

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

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Physical symptoms impact mental well being. All can affect quality of life and relationships.

FATIGUE, ANXIETY & DEPRESSION

• Fatigue is the most common reported symptom (98.8%) Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

Physical Psychological

• Anxiety reported in >35% • Depression nearly 25% Financial concerns, disease progression, end-of-life, and change in social and sexual function were highlighted sources

Often, people do not share these symptoms with their provider. Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available. Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790. Catamero D et al. CJON. 2017; 21(5)suppl:7-18.

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REST AND RELAXATION CONTRIBUTE TO GOOD HEALTH 🐑🐑 Adequate rest and sleep are

essential to a healthful lifestyle

Short and disturbed sleep increase risk of • Heart related death • Increase anxiety • Weaken immune system • Worsened pain • Falls and personal injury

🐑🐑 Things that can interfere with sleep • Medications : steroids, stimulants, herbal

supplements, alcohol • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, nocturia, pain, inactivity, heart issues Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227. National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene

Psychological

🐑🐑 Sleep hygiene is necessary for

quality nighttime sleep, daytime alertness

• Engage in exercise but not too near • • • • • •

bedtime Increase daytime natural light exposure Avoid Daytime napping Establish a bedtime routine - warm bath, cup of warm milk or tea Associate your bed ONLY with sleep Sleep aid may be needed Avoid before bedtime: • Caffeine, nicotine , alcohol and sugar • Large meals and especially spicy, greasy foods • Computer screen time

Mustian et al. Journal of clinical Oncology. Sep 10 2013;31(26):3233-3241. Stan DL, et al. Clin J Oncol Nurs. Apr 2012;16(2):131-141. Zeng Y et al., Complementary therapies in medicine. Feb 2014;22(1):173-186.

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Manage stress

HEALTHFUL LIVING STRATEGIES: PREVENTION

• Rest, relaxation, sleep hygiene • Mental health / social engagement • Complementary therapy

Maintain a healthy weight • Nutrition • Activity / exercise

Preventative health care • Health screenings, vaccinations • Prevent falls, injury, infection • Stop smoking

Physical Psychological

Maintain renal health • Myeloma management • Hydration • Avoid renally-toxic medications – Dose adjust to renal function • Diabetes management

Protect your bones • Nutrition, Calcium + D supplement • Weight-bearing activity / walking • Bone strengthening agents

• Dental care

“An ounce of prevention is worth a pound of cure.” Benjamin Franklin Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476. Brigle K, et al. CJON. 2017;21(5)suppl:60-76. Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Faiman B, et al. CJON. 2011;15suppl:66-76. Miceli TS, et al. CJON. 2011;15(4)suppl:9-23.

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Financial

FINANCIAL BURDEN Financial burden comes from • Medical costs • • • •

Premiums Co-payments Travel expenses Medical supplies

• Prescription costs • Loss of income

• Time off work or loss of employment • Caregiver time off work

Contact the Social Services department at your hospital or clinic to talk to a social worker for assistance.

Funding and assistance may be available • • • •

Federal programs Pharmaceutical support Non-profit organizations Websites: • • • • • • •

Medicare.gov SSA.gov LLS.org Rxassist.org NeedyMeds.com HealthWellFoundation.org Company-specific website

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YOU ARE NOT ALONE

Thank you to our sponsors!

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