Episode 046: Myeloma Series, Pt.7- Autologous Transplant in Multiple Myeloma
In this continuation of our myeloma series, we discuss all the key principles and data surrounding autologous stem cell transplant in myeloma. We provide a succinct summary of key trials in this space that will give you a deep understanding of the field.
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
First we want to define cooperative groups which are commonly referenced in many myeloma trials particularly in transplant and maintenance:
IFM = French
PETHEMA = Italian
GIMEMA (GEM) = Spanish
HOVON = Dutch and Belgium
GMMG = German
ECOG, SWOG, CALGB = United States
Essential historical context before getting into current data:
Historically, patients got induction combination cytotoxic chemotherapy with vincristine + doxorubicin + dex (VAD) prior to transplant
Numerous historical studies showed the benefit of high dose melphalan followed by autologous stem cell rescue after this induction chemotherapy
Some studies looked at efficacy one transplant
Some studies looked at two transplants: “tandem transplant”
Patients would get melphalan + transplant → recovery (~1-2 month) → another dose of melphalan + transplant
Idea that this would lead to a deep, durable response
As we discussed last week, we improved induction with the doublet combinations of IMID (thalidomide or revlimid) + dex and PI (velcade) + dex
Led to improved efficacy and toxicity
Ultimately, we progressed to the triplet VRD as standard of care based on SWOG 0777 trial
We then questioned the role of high dose chemotherapy followed by transplant in the modern era of effective induction regimens, maintenance therapy, and relapse treatment options.
We thought that patients may achieve deep durable responses with VRD induction followed by VRD consolidation and revlimid maintenance mitigating the need for up front high dose melphalan followed by transplant
This led to these two key trials in the modern era
IFM 2009 trial…what did it show and why do people call it early vs. delayed transplant in myeloma?
Run by the French cooperative group
All patients got RVD induction x 3 cycles
Then randomized 1:1 to
Group A: transplant followed by 2 cycles of RVD vs.
Group B: 5 cycles of RVD consolidation
All then went on to revlimid maintenance x 1 year
Important to note that all patients had stem cells collected regardless of randomization
Primary endpoint: PFS
Included a total of 700 patients
Found PFS benefit but no OS benefit
8 year PFS: 35% vs. 23% → ~10% better PFS
8 year OS: ~60% in both groups
77% in the no up front transplant group got transplant at relapse
Better median second PFS in the no up front transplant group at 36 months compared to 25 months
Key takeaway:
Really this a trial of early vs. delayed transplant and showed PFS1 benefit but no OS benefit
35% of patients at 8 year follow up were still in remission off treatment → essentially 6 years of nothing (remember only 1 year of maintenance) which is 10% higher than the group who did not get up front transplant
This gave us insight into the idea that a subset of these myeloma patients likely reach an operational cure with a durable treatment free remission
What did patients get in relapsed or refractory disease in IFM2009? Was MRD assessment performed?
Only ~4% of patients got dara or carfilzomib at relapse and evenly distributed between the two groups so the results are not confounded
MRD negative was assessed after 1 year of maintenance
Those who were MRD negative had better PFS and OS regardless of which arm the patient was assigned which further supports the prognostic significance of MRD
More MRD negative in the early transplant arm (30% vs. 20%) and this interestingly did not translate into OS benefit but did correlate with a PFS benefit
Caveat was MRD here was done by flow with sensitivity of 10-4 and this was one time point of MRD, not sustained MRD which is key
Sustained MRD, as we will show you in our maintenance episode, is a better surrogate marker than one time point of MRD
What about the other key trial in transplant called DETERMINATION?
Run in parallel to IFM 2009 in the United States
Similar treatment paradigm as IFM2009 except revlimid maintenance was continued until disease progression and key thing to note is fewer patients got transplant at relapse
All got 3 cycles VRD then randomize 1:1
Group A: melphalan + transplant followed by 2 cycles VRD vs.
Group B: 5 cycles VRD consolidation
All got revlimid maintenance until disease progression or unacceptable toxicity
Primary endpoint: PFS
Included 873 patients
20% were high risk disease
Median PFS 67 months vs. 46 months
This was notably ~20 months longer in both arms compared to IFM 2009 (median PFS 50 months vs. 26 months) suggesting that continuous revlimid maintenance improves outcomes over 1 year of fixed duration maintenance
Big caveat → cross trial comparisons have significant limitations but this does inform our standard of care for revlimid maintenance until progression
We will go into more details on maintenance in the next episode
Key Takeaways:
No difference in OS despite PFS benefit in this trial where a more limited number of patients got transplant at relapse compared to IFM 2009
Continuous revlimid maintenance appears to produce numerically longer PFS compared to fixed one year duration
Interestingly with median of over 6 years of follow up, only a little over a quarter (28%) got transplant at relapse in the no transplant arm
This finding illustrates the great efficacy of novel agents in relapsed setting and really puts into question the need for early transplant for all patients
What did patients get in relapsed or refractory disease in DETERMINATION? Was MRD assessment performed?
About 10-20% of patients got daratumumab for both arms in this trial which does raise the question of the need for early transplant vs. delayed transplant if more patients get daratumumab at relapse
Only 28% of patients got transplant at relapse in the no up front transplant group
MRD negative was assessed by NGS at 10-5
Those who were MRD negative had better PFS and OS regardless of treatment arm
MRD negative was ~15% higher in transplant group at the start of maintenance (54% vs. 40%) which translated into PFS benefit but not an OS benefit
Sustained MRD was not reported which could provide better information
Why does PFS matter and what is the argument for early transplant if there is no OS benefit?
