Episode 049: Myeloma Series, Pt.10- Multiple Myeloma Capstone
It’s been a long road, but incredibly educational journey, through our Myeloma Series. We finish off our series with a bang by sitting down with Multiple Myeloma Superstar, Dr. Manni Mohyuddin. In this episode, Dr. Mohyuddin takes us through his approach to complex decisions in the care of patients with myeloma, highlighting that myeloma treatment is an art in which we take imperfect data and try to make the best decisions for our patients. Trust us, folks, you do NOT want to miss this episode!
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
How do you define high risk Myeloma?
First of all! FISH specimen should be enriched for CD-138 plasma cells! A completely negative FISH panel often means that it was not run on a CD-138 selected specimen.
FISH and cytogentic features (e.g deletion 17p, t(4;14), t(14;16) or t(14;20), gain 1q)
Extramedullary disease
Circulating plasma cells/plasma cell leukemia
Having ISS-3 (high beta-2 microglobulin, low albumin)
How does karyotype influence your initial treatment and maintenance strategies in Myeloma?
For initial induction therapy, regardless of risk features, can use 4 drug combination in a fit and young patient: Dara, Velcade, Revlimid and Dexa (phase-2 GRIFFIN trial)
Some experts advocate for KRD (Carfilzomib, Revlimid, Dexa) for high risk Myeloma. But 2 large randomized trials prove no benefit.
ENDURANCE trial
Compared KRD vs VRD:
This trial included patients with gain 1q and t(4;14), but did NOT include del 17p, t(14;16) and t(14;20).
Did not show any benefit with KRD compared to VRD
CLARION trial:
Compared Carfilzomib+ Malphalan+ Prednisone vs Velcade+ Malphalan+Prednisone in transplant ineligible population
Did not show any benefit of Carfilzomib to Velcade.
When do you consider switching therapies during Induction?
Disease trajectory could be variable regardless of initial response!
Very rapid response sometimes predicts poor outcomes and slow response could mean overall low risk disease.
If 3-4 cycles without even a partial response, then switching therapies would be appropriate.
Which one is better: 3 drug (VRD) vs 4 drug regimen (Dara VRD)?
Regardless of high risk or standard risk, 4 drug regimen is better for induction therapy for the following reasons:
Addition of a fourth drug (Dara) does not dramatically increase toxicity (slight increase in neutropenia and viral infection risk)
Studies presented in ASH 2022 reported that better quality of life was achieved quicker in quad arm patients compared to 3 drug arm.
Adding Dara for a short period of time (during induction) does not worsen the quality of life in terms of infusion visits, but adding it to maintenance therapy would compromise the quality of life as it would subject the patient to weekly infusion visits for years.
He does not include for all patients in maintenance
Is adding more drugs to Revlimid maintenance therapy a better idea?
FORTE trial shows that you can also get PFS advantage in Myeloma by augmenting Revlimid maintenance with Carfilzomib, but overall quality of life is worse (more infusions) in standard risk patients.
Doublet therapy would be useful in high risk patients.
What are the considerations of using revlimid in patients with renal dysfunction?
For CrCl 30-40, Revlimid can still be used.
With lower CrCl, start with Dara-CyBorD then can be transitioned to Revlimid based regimens after a few cycles once there is an improvement in kidney function.
Starting with a Cyclophosphamide and Velcade based approach is reasonable in patients who cannot be given Revlimid because of their kidney function.
In patients with newly diagnosed multiple myeloma, what is your approach?
Manni pushes for CyBorD in the hospital for patients who need treatment; he does not use pulse dose steroids routinely
Is twice weekly Velcade better than once weekly Velcade? And how to approach dose reduction?
Outcomes are similar, but twice weekly Velcade has a lot more risk of side effects (neuropathy) and increases infusion visits.
Dose reduction should be considered in neuropathy, and it is reasonable to stop Velcade altogether to prevent debilitating neuropathy!
How to ask patients about neuropathy symptoms?
Ask questions like:
Can you button your shirt?
Numbness/tingling in hands and feet that is persistent?
Balance issues: Are you more unsteady on your feet? Falls?
In a patient with standard risk on Dara VRD, how often is lab monitoring required? And what is the goal response before stem cell collection for transplant?
Myeloma labs are repeated with every cycle (21 or 28 days) to see if M-proteins and light chains are responding appropriately.
