Episode 153: Myeloma Capstone, Pt 2 - MRD-Guided Therapy, Maintenance, and Relapsed/Refractory Sequencing
This week, we kick off the first of our myeloma capstone roundtable discussions with two experts who treat myeloma every single day. We welcome back Dr. Manni Mohyuddin from the Huntsman Cancer Institute at the University of Utah, and introduce a new friend of the show, Dr. Adeel Khan from UT Southwestern. In part two, we cover three practical and rapidly evolving topics: the role of MRD testing in guiding treatment decisions, how to individualize maintenance therapy in 2026, and how to approach sequencing of CAR-T and bispecific therapies in the relapsed/refractory setting.
In this week’s show notes, we summarize the key thoughts about how our experts think about approach to their patients.
If you have not already done so, be sure to check out Part 1 of this discussion!
This episode is brought to you by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here! As a special bonus, one of our guests, Dr. Mohyuddin, is an expert on Primum ready for your questions.
How do you incorporate MRD testing into your clinical practice, and would you ever consider stopping treatment based on MRD status?
MRD testing has become standard in clinical trials and is increasingly requested by patients; check it at every bone marrow biopsy opportunity unless overt disease makes it uninformative
Key time points to assess MRD:
After induction, particularly when making a transplant or CAR-T decision
Post-transplant to assess depth of response.
At least one year after achieving MRD negativity, to evaluate durability
Important caveat: most trial data used 10⁻⁵ sensitivity, while modern clinical practice uses 10⁻⁶ – a deeper threshold that will yield lower MRD-negativity rates than reported in older trials
Practical applications of MRD in decision-making:
MRD negativity after induction can prompt a meaningful discussion about whether transplant will add further benefit
MRD negativity at critical junctures supports de-escalating treatment, particularly in patients on doublet maintenance (e.g., dara + lenalidomide) who wish to reduce treatment burden
Relevant trials: MIDAS (MRD-guided transplant decision) and the ongoing MRD2STOP study
How many cycles of induction do you give before checking MRD, and when do you use sustained MRD negativity to de-escalate maintenance?
Cycle length before first MRD assessment:
The longer the induction, the more fully the treatment effect is captured before making a transplant decision
MIDAS trial used 6 cycles of quad therapy before MRD-guided transplant decisions
MRD-negativity rates seen in MIDAS are not replicated with standard dara-VRd – 6 to 8 cycles of quad induction are preferred before using MRD to guide a transplant decision
CASSIOPEIA and GRIFFIN established the 4- and 6-cycle induction frameworks; the American approach of moving 2 consolidation cycles upfront has made 6 cycles the predominant standard
Stopping maintenance based on sustained MRD negativity:
The most mature data comes from a Spanish randomized trial of ixazomib + Revlimid vs. Revlimid alone in maintenance – the primary endpoint was negative, but the stopping rule is the lasting legacy
Patients who were MRD-negative at 10⁻⁶ for two full years of maintenance had treatment stopped; 4-year PFS from that stopping point was approximately 83%
MRD-positive patients kept on Revlimid had a 4-year PFS of approximately 50%
In practice: maintenance is routinely stopped at the 2-year MRD-negativity mark for standard-risk disease
High-risk disease is less clear – anecdotal experience suggests some patients with 2+ high-risk cytogenetic features may relapse within ~1 year of stopping even at the 3-year mark; the jury is still out
Future direction: trials should test stopping even earlier (e.g., 6 months after achieving MRD negativity) for standard-risk patients
How do you individualize maintenance therapy in 2026?
A one-size-fits-all maintenance approach does not work – but that is what trials are necessarily forced to use
Context matters: maintenance data comes from an era of less effective induction and fewer relapse options; the OS benefit of Revlimid maintenance is unlikely to hold in the modern treatment landscape
Dara-len doublet maintenance (supported by the AURIGA trial):
Preferred for patients who did not receive a stem cell transplant, and for those with high-risk disease
Lenalidomide concerns in the long run include secondary primary malignancy risk and tolerability
Daratumumab is generally well tolerated; AURIGA provided maintenance-space support
Single-agent Revlimid maintenance:
Still appropriate for standard-risk patients who achieved a good response and underwent stem cell transplant
Overall survival benefit from the historical meta-analysis is acknowledged, but its applicability in 2026 is increasingly questioned
High-risk disease: regardless of approach (MASTER strategy of stopping vs. continued dara-Revlimid per GRIFFIN), the 3-year relapse risk for patients with 2+ high-risk cytogenetic abnormalities remains approximately 50% – acknowledging this, dara-len doublet is the preferred approach for high-risk patients
The importance of preserving drug sensitivity: avoiding overexposure to agents like daratumumab in the maintenance space may preserve efficacy at relapse, when options like dara-tec will be needed
Financial toxicity is real: even generic lenalidomide remains prohibitively expensive for many patients; for those who truly cannot afford it, watchful waiting is a reasonable, guideline-informed conversation
What is on the horizon for maintenance therapy, and how will the CELMoD agents change practice?