PFS can mean that a patient doesn’t have to worry about their disease, stay away from the infusion center, have less doctors visits, and have a better quality of life overall
Each subsequent relapse in MM has shorter PFS likely due to selection of more resistant clones and clonal evolution
Many people believe that there is an “operational cure” for patients that can really only be achieved probably during the first attempt at treatment
Operational cure means a long, treatment free remission or remission on minimal treatment like revlimid maintenance
This can be shown by the fact that 35% of people who got transplant were not on treatment at 8 years of follow up in the IFM 2009 study
Remember that this is with only 1 year of revlimid maintenance
This is a 10% absolute increase from the control group which is huge in cancer medicine → think about adjuvant chemotherapy in NSCLC with the LACE pooled analysis showing a 5% OS gain
So here we have a 10% gain in patients off treatment for a long period of time
Ok interesting but what is the argument for delaying transplant?
The idea of operational cure is very intriguing; however, we don’t know if we could achieve that same success with delayed transplant in the era of daratumumab based salvage regimens
There is still a good fraction of patients in IFM 2009 who were progression free at 8 years of followup, off treatment, and did not ever have transplant
We should start looking at quality of life through PFS1 and PFS2 and powering for the PFS2 endpoint
Notable that quality of life was no different overall in the DETERMINATION trial (other than worse in the transplant arm during the time of the transplant period) but this was only looked at for 3 years
Also there was similar survival benefit even though few patients got daratumumab in subsequent therapy on the trial (~10-20%) so increased use of these agents at relapse may further support the idea that we may be able to forgo transplant entirely in select patients which we may see using MRD risk adaptive algorithms in the future
One could argue that historically in myeloma, more targeted less toxic approaches have been found to be better than more toxic approaches
How do we approach transplant for high risk patients in myeloma and why do guidelines suggest considering tandem transplant?
We have discussed that a change of induction regimen is reasonable:
Consider KRD or quadruplet daratumumab based regimen
Many myeloma experts believe that maintaining the remission is key and as a result a change in maintenance approach is important which will be discussed in the next episode
Tandem transplant is an option for high risk patients in myeloma based on some weak evidence
What is a summary of the data for tandem transplant for high risk patients?
Historical perspective for tandem transplant:
The mantra in the history of oncology is generally more is better which often doesn’t work out
In the mid 90’s the IFM group did a randomized trial looking at single vs. double transplant and found benefit for double transplant particularly for those who did not get to VGPR or better after one transplant
This was done for patients who got the inferior Vincristine + doxorubicin + dex induction and interferon maintenance so unclear if this was necessary with modern agents
This and other studies led eventually to the modern STAMINA trial
STAMINA Trial - Important for fellows
United States study
Included patients who got 2-12 months of induction therapy with mainly RVD but some CyBorD (remember RVD is superior)
All patients got a transplant and then we looked at should we consolidate with a second transplant vs. cycles of RVD consolidation vs. nothing and everybody went on to revlimid maintenance
Randomized 1:1:1
Tandem transplant followed by revlimid maintenance
Singe transplant followed by RVD x 4 consolidation followed by revlimid maintenance
Single transplant followed by revlimid maintenance without consolidation
Key Takeaways:
No improvement in PFS or OS for the more intensive approaches compared to single transplant followed by revlimid maintenance
This is essentially why our current standard of care is a single transplant and not tandem
Results contrasted with a European study (linked in references):
This study was complicated but it suggested tandem superior and driven mainly by high risk
Several limitations to this study including the fact that everybody in that trial got CyBorD induction x 4 cycles instead of RVD induction which we knew would be inferior especially for high risk patients
Difficult to draw reliable conclusions because of inferior induction approach with the idea that RVD likely mitigates the need for a second transplant based on the results of the STAMINA trial
So it seems like there’s minimal benefit to doing tandem transplant based on that data but why is it in the guidelines for high risk?
European trial did show benefit even though hard to draw conclusions with the CyBorD induction approach but technically this result would support tandem approach
If you look at those who actually got a second transplant in the STAMINA trial, then there is a significant PFS benefit compared to single transplant for high risk subgroup
Issue is this is a “per protocol analysis” and selecting for patients who likely have better disease biology and performance status introducing a lot of bias
Not appropriately powered to make conclusions
It is only a suggestion to consider tandem but as we have discussed there is no high quality trial level evidence that supports this especially given the intention to treat results in the STAMINA trial
Majority of providers do not routinely perform tandem transplant in high risk and believe the key is to get the job done in the maintenance setting
References:
https://www.nejm.org/doi/full/10.1056/NEJMoa1611750: IFM 2009 trial showing PFS but no OS benefit for early vs. delayed transplant
https://ashpublications.org/blood/article/136/Supplement%201/39/470028/Early-Versus-Late-Autologous-Stem-Cell-Transplant: Long term follow up of IFM 2009 trial
https://www.nejm.org/doi/full/10.1056/NEJMoa2204925: DETERMINATION trial showing PFS but no OS benefit for early transplant
https://ascopubs.org/doi/full/10.1200/JCO.18.00685?role=tab: STAMINA trial showing no benefit of tandem transplant vs. single transplant
https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.8506: Updated STAMINA results showing the per protocol analysis which has several limitations
https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30099-5/fulltext: Complex trial with key limitations including inferior induction regimen that suggested benefit of tandem transplant vs. single transplant particularly for high risk subgroup
This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Vivek Patel
Shownotes: Vivek Patel
Graphics, social media management: Ronak Mistry