PR (partial response) is enough depth of response required for transplant provided bone marrow is concordant with response in the serum. Data from Mayo clinic suggests that Interventions to deepen response before transplant did not improve outcomes.
Should transplant be considered in all the patients with standard risk disease?
In standard risk myeloma, transplant should be individualized based on patient preference.
Have shared decision-making with patients to see what is important to them
Patients that are responding well to therapy (e.g, CR even if they are MRD positive), can defer transplant to see if better response can be achieved through drug therapies (but stem cells are usually collected so that option of transplant is open).
In patients with PR, transplant is usually considered although data is limited.
Is transplant preferred in High risk Myeloma?
High risk Myeloma is represented only as a subset in transplant vs no transplant trials.
A meta-analysis done by Dr. Chakraborty which pools the data from all of these trials shows that outcomes are dismal for high risk myeloma with non-transplant approach.
Median PFS of 17 months with non-transplant.
Median PFS of 51 months with transplant approach.
Therefore, transplant is the preferred approach in Myeloma with high risk features.
In a standard risk patient on Dara-VRD (with stringent CR) with no transplant, how many cycles are considered, and what is the maintenance strategy?
To date, there are no randomized phase 3 trials that have used quad therapy in non-transplant population.
Amongst trials, 8 cycles with quad, de-escalation can be done by dropping Velcade first (given the risk of Neuropathy)
No data is currently available to decide about when to stop Dara.
Possible use MRD?
When to go to just revlimid, base it based on patient preferences, quality of life?
What is the utility of MRD testing?
No high quality data to guide the use of MRD testing for making clinical decisions
Escalation of treatment based on MRD positivity is not recommended.
De-escalating treatment based on MRD negativity can be considered (trials are pending to support this)
There is no utility of checking MRD longitudinally in elderly, transplant ineligible population.
Also limited utility of MRD in relapsed/refractory myeloma, as patient can relapse even with MRD negativity
De-escalation of therapy based on persistent MRD negativity (e.g >1 year) is appropriate but completely stopping treatment is not!
What are the preferred regimens in relapse/refractory settings after transplant?
Earlier relapse after a transplant represents worse prognosis
Add CD-38 therapy if they have not received it before (Dara/Isatuximab).
If patient is Revlimid naive (wasn’t getting Revlimid for maintenance), then can go for Dara+Revlimid+Dexa (POLLUX trial).
If patient is NOT Revlimid naive (has progressed on Revlimid), then there are multiple options that incorporate CD-38 monoclonal antibody, have phase-III data to support them and exclude Revlimid:
Dara+Carfilzomib+Dexa (CANDOR trial)
Isatuximab+Carfilzomib+Dexa (IKEMA trial)
Dara+Pomalidomide+Dexa (APOLLO trial)
Isatuximab+Pom+Dexa (ICARIA trial)
Dara+Velcade+Dexa (not a go to therapy because of the risk of neuropathy)
Velcade+Pom+Dex (Non-CD38 containing regimen)
Carfilzomib+Pom+Dex (Also non-CD38 containing regimen; does not have phase-III data).
In patients who are fit, no cardiac issues and can come for frequent infusions, Dara+Carfilzomib+Dexa
There is best PFS for CD-38 (Dara/Isatuximab) + Carfilzomib+Dexa.
If someone had quad therapy upfront, can we still use other CD-38 therapy (Isatuximab) in relapse/refractory settings?
Depends on whether CD-38 therapy was used for a short period of time or it was given continuously during maintenance as well.
If progression occurs while receiving CD-38 therapy, then CD-38 therapy is off the table.
If progression occurred while being off CD-38 therapy for several years, it can still be used, although efficacy might not be the same as some mechanisms of resistance may have developed given past exposure.
If the disease is refractory to Dara, then it is unlikely to respond to Isatuximab
There is some data that shows rechallenging patients who were previously on CD-38 therapy with a CD-38 containing combination therapy (2 or 3 drug regimen) may have some activity
There are limitations to this – how much is reusing the monoclonal actually adding?
In patients who are just on Revlimid (not on Dara) and they relapsed, how long is Dara-KD continued?
Again, no data available.
Carfilzomib has more toxicity than Dara, so it dropped first (usually about a year of therapy).
Also, the frequency drops for Dara (every week for first 2 months, every other week for next 2 months, 6 months beyond it’s once a month).So can continue Dara for longer periods.
Dose of steroids is reduced aggressively.
When to use Venetoclax in relapse/refractory myeloma with t(11;14)?