CELMoDs (e.g., iberdomide, mezigdomide) represent the next generation of IMiD-class agents with enhanced potency
Iberdomide is anticipated for approval based on the EXCALIBER data, potentially as soon as late 2025/2026; maintenance trials are ongoing for both iberdomide and mezigdomide
The era of giving a single maintenance drug indefinitely (as with Revlimid) is likely ending – the field needs trial data rather than convention to guide these decisions
Financial considerations will remain central: as new agents enter the market, cost and access will continue to shape real-world maintenance decisions
For a patient at first relapse, how do you sequence BCMA-directed therapy?
(Example: 55-year-old with standard-risk IgG kappa myeloma post D-RVd and auto-transplant, now with biochemical relapse and new lytic lesions)
Three randomized trials now show an overall survival advantage for BCMA-directed therapy over daratumumab-based triplets at first relapse:
Belantamab mafodotin (DREAMM-7)
Teclistamab – MajesTEC-3 (dara-tec combination)
Cilta-cel – CARTITUDE-4
Belantamab mafodotin: inconvenient, toxic, and uncertain downstream impact on other therapies – generally not a preferred first choice
Cilta-cel vs. teclistamab:
Teclistamab (MajesTEC-3 / dara-tec): 3-year PFS ~83%; patient population was less heavily pretreated – 0% dara-refractory, ~5% dara-exposed
Cilta-cel (CARTITUDE-4): ~30-month PFS ~59%; population included ~23% dara-refractory patients, higher rates of lenalidomide and PI refractoriness
Remember! Direct cross-trial comparison is a sin – the populations are different, conclusions can’t be assumed to transfer
Practical decision framework:
Daratumumab-naive / daratumumab-sensitive patient: dara-tec (dara + teclistamab) is preferred – strong efficacy and more predictable safety profile; ideally used for finite duration
Young, high-risk patient with aggressive/rapidly progressive disease (e.g., blasted through induction and auto): cilta-cel's extra potency may be more impactful; CARTITUDE-4 data better fits this population
Dara- and lenalidomide-refractory patient with early relapse post-transplant: as of early 2026, narrowly favor cilta-cel – though MajesTEC-9 data (expected mid-2026) may shift this calculus
Pure biochemical relapse many years post-transplant without organ damage: observation remains a valid option
Lytic lesions on imaging: treat; don't watch
This is a rapidly evolving space – MajesTEC-7 (frontline teclistamab), MajesTEC-9, and IMS/ASH/ASCO/EHA conferences will continue to redefine sequencing every 6 months
If you choose CAR-T cell therapy, how do you approach bridging therapy and apheresis timing?
Bridging options:
KPd (carfilzomib + pomalidomide + dexamethasone) remains an appropriate and commonly used bridge
Talquetamab (GPRC5D-directed bispecific): dramatically lowers disease burden within 1-2 cycles; best used before significant skin/nail/oral toxicities accumulate (typically after ~2 months of therapy)
Cytotoxic chemotherapy (e.g., for extramedullary disease): consider collecting CAR-T cells before initiating if at all possible
PACE-style regimens are generally not ideal in the modern era given risk of depleting the CD3 T-cell pool needed for CAR-T efficacy
Apheresis timing is critical:
Apheresis should be performed before giving talquetamab or cytotoxic chemotherapy whenever possible – T-cell engaging therapies increase the risk of an out-of-spec product
If talquetamab must be given first: achieve deep response, hold therapy for at least 4 weeks, then attempt re-collection
With chemotherapy: collection around the time of count recovery is often feasible, though not ideal
Cytotoxic agents can deplete the CD3 cascade needed for effective CAR-T manufacturing – the immune system must be relatively intact for T-cell-redirecting therapy to take hold
Lines-of-therapy navigation: a little finagling around the definition of a line of therapy can sometimes get a patient to the required 4th line for talquetamab access – steroid pulses, prior radiation, etc. can count
Cilta-cel is unequivocally safer when administered at a time of low disease burden – whether it is more effective in this setting is harder to establish given confounding in retrospective data
This episode is brought to you by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here! As a special bonus, one of our guests, Dr. Mohyuddin, is an expert on Primum ready for your questions.
About our Guests
Dr. Manni Mohyuddin
Assistant Professor at the Huntsman Cancer Institute at the University of Utah, where he specializes in the treatment of plasma cell dyscrasias. He is a returning guest of the show and has contributed to the myeloma literature, including a commentary on the AQUILA trial published in AJH.
Dr. Adeel Khan
Assistant Professor in the Department of Internal Medicine and the Department of Public Health at UT Southwestern Medical Center, where he focuses on the management of multiple myeloma and related conditions.
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: Daniel Hausrath, Ronak Mistry
Graphics, social media management: Ronak Mistry
