An Update on Treatment Options in Multiple Myeloma - Patrick A Hagen, MD, MPH Assistant Professor Hematology and Bone Marrow Transplantation ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
An Update on Treatment
Options in Multiple Myeloma
Patrick A Hagen, MD, MPH
Assistant Professor
Hematology and Bone Marrow Transplantation
Loyola University
Outline 1. Risk in Multiple Myeloma: Apples and Oranges 2. Current Myeloma Therapies for Newly Diagnosed Patients 3. Relapsed and Refractory Disease: proven therapies and those in development 4. Improved outcomes
• 1844 – First documented case of myeloma
• 39-year-old Sarah Newbury https://www.mediastorehouse.com/granger-art-
on-demand/medicine/
• Fatigue and multiple bone fractures. woman-using-leeches-bloodletting-woodcut-
8864787.html
• Passed away 4 years after onset of symptoms https://www.chineseherbsdirect.com/products/rhubarb-formula-90-ct-dr-
shens?gclid=CjwKCAjwtvnbBRA5EiwAcRvnpkpHY30YAiGkD32jNaZ-
CmAxNJIY2sHxhFz3j0hGOG8V6SdWg_ucJRoCtMgQAvD_BwE
m.ca/content/orange-peel
http://www.herbmuseu
Treatments:
• Rhubarb pills
• Orange peel infusions
• Dover powder
• Leeches: the first “maintenance therapy”
Risk and Myeloma “Doctor, what stage is my cancer?”
Risk in Myeloma: at diagnosis
• Blood tests and bone
marrow biopsy
• High Risk features:
– High risk FISH
changes on the bone
marrow biopsy
– Elevated serum LDH
• 5-year OS by stage
– I: 82%
– II: 62%
– III:40%
Palumbo et al, JCO 2015; 33(26): 2863-2869
Up-Front ASCT Up-Front non-ASCT
Up-Front IMID Up-Front PI
Palumbo et al, JCO 2015; 33(26): 2863-2869
Therapies in Multiple Myeloma: oldies but goodies
Proteasome Monoclonal
Alkylating
Inhibitors Immunomodulators Antibodies
agents
Mechanisms • Makes cancer DNA
of Action unstable
• Melphalan
Early Use • Cyclophosphamide
Later
• Busulfan
generations:
Soon to
• Melflufan
come:
Therapies in Multiple Myeloma: oldies but goodies
Alkylating Proteasome Monoclonal
Immunomodulators
agents Inhibitors Antibodies
• Inhibits proteasome
• Cellular stress
Mechanisms
• Apoptosis
of Action (programed cell
death)
Early use • Bortezomib (2003)
Later • Carfilzomib (2012)
generations: • Ixazomib (2015)
• Marizomib
Soon to
• Oprozomib
come:
Therapies in Multiple Myeloma: oldies but goodies
Alkylating Proteasome Monoclonal
Immunomodulators
agents Inhibitors Antibodies
Multiple:
• Engages immune
Mechanisms system
of Action • Inhibitors
angiogenesis
• Thalidomide
Early use (2006)
• Lenalidomide
Later (2006)
generations: • Pomalidomide
(2013)
• Iberdomide (CC-
Soon to
220)
come: • CC-92480
Therapies in Multiple Myeloma: oldies but goodies
Alkylating Proteasome Monoclonal
Immunomodulators
agents Inhibitors Antibodies
Multiple targets
Engage your immune
system to fight off the
Mechanisms
myeloma cancer cells:
of Action • SLAM7
• CD38
• BCMA
Early use • Elotuzumab (2015)
• Daratumumab
Later
(2016)
generations: • Isatuximab (2020)
Soon to
• Many others
come:Treating up-front Multiple Myeloma
• As of 2020, multiple myeloma is a chronic disease
• 3 primary goals of therapy: regardless of intent to
transplant
– Get into a deep remission
– Stay in remission for as long as possible
– Do so with the least impact on quality of life
• 3-step process:
– Induction: induce (or get) the myeloma into a remission
– Consolidation: consolidate (improve/deepen) that remission –
typically with high dose melphalan
– Maintenance: maintain a deep remission
Highly encourage all patients to participate in clinical trials –
your best chance at an improved outcomeStandard induction therapy • 3-drug induction regimen is considered the standard of care • Backbone includes: – Dexamethasone – oral steroid – Lenalidomide (Revlimid) – IMID • 3rd drug……..
“Doctor, which three drug combination is best?”
ENDURANCE TRIAL
Answer: MAI TRIAL
• The third drug depends on:
– Intention to move towards high dose melphalan and
autologous bone marrow transplantation
– Potential toxicities of the agent and medical problems
of the patient
– Ability to tolerate 3 drugs – consider frailty
• Doublet sometimes ok • Median Progression Free Survival
(PFS):
• RVD-lite – Dara-RD: not reached
• Clinical trials are being designed
– RD:specifically
31.9 months to answer this
question • 30 months PFS:
– Dara-RD: 70.6%
– RD: 55.6%
Kumar et al Lancet Onc 2020 – HR: 0.56; PDoctor, do I really need a bone marrow transplant?
