Episode 048: Myeloma Series, Pt.9- Transplant in Myeloma Capstone
In episode 046, we discussed the fundamentals of transplant in the treatment of patients with multiple myeloma. This week, we sit down with two incredible hematologists who specialize in transplant to discuss the real-life decision-making that goes into evaluating each patient. We are so excited to welcome two special guests this week, Dr. Shonali Midha and Dr. Amar Kelkar, joining us from the Dana-Farber Cancer Institute in Boston!
How do you determine what makes a patient transplant eligible?
There is no uniform “algorithm,” rather each patient is discussed on a case by case basis. Some of what goes into that decision-making includes:
Age
Performance status
Frailty
Cytogenetics of disease
What was the clinical presentation of their disease
Life expectancy
Most importantly: What does the patient want based on the data presented to them?
Need to consider things like patient’s ability to be away from work for extended periods of time (average 90-100 days)
Caregiver availability
Health literacy
Objective measures:
How have they responded to induction therapy?
Cardiac status (assessed with Echo or MUGA)
Pulmonary function testing
Renal function
No single metric will rule in or rule out a transplant; all needs to be considered together
When counseling patients, what expectations them about the transplant?
Dr. Midha describes the process as feeling “like you got hit by a truck.” There will definitely be some hard days, but with time, things will slowly turn around
Expect to be away from work for about 90-100 days
At the end of process, hope is to bring you back to your prior quality of life, if not better
Toxicities associated with treatment
An important drug we previously discussed is melphalan, which is given to patients prior to their autologous stem cell rescue. What level of renal dysfunction is permitted in order for a patient to get high dose melphalan?
If the renal dysfunction is from myeloma, then you take their renal function into consideration but it is not a contraindication.
Renal function is important to consider, as patients with poor renal function will have longer cytopenias
Typically dose is 200mg/m2.
In some patients, this can be reduced to 140mg/m2, with studies showing no major difference in outcomes
In patients with ESRD, 100mg/m2 melphalan can be used
It is important to understand that the melphalan is actually the drug that is the active agent in an autologous stem cell transplant; in fact, the cells are used as a rescue
In the end, the deeper the response to treatment with induction therapy and melphalan, the better the outcome
How does the general process for apheresis work and what is a general timeline for this procedure?
Prior to apheresis, patients are given 4-6 cycles of induction therapy; more than this makes the stem cell collection process more difficult, particularly with the use of revlimid
Hold therapy 3-4 weeks before collection is planned
During this time, repeat vital organ testing (Echo, PFTs), repeat bone marrow biopsy, and consider MRD testing
The actual apheresis process is relatively straightforward
Stem cells are collected from the periphery via an apheresis catheter (looks like a dialysis catheter) and the machine specifically collects CD34+ cells
In order to mobilize the stem cells from the marrow, different approaches can be considered (below); typically growth factor (G-CSF) is given about 5 days prior to collection
The day prior to procedure, labs are drawn and tunneled catheter is placed; if CD34+ cells are lower/at threshold, plerixafor is given (takes about 12 hours to work!)
Day off, patient is started on apheresis
Hold antihypertensives the day of
Take breaks throughout the day
What agents are used to mobilize stem cells?
G-CSF: Enhances protease activity to cleave CXCR4 on stem cells
CXCR4 typically helps cell binds to adhesion molecules
Plerixafor: Selective inhibitor of CXCR4; therefore allows stem cells to leave the marrow
Cyclophosphamide: less commonly used now; Also promotes protease-mediated cleaving of CXCR4
How many stem cells do you collect when a patient presents?
To assess how many cells are “enought” they count the number of CD34+ cells; goal is 4 million cells/kg (Patients need >2 million/kg at least; they aim to collect between 4-6 million/kg)
The fewer the cells collected, the slower the anticipated count recovery
How does therapy impact ability to collect stem cells? How many cycles with an IMID might prohibit collection and why is that?
This is a case by case basis
In general, IMIDs limit mobilization of stem cells, especially when given for more than 6 months of therapy
More so seen with lenalidomide than with thalidomide or pomalidomide, but this is also because lenalidomide is used more commonly
Daratumumab may have some impact, too. Recent ASH Meeting posters suggest that there may be a decrease in stem cell mobilization, but not statistically significant.
