MCRT Webcast: American Society of Hematology Meeting Review (Part 1)
Posted: Mar 07, 2021
The annual American Society of Hematology (ASH) meeting is the most important scientific meeting of the year for the hematology community. It is held annually in early December and attracts more than 30,000 attendees from throughout the world who get information on the latest, most important studies in their respective fields of interest. For myeloma specialists, it updates the standards of clinical practice for the coming year and informs them about the latest research activities ranging from basic biology to advanced clinical trials. The two part Myeloma Crowd Round Table (MCRT) featured six myeloma experts who reviewed a variety of ASH studies that will impact clinical care today and in the coming year.
Drs. Adam Cohen, Ashraf Badros, and Noopur Raje were featured in part one of the MCRT webcast on Saturday, January 30:
Adam Cohen, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA: CAR T Cell Therapy for Multiple Myeloma
All the cells in blood come from the hematopoietic stem cell (HSC), which is collected for a stem cell transplant
One of two lineages HSCs produce are common lymphoid progenitors which create the immune system which is made up of natural killer (NK) cells, B cells and T cells
T cells are unique cells that recognize other cells in the body that become infected
T cells develop “memory” to recognize and respond to pathogens
Sometimes they can kill cancer cells, but over time cancer cells learn to evade T cells
Approaches to overcome this evasion include:
Checkpoint inhibitors have been effective in solid tumors by “waking up” exhausted T cells, not shown to be as effective in blood cancers
Cellular therapies, when T cells are re-engineered to recognize cancer known as CAR T (chimeric antigen receptor)
Bispecific antibodies/T cell engagers (BiTEs) are discussed below
CAR T cells have the “head” of an antibody and the “body and tail” of a T cell receptor, which allows T cells to grow and divide create a “memory” to kill cancer cells
A vector is needed to get CAR gene into T cell, most often derived from viruses that have disease-causing “guts” taken out
CARs create cytotoxicity, or killing, by producing cytokines, which communicate with other cells in the immune system
This creates a living drug with long term persistence that only needs to be infused once
CAR T cell therapy process:
Leukapheresis, taking T cells out of body
Activate T cells and grow, infuse back into patient after chemotherapy
First shown to be successful in B cell cancers
Short video on first pediatric patient treated here
Side effects of CAR T cell therapy:
Cytokine release syndrome (CRS), when cytokines mimic infection and become over-activated
Tocilizumab, an anti-IL6 receptor antibody, treats severe CRS
Early CAR T studies in myeloma target BCMA, which is a target highly expressed in myeloma cells
Four studies demonstrated responses in 63-90% of patients
Two CAR T products are moving toward FDA approval
bb2121, now called idecabtagene vicleucil (ide-cel) is awaiting FDA approval
KarMMa clinical trial, showed 73% overall response rate (ORR) and 33% complete remission (CR) in heavily-treated patients, 84% who were at least triple refractory to standard treatments
Mostly manageable side effects, durable survival rates in short time observed
Ciltacabtagene autoleucel (cilta-cel), still in FDA review process
CARTITUDE-1 clinical trial of 97 heavily-treated patients, 67% achieved a stringent CR (sCR), many demonstrated MRD negativity
Side effects were more delayed, slight more than ide-cel
Denosumab (XGEVA ®) inhibits the RANK ligand, which promotes bone destruction
Has equivalent bone strengthening to Zometa ®, but has slightly better progression-free survival (PFS)
Preferred for patients with kidney issues
Calcium and vitamin D supplements are recommended
CAR T cells
Ide-cel (see Dr. Cohen’s presentation above), patients who achieved MRD negativity had longer survival rates
Positive results in heavily pretreated patients, CRS is manageable in 90% of patients
Orvacabtagene autoleucel EVOLVE study ongoing
No good answer yet about which CAR for which patient
Cancer patients with COVID and active disease have worse outcomes
Mortality rates are higher in patients with plasma cell disorders
Risk factors associated with death are age, high-risk disease, renal disease, and less control of myeloma
Risk factors associated with risk of hospitalization include being male, having cardiovascular risk, and not being in CR or sCR
General guidelines for myeloma patients
Self education, understand your individual risks, use telemedicine when possible
Use oral drugs whenever possible, reschedule procedures, reduce dex
Keep disease under control
No data to avoid specific drugs
mRNA vaccines (Pfizer and Moderna) are available
Recently approved Johnson and Johnson vaccine is not inferior for patients
Take any vaccine that is available
Maintain use of masks, social distancing, reduce possibility of exposure
Audience Questions & Answers
0:55 - What will the cost of iberdomide be as compared to currently used IMiDs and is it an oral medication?