Answer:
Up-Front High-Dose Melphalan and Autologous
Stem Cell Transplantation (v delayed)
Yes: every patient should be evaluated for
Published PFS: median OS
the role of high dose melphalan and
NEJM 2017:
50 v 36m 4 year: 81 v 82%
autologous stem cell transplantation
IFM
ASH 2017:
EMN02 NR v 44m 3 year ~ 85% in both arms
Lancet Onc 2015: 4 year: 86 v 73%
Italy, Czech, Australia 43. v 30m (p=0.004)
NEJM 2014: 4 year: 81.6 v 65.3%
GIMEMA 43 v 22m (p=0.02)Doctor, if I’m in a deep remission after transplant, why do I need to continue therapy? Do I really need maintenance?
Post-Transplant Maintenance: Lenalidomide
• Myeloma is a chronic disease
• Engage the immune system in
surveillance
• Improved time to progression:
– By at least 18 months
– Likely much longer
• Improved survival:
– Inconsistent between trials
– Shown in this and other large meta-
analysis
• Next steps:
– Risk adapted maintenance
approaches
McCarthy et al JCO 2017• Doctor, if I’m in a deep remission after transplant, why do I need to continue therapy? Do I really need maintenance? Answer: Yes: This will improve your remission duration and likely will improve your survival. May improve your long term quality of life – being studied More to come: • MASTER trial • SWOG1802
Important Supportive Care • Ca/Vit-D supplementation for bone health • Bisphosphonate or RANK-ligand therapy to reduce “skeletal events” • Aspirin or low dose blood thinners to help prevent blood clots • Antiviral therapy to help prevent viral reactivation (particularly shingles) • Proper vaccinations
Relapsed and Refractory Multiple Myeloma
•Risk
Encourage all patients
readjusted: talk to to participate
your in you
doctor so clinical trials
• Many of the
understand expectations of therapy
same principles apply:
–3 drugs
Are areany
there better
newthan
high2 risk FISH/Cytogenetics in the
– bone marrow
Treat until progressive disease
– Ongoing
How longimportance of supportive
did the patient go fromcare
initiation of first
• Lack
lineoftherapy
head to(orhead
transplant)
clinical until
trialsrelapse?
to compare
different myeloma regimens
• There is no one best treatment regimen/approach
for any given patient
• Treatment tailored to tolerance and comorbiditiesTriple Regimens extremely active in Relapsed Disease
Median time to
progression:
• KRD: 26.3 months
• RD: 17.6 months
Stewart et al NEJM 2015
Median time to
progression:
• Dara-Car-Dex: not
reached
• Carfilzomimb-Dex: 15.8
months
Dimopoulos et al; Lancet 2020Comparing Regimens: Van Beurden-Tan et al JCO 2017
Other Important Treatment
Considerations:
• 2nd Transplant:
– Depends on length of remission following 1st
transplant
• 18 months without maintenance
• 36 months with maintenance
Michaelis et al BBMT 2013New kids on the block: Rapid Drug Development in MM
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
Alkylator
Improved deliver
Mechanisms
to myeloma cell
of Action
Less off target
toxicity
Clinical
Trial Data
Future
directions:Chaudan et al Clinical Cancer Research 2013
New kids on the block:
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
Alkylator
Improved deliver
Mechanisms
to myeloma cell
of Action
Less off target
toxicity
Horizon Study:
phase II
Clinical OCEAN study:
Trial Data Phase III
Melflufen Dex
v Pom-Dex
FDA granted
Future priority review
directions: 8/29/2020New kids on the block:
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
An antibody targets
the myeloma cell –
once introduced it
releases its
“payload” killing the
Mechanisms
cancer cell
of Action
Ex:
Belantamab
mafodotin (blenrep)
Clinical
Trial Data
Future
directions:Cohen; BLOOD 2019
Belantamab Mafodotin: BCMA-Targeted ADC Tai. Blood. 2014;123:3128. Trudel. Lancet Oncol. 2018;19:1641. Trudel. Blood Cancer J. 2019;9:37.