It is useful but not a cure for t(11;14)
Less commonly used at first relapse. Can be used as later line of therapy.
Considerations while using Venetolax:
Antimicrobial prophylaxis should be used
Watching IgG levels, considering IVIG
When to use VDT-PACE in patients with Myeloma?
When there is significant extramedullary disease burden and urgent cytoreduction is needed.
It can help debulk the disease but the responses are short lived.
It should be used as a bridge to some long term treatment like transplant or cellular therapy.
When to use VDT-PACE in patients with Myeloma?
When there is significant extramedullary disease burden and urgent cytoreduction is needed.
It can help debulk the disease but the responses are short lived.
It should be used as a bridge to some long term treatment like transplant or cellular therapy.
How promising is CAR-T (cellular therapy)?
Long waiting list.
About 2 months waiting period from collection to delivery of cells.
Selection filter: people with most aggressive disease die.
For those who make it to CAR-T, the data is promising.
Cilta-cel: PFS is not reached at 26 months of follow up!
Ide-cel: PFS is <1 year, so underwhelming!
Bispecifics (not CAR-T!) are able to be used faster since off the shelf, but increased risk of infections
There is a highly anticipated trial being run in Europe which compares with Dara VRD followed by transplant vs Dara VRD followed by Cilta-cel.
Treatment related mortality is higher in CAR-T as compared to autotransplant in relapse/refractory settings.
How useful is Selinexor in the treatment of relapse/refractory disease?
When used at a lower dose once a week dosing, it has less toxicity than was described in the initial studies.
Very limited role in multiply relapsed setting if the patient is willing to undergo treatment despite all the toxicities.
Despite all its flaws, BOSTON trial was able to show that progression free survival was better (3.5-4 months PFS improvement) in Selinexor+Velcade+Dex than Velcade+Dex alone.
Bridging strategies:
Observation: If disease is stable enough that they can wait a few weeks, then no bridging is required.
If somebody was responsive to previous treatment, then that treatment can be continued.
In alkylator naive patients, Cyclophosphamide based regimen can be given for a short period.
Dex can also be used sometimes.
About our guests:
Dr. Manni Mohyuddin is an Assistant Professor at the Huntsman Cancer Institute at the University of Utah specializing in the treatment of multiple myeloma. Dr. Mohyuddin completed his medical training Aga Khan University (Pakistan), after which he completed his internal medicine training, Chief Residency, and Hematology/Oncology fellowship at Kansas University Medical Center where he served as Chief Resident. Dr. Mohyuddin is an absolute ROCKSTAR despite starting his career as an attending just a few years back.
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
References:
GRIFFIN trial: https://doi.org/10.1182/blood.2020005288 : Dara VRD for transplant eligible patients.
ENDURANCE trial: https://doi.org/10.1016/S1470-2045(20)30452-6 Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation.
CLARION trial: https://doi.org/10.1182/blood-2018-09-874396. Carfilzomib+ Malphalan+ Prednisone vs Velcade+ Malphalan+Prednisone in transplant ineligible population. Did not show any benefit of Carfilzomib to Velcade.
FORTE trial: https://doi.org/10.1016/S1470-2045(21)00535-0 shows that you can also get PFS advantage in Myeloma by augmenting Revlimid maintenance with Carfilzomib
https://doi.org/10.1002/cncr.34211 Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials. Chakraborty et al.
POLLUX trial: http://creativecommons.org/licenses/by-nc-nd/4.0/ Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial
CANDOR trial: https://doi.org/10.1016/S0140-6736(20)30734-0 Dara-Carfilzomib+Dexa in patients with relpased or refractory MM.
IKEMA trial:https://doi.org/10.1016/S0140-6736(21)00592-4 Isatuximab+Carfilzomin+Dexa improved survival in relapsed MM.
APOLLO trial: https://doi.org/10.1016/S1470-2045(21)00128-5 Dara+Pomalidomide+Dexa vs Pom+Dex alone improved survival.
ICARIA trial: https://doi.org/10.1016/s0140-6736(19)32556-5 Isatuximab+Pom+Dexa improved survival in relapse/refractory MM.
BOSTON trial: https://doi.org/10.1016/S0140-6736(20)32292-3 shows progression free survival was better in Selinexor Velcade Dex than Velcade Dex.
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Ronak Mistry, Vivek Patel
Shownotes: Maria Khan, Ronak Mistry
Graphics, social media management: Ronak Mistry