1:31 - Will iberdomide and other CELMoDs replace currently used IMiDs in maintenance?
3:32 - Does CAR T make tumors smaller (de-bulk) or will the therapy need other drugs to help?
5:43 - Do patients with lower tumor burdens have better results with CAR T therapy?
8:13 - Is there an age cutoff for CAR T?
9:45 - How do response rates differ between BiTEs and Car Ts?
11:05 - What should patients who are refractory to the three main classes of drugs used in myeloma consider?
13:59 - From a patient who had CAR T therapy in 2018 and is still MRD-: If relapse occurs, is there a way to determine if it is related to persistence of loss of BCMA as she determines therapy options?
16:10 - Are there secondary targets to consider if CAR T doesn’t work of if BCMA is no longer present?
18:14 - If a patient has osteoporosis before a myeloma diagnosis, what’s the right strategy for bone strengthening agents with lytic lesions or bone problems at diagnosis?
19:34 - How does one decide between a CAR T vs. a BiTE vs. an antibody drug conjugate?
22:49 - Can the JnJ vaccine be taken later if one had had the Pfizer vaccine? And if one gets COVID, how long should one wait to have a vaccine? Or after treatment?
Questions Answered in Chat Forum
Is age a bar to CAR T treatment? I am 76 and had an autologous stem cell transplant in 2016.
Dr. Cohen answered: There is no upper age limit - it really depends on overall medical condition/co-morbidities. Patients with advanced heart failure or lung disease would not be candidates but we've treated patients well into their late 70s and there's no reason a healthy 80-ish year old couldn't consider CAR T cells.
How does disease PFS with CAR-T cells compare between those who had complete remission (MRD negative) and those who were VGPR or just partial remission?
Dr. Borrello answered: In general, the data has shown that the deeper the response, the better the PFS. The same results also appear to be applicable for the depth of response with CAR-T cells.
Re: DREAMM-2: "Most recoveries occurred on treatment" was stated. By doing what...dosage reduction, dosage hold, nothing?
Dr. Badros answered: Hold therapy until resolution or less than grade 1, and if recurrent/persistent, decrease the dose from 2.5 to 1.9 mg/kg. Most patients will have 1-2 delays. And such delays did not lead to loss of response.
Is there a significant difference in effectiveness between oral or IV dexamethasone?
Dr. Borrello answered: Not really. They are interchangeable.
What is standard care post autologous transplant?
Dr. Borrello answered: Most would recommend Revlimid as maintenance post-auto but there could be modifications to this based on an individual's unique characteristics.
Are we moving toward stem cell transplant no longer being a standard of care, particularly in a time of active Covid-19?
Dr. Raje answered: No, stem cell transplant still the standard of care.
Do you foresee a time when CAR T therapy will be done first (before SCT) for newly diagnosed patients? If so, how far in the future?
Dr. Raje answered: Yes, we are already doing so in cases of high-risk disease.
After someone has received two Covid vaccinations, can they still get a mild case or be asymptomatic and infectious to others? Would they be less infectious than someone who was never vaccinated?
Dr. Raje answered: You can still transmit the infection but you will get less severe disease, therefore it is important to mask up and social distance.
Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical research. Founder of HealthTree Foundation (formerly Myeloma Crowd).