New kids on the block:
Nuclear Multi and Bi-
CAR-T Other:
Melflufen Antibody-Drug Conjugates Export Specific
Therapy
Inhibitors Engagers
An antibody targets the
myeloma cell – once
introduced it releases its
Mechanisms “payload” killing the cancer cell
of Action
Ex:
Belantamab mafodotin
(blenrep)
Phase I and II data mature
Ongoing extensive phase II and
Clinical III studies
Trial Data
Unique ocular toxicity
ORR: ~30% -- DOR 11 months
FDA approved
4 prior therapies
Future Must work in conjunction with an
directions: ophthalmologist
Being extensively studies in
variety of combinationsNew kids on the block:
Nuclear Multi and Bi-
Antibody-Drug Other:
Melflufen
Conjugates
Export Specific CAR-T Therapy
Inhibitors Engagers
Drug: Selinexor
(Xpovio)
Mechanisms
of Action
Nuclear export
Inhibitor
Clinical
Trial Data
Future
directions:https://www.myelomacrowd.org/the-storm-study-selinexor-the-active-clinical-trials-using-this-drug/
New kids on the block:
Antibody- Multi and
Nuclear Export Other:
Melflufen Drug Bi-Specific CAR-T Therapy
Inhibitors
Conjugates Engagers
Drug: Selinexor
(Xpovio)
Mechanisms
of Action
Nuclear export
Inhibitor
STORM2: 21% ORR
duration of response
3.8m
Clinical
Boston Data: more
Trial Data promising – different
dosing
Toxicity: many
Approved in
Penta-refractory
patients with 4
Future
prior lines of
directions: therapy
“Storming” aheadNew kids on the block:
Antibody-Drug Nuclear Export Multi and Bi- CAR-T Other:
Melflufen
Conjugates Inhibitors Specific Engagers Therapy
Helps the
body’s
immune
Mechanisms
of Action system target
cancer cells
Ex: AMG-701
Clinical
Trial Data
Future
directions:Cohen; BLOOD 2019
How do “BITEs” work
New kids on the block:
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
Mechanisms
of Action
Variety of
phase 1
Clinical
and 2
Trial Data
studies
underway
Further
development
Future
as single
directions: agent and in
combinationNew kids on the block:
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
Type of cellular
therapy
Mechanisms Reprograming
of Action your immune
system
Clinical
Trial Data
Future
directions:CAR-T
• Donor lymphocytes (or
T-cells) are removed
from patients then
“engineered” to fight
cancer
– Various chimeric
antigen receptors
(CARs) are transduced
into the T-cells to then
target cancer antigens
• Targets: BCMA: B-Cell
Maturation Antigen
Srivastava et al, The Journal of Immunology 2018• Phase 1 study
• Heavily pre-treated:
– median of 7 previous
myeloma regimens
• CAR-T therapy has a
unique and serious
toxicity profile
• Unprecedented
response rates in
heavily pre-treated
patients:
– CR rate of 45%
– PFS of 11.8 months
• Patients are relapsing
Raje et al NEJM 2019 thoughImportant Ongoing and Planned Future Studies
Study phase and Inclusion CAR-T Treatment
Study/NCT# Institutions planned enrollment Criteria Construct Arms
Phase 1; • ≥3 prior lines Novel Fully-human
NCT03602612 NIH • PI/IMiD exposed
Single arm
N=42 Anti-BCMA CAR
• ≥3 prior lines;
KarMMa Multicenter Phase 2; • PI/IMiD/CD38mAb Single arm
exposed
Bb2121
NCT03430011 worldwide N=150
• refractory to last line
KarMMa-2 Multicenter Phase 2; • 4-cohorts
• ≥3 prior lines
Bb2121 Single arm
NCT03601078 worldwide N=181
• 2-4 prior lines;
2:1 Randomization
KarMMa-3 Multicenter Phase 3; • PI/IMiD/CD38mAb
exposed
Bb2121 Arm-A: CAR T
NCT03651128 worldwide N=381 Arm-B: SOC
• refractory to last line
• ≥3 prior lines
CARTIFAN-1 Multicenter Phase 2; • PI/IMiD exposed
• PD on last treatment or
LCAR-B38M Single arm
NCT03758417 China N=60
within 12m from its end
BMT-CTN • High Risk Post-ASCT
Multicenter
1901 and “Parallel” Phase 2 • Suboptimal response Bb2121 Single arm
US post -ASCT
1902New kids on the block:
Multi and Bi-
Antibody-Drug Nuclear Export Other:
Melflufen Specific CAR-T Therapy
Conjugates Inhibitors
Engagers
Type of cellular
therapy
Mechanisms Reprograming
of Action your immune
system
Clinical
Trial Data
Both BB2121
and JNJ-4528
Future
are likely to be
directions: approved in
2021New kids on the block:
Antibody-Drug Nuclear Export B-Specific Other:
Melflufen CAR-T Therapy
Conjugates Inhibitors Engagers
AKT inhibitors
Venetoclax
Mechanisms Ibrutinib
of Action
BCMA: BITEs,
mAb
CD56:
Antibody-drug
Clinical conjugate
Trial Data HDAC
inhibitors
PARP inhibitors
Future BET inhibitors
directions:
Radio-
ImmunotherapySEER registry study from
US: 1993-2012
• Improvement in 5 year
survival: seen in all ages
and ethnic groups:
– < 65 years of age: 38.2%
61.8
– 65 -74 years of age: 29.0%
48.4%
– >75 years of age: 21.1%-
Costa et al
34.0% BLD ADV
2017Thank you for your attention! • Patrick A Hagen, MD, MPH • Assistant Professor • Hematology and Bone Marrow Transplantation • Loyola University
You can also read
