Episode 149: Myeloma Series, Pt. 9 - Maintenance for Multiple Myeloma (2026)
This week, we turn our attention to what we do in the maintenance setting for management of myeloma. At this point, our patient has gone through initial therapy; for patients who are able to undergo a transplant, we have consolidated their disease with a transplant; and now, we want to maintain that response using a lower dose of therapy, all while trying to minimize toxicity and maximize the patient’s quality of life. We discuss this in detail in this week’s episode!
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Lenolidomide (revlimid) has long been the standard for maintenance therapy for patients with multiple myeloma. Where did the data to support this come from?
Based on a meta analysis (high yield!) by McCarthey et al
Combined three RCTs
CALGB trial - US
GIMEMA trial - Italy
IFM trial - French
The three prior RCTs were powered for PFS and all showed an improvement in PFS but only the CALGB study showed an OS benefit
This meta analysis was powered to find an OS benefit
7 year OS was 62% vs 50%
Increased risk of second primary hematologic and solid tumor malignancy
Hematologic: 6% in revlimid group vs. 3% in placebo group
Solid tumor: 7% in revlimid vs. 4% in placebo group
Key takeaway: Maintenance therapy provides an overall survival benefit
Now that we have quadruplet inductions, should we be giving all patients Anti-CD38 + revlimid in maintenance?
Short answer is that we really don’t know
What data do we have, though?
Randomized patients to Dara-VTD or VTD
There was a second randomization for maintenance
Daratumumab vs. placebo*
*Note that this revlimid was essential the SOC at the time
Let’s focus on the second randomization with the most recent publication at 80 months median follow up
Dara-VTD followed by dara maintenance had a barely significant PFS benefit over Dara-VTD followed by observation which makes sense because something is better than nothing but no OS advantage
Interestingly, VTD induction followed by dara maintenance had the same PFS as Dara-VTD induction followed by dara maintenance
Key Takeaway: If dara is used in induction, no difference between dara vs. placebo for maintenance. It appears that benefit can be achieved as long as the patient received dara at some point in their treatment course.
What we don’t know:
Overall survival information
How does lenolidomide fit into this
How important is dara maintenance in the modern era of effective second line regimens including CAR T cell therapy and bispecific antibody therapy
The lingering question of would it be better to retreat with dara at relapse after used in induction to have an improved PFS2
All patients got Dara-R maintenance x 2 years and then there were stopping and restarting criteria
For MRD negative patients sustained for > 12 months, patients would stop dara and continue revlimid alone with reintroduction of dara based on MRD resurgence
For MRD positive patients, everybody continued Dara-R until progression
Key Takeaway: Roughly 64% of patients came off daratumumab and continue revlimid monotherapy in maintenance given 2 years of maintenance with sustained MRD negativity
What we don’t know:
Should we use Dara-R or R maintenance after quad induction and transplant?
Risk adapted MRD approach to maintenance strategy
All patients got Dara-KRD followed by auto
They then got more Dara-KRD consolidation if they did not have sustained MRD negativity at two timepoints
Those who had MRD negativity sustained went on to observation without maintenance therapy
Key Takeaway: Results showed that standard risk patients could reasonably undergo a risk adapted MRD approach to discontinue maintenance
There was a low resurgence of MRD at 1 year off therapy in that trial
Enrolled patients who did not get dara in induction but got something like VRD x 4 cycles followed by auto
Their best response was VGPR or better but were MRD positive
200 patients were then randomized to Dara-R maintenance vs. R maintenance
There was more MRD conversion with Dara-R at 50% vs. 20%
30 month PFS rate was roughly 80% in the Dara-R arm vs. 65% in the revlimid alone arm
Key Takeaway: If patients did not get dara in upfront setting, then they should get it in maintenance
What we don’t know: What about patients who got quadruplet inductions up front?
What we learned from CASSIOPEIA and AURIGA is that as long as daratumumab is given at some point, patients do well overall. Therefore, these data strongly suggest that we should be giving daratumumab in the upfront setting.
What remains unanswered is how long daratumumab is actually needed?
What is the role of MRD testing outside of a clinical trial and what do you do with that information?
Single center trial that looked at 47 patients who were MRD negative by flow and ClonoSEQ at 10-6 sustained for > 12 months on lenalidomide maintenance
For the study, they also used a more sensitive MRD test looking at 10-7 which 80% of the study population had achieved
Lenalidomide was discontinued and they were monitored for MRD resurgence
Median time on maintenance was 3 years
Disease resurgence (MRD ≥10⁻⁶) occurred in 11 patients (23%)
However, only 5 patients (11%) had disease progression
One patient died from a second cancer (not myeloma)
Key Takeaway:
3-year PFS: 92% for MRD <10⁻⁷ vs. 49% for MRD ≥10⁻⁷ (but still were <10⁻6) (HR 10.1, p<0.001)
The deeper the remission and sustaining MRD-negativity is important
Limited by small sample size but may suggest a higher threshold for MRD stopping rules
In high-risk patients, the key to their success is maintaining remission after transplant. How should we approach maintenance therapy in these patients?
One important thing to note is the only high quality trial level evidence is the use of single agent revlimid post transplant, but we know that in general high risk patients have median PFS of only 2 years. High risk patients can get into remission but don’t stay in remission.
We don’t have the ideal evidence simply because these patients comprise a small subset of the overall enrolled population but we do have data to support dual maintenance with proteasome inhibitor + IMID in these patients
What are some of the available data for management of high risk patients?
Looked at 1000 consecutively treated patients from 2007-2016 treated with RVD induction
Patients with high risk cytogenetics got RVD maintenance after transplant
Median PFS was 40 months (little over 3 years) and OS 78 months
Significant improvement over other trials looking at single agent revlimid which showed median PFS ~2 years
Phase two trial that looked at 3 different induction triplets using second generation PI carfilzomib
KCyd x 4 + auto vs. KRD x 4 + auto vs. KRD x 4+ KRD x 4 consolidation
Then randomized to two different maintenance strategies:
KR vs. R
First randomization was powered for VGPR prior to maintenance
Second randomization was powered for PFS
Focusing on the maintenance portion:
KR vs. R maintenance had improved 3 year PFS 75% vs. 65%
For high risk subgroup, 3 year PFS ~70% vs. 55%
Key Takeaways:
Dual maintenance improved PFS
For high risk patients, dual maintenance should be used
Unanswered questions:
Does sequencing matter? I.e., can we give single agent and then start a second agent at relapse? We don’t know KR vs. R improved PFS which is expected because two drugs should be better than one drug
Notable that the single agent R arm did better than expected with median PFS ~3 years compared to 2 years in prior studies
What are the TFOC recommendations?
There are going to be institutional differences
For most patients, continue lenalidomide
For high risk patients, in the present day, the best data we have is from PERSEUS so for most high risk patients, dara + lenolidomide (not using PIs in maintenance)
Save proteosome inhibitors for relapse to bridge to other therapies
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The crew behind the magic:
Show outline: Vivek Patel, Sean Taasan, Ronak Mistry
Production and hosts: Sean Taasan, Vivek Patel, Ronak Mistry
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Graphics, social media management: Ronak Mistry