With all the advances in treatment options today, is there still a role for transplant?
This is currently being heavily studied - we do not know the answer to this question
What we are learning more is that MRD matters; patients with MRD have better PFS and OS
The other question is should we be doing more genetic testing in all our patients at the time of diagnosis to help guide treatment/stratify higher risk patients?
Raises the question about “CHIP” (clonal hematopoiesis of indeterminate potential)
These are mutations that are found on NGS that have implications in people with certain hematologic diseases, but these patients don’t actively have that disease at the time.
For example: If someone has a mutation, should we treat them differently? For instance, lenolidomide has been known to rarely cause secondary malignancies; if someone has a genetic predisposition for a blood disorder, should we avoid this drug?
We talked about the concept of “functional cure” meaning a good treatment free remission for quality-of-life benefit. Do you think transplant up front is really the way to go to get to that point or do you see an MRD based approach as the future for these patients?
In myeloma, the goal has always been to achieve a cure (but we typically do not use this word in myeloma!)
We are now exploring the role of MRD negativity in the treatment of this disease; sustained MRD negativity for >6 months has been shown to result in better PFS and OS
This is being explored in the MASTER Trial (https://ascopubs.org/doi/abs/10.1200/JCO.21.01935)
What MRD means is in flux; as levels of detection get better, we will have to redefine these numbers
If a patient does not want a transplant and achieves MRD negative disease, would you delay transplant?
At this time, there is no confirmatory data to say that we can defer a transplant, however, it is important to discuss this with patients
If a patient is transplant eligible, can consider collecting cells and storing them in the event that they need them later
Can consider maintenance therapy, as we don’t have data for monitoring patients off therapy
That being said, it provides some reassurance to physicians if a patient is MRD negative if patient opts to forego transplant and/or maintenance
Important to recognize that transplant is a big decision
Physically taxing
Cost implications: expensive drugs, procedure itself is very expensive
Lots of hidden costs in the treatment of myeloma
If a patient has had one autologous transplant and then was lenalidomide maintenance, after which they had a relapse, would you offer a second transplant?
Typically, it is not offered
However, if patients got more than average benefit from transplant (average benefit 4-5 years), then Shonali does consider it if the patient is healthy/fit enough
The concern is the high dose melphalan
Will we ever do allogeneic stem cell transplants in myeloma?
The major benefit of an allogeneic stem cell transplant in other hematologic malignancies is the graft vs. leukemia effect; there is very little evidence that this has a role in the treatment of myeloma
Anecdotally, Amar has seen a patient getting a syngeneic transplant (allo transplant from an identical twin) where the outcomes were good; but in other malignancies, syngeneic transplants are inferior because of reduced graft vs. leukemia effect
About our guests:
Dr. Shonali Midha, MD is a hematologist specializing in the treatment of multiple myeloma at the Dana-Farber Cancer Institute and an Instructor in Medicine at the Harvard Medical School in Boston, MA. Dr. Midha completed her medical school and residency at the University of South Florida Morsani College of Medicine. She completed her fellowship in hematology/oncology at the Moffitt Cancer Institute in Tampa, Florida.
Dr. Amar Kelkar, MD, FACP is a Stem Cell Transplantation Physician at the Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School in Boston, MA. Dr. Kelkar attended medical school at St. George’s University School of Medicine, after which he completed residency at University of Illinois College of Medicine Peoria. He then went to University of Florida in Gainesville, Florida for his hematology/oncology fellowship; and most recently, he graduated from his bone marrow transplant fellowship from Dana-Farber Cancer Institute
References:
https://ashpublications.org/blood/article/138/Supplement%201/3886/481031/Impact-of-Daratumumab-Containing-Induction-on-Stem - Recent ASH Abstract about impact of daratumumab on stem cell mobilization
https://ashpublications.org/blood/article/140/Supplement%201/10441/492847/Effect-of-Daratumumab-on-Stem-Cell-Mobilization - Recent ASH Abstract about impact of daratumumab on stem cell mobilization
https://ascopubs.org/doi/abs/10.1200/JCO.21.01935 - MASTER trial
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Graphics, social media management: Ronak Mistry
