Episode 152: Myeloma Capstone, Pt 1 - Smoldering Myeloma & Frontline Treatment in the Elderly
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 one, we tackle two highly practical topics: the AQUILA trial and its real-world implications for smoldering myeloma management, and how to approach frontline therapy in the older myeloma patient.
In this week’s show notes, we summarize the key thoughts about how our experts think about approach to their patients.
Stay tuned for part 2 of this discussion next week!
For our listeners who may need a refresher - what is the AQUILA trial, and what did it show?
Phase 3 randomized controlled trial evaluating fixed-duration daratumumab versus active surveillance in patients with high-risk smoldering myeloma
Results demonstrated an improvement in progression-free survival and an apparent improvement in overall survival
How are you applying the AQUILA data in your clinical practice, and what are its limitations?
On the surface, daratumumab improved numbers - but did it change morbidity?
The majority of progression events were asymptomatic lab changes (e.g., reaching light chain threshold of 100 or bone marrow plasma cells >60%), not clinically significant events
Anemia events were asymptomatic; median hemoglobin drop was 1.7 g/dL, with no fatigue on patient-reported outcomes and no transfusions required
Of 166 progression events, only 3 were symptomatic bone events - and 2 of those 3 occurred in the daratumumab arm
Surveillance approach in AQUILA was less rigorous than modern practice:
PET scan was optional; CT was preferred
MRI was limited to spine and pelvis, not whole-body
Modern surveillance (e.g., whole-body MRI every 6 months) would be expected to produce even better outcomes in the observation group
The overall survival benefit is difficult to extrapolate to today's patients:
Many patients on the trial who progressed received substandard therapy by current benchmarks - doublets, monotherapy, or no treatment at all
Patients today who smolder for 3-4 years will likely have access to BCMA-directed therapies when they do need treatment
Some patients died prior to receiving any treatment, raising questions about whether AL amyloidosis was rigorously screened for
The AQUILA risk definition is not the same as our modern high-risk definition:
The trial came off the heels of the phase 2 CENTAURUS trial and used a different high-risk definition than the 20-20-20 criteria used today
Factors like IgA and immunoparesis were used as high-risk criteria in AQUILA but are not part of the modern standard
A brief history of smoldering myeloma as a category:
Coined by Dr. Robert Kyle in 1980 as an intermediary state - more disease than MGUS, but without CRAB criteria
Threshold numbers (10% plasma cells, >3 g/dL M protein, >500 mg/24hr proteinuria) were chosen pragmatically/arbitrarily and don't necessarily reflect an underlying biological reality
The field has since recognized far more heterogeneity; smoldering myeloma is better understood as a spectrum
In practice, uptake of daratumumab for smoldering myeloma has been low:
Despite patient advocacy awareness, patients counseled about the data often decline treatment
Concerns about infection risk, financial toxicity, and time toxicity all factor in
Clinical trial enrollment has been more successful than daratumumab uptake off-trial
Dr. Mohyuddin’s commentary on this topic: https://onlinelibrary.wiley.com/doi/10.1002/ajh.70159
Does patient age influence your decision to recommend daratumumab for high-risk smoldering myeloma?
Age is not something the AQUILA trial was designed to address, but it does come up in practice
One scenario where daratumumab may be reasonable: the older, frailer patient with worsening labs where the concern is about eventually needing an intensive 3- or 4-drug regimen
In this context, daratumumab may "kick the can down the road" and delay or reduce the intensity of future treatment
For younger, fitter patients with clearly worsening smoldering disease, leaning toward full myeloma-type treatment is generally preferred over daratumumab alone
An important gap in our risk models: current tools (20-20-20, PANGEA 2.0) use single time-point measurements
Rate of change in M protein or disease markers over time is not captured - yet this may be one of the most clinically relevant variables
A rapidly rising M protein is a very different patient from one who has been slowly rising over a decade, even if they look identical on a risk calculator
When there is no clear right answer, there is no clear wrong answer
How do you approach frontline treatment in an older patient, for instance an 80-year-old fit male with IgG kappa myeloma?
The landscape has evolved significantly:
Older regimen: RVd-lite (attenuated triplet for tolerability)
The MAIA trial introduced daratumumab + lenalidomide + dexamethasone (DARA-Rd) as a better-tolerated standard with strong PFS outcomes
2024 data: The IMROZ trial introduced isatuximab + RVd; a similar daratumumab-based quadruplet trial has also reopened the quadruplet conversation for older patients
General approach:
Unless a patient is particularly frail, a quadruplet is worth attempting - the data supports it, and patients can often handle it initially, dropping disease burden meaningfully
For the truly frail patient: DARA-Rd (or ISA-Rd) is an excellent, well-tolerated option
If someone's poor performance status is due to the myeloma, they may actually benefit from a more intensive upfront approach to improve quality of life
The BENEFIT study isolates the contribution of the proteasome inhibitor (ISA-VRd vs. ISA-Rd):
Adding bortezomib doubles neuropathy risk (~25% → ~50%)
Doubles MRD negativity rate (~25% → ~50%)
Overall survival benefit is uncertain; post-relapse therapy options are excellent
Many older patients, when presented with this tradeoff, choose a triplet - and that is a reasonable, values-aligned decision
A CD38-based triplet is preferred over VRd not because of proven OS benefit, but because of improved tolerability
How do you think about dexamethasone use in older and frail myeloma patients?
The "down with dex" movement: minimize steroids as much as reasonably possible in this population
Practical dosing approach:
Start at 20 mg (never 40 mg); many providers use 12 mg
Begin tapering as early as cycle 3; consider stopping by cycle 6
Retrospective data supports no meaningful loss of efficacy with dose reduction
Supporting evidence:
Secondary analysis of two large SWOG trials showed ~2/3 of patients required steroid dose reductions - without any difference in outcomes compared to those who maintained full doses
The IFM-2017-03 trial evaluated stopping dexamethasone entirely after 2 months in frail patients (DARA premedication with prednisone permitted); outcomes compared favorably to the frail patient subgroup from MAIA
How do you approach Revlimid (lenalidomide) dosing in older or frail patients?
Renal function is the primary driver - always dose-adjust to creatinine clearance before anything else
The CD38 monoclonal antibody does most of the heavy lifting in terms of efficacy - and is the best-tolerated agent in our armamentarium
Practical approach for frail patients:
Consider starting with the CD38 antibody + low-dose steroids alone for the first cycle or two, then adding an IMiD
Starting lenalidomide at 5-10 mg and titrating up is preferred over starting at 25 mg and having to backtrack
In practice, 15 mg tends to be the realistic ceiling for many older/frail patients
It is equally reasonable to start at 25 mg and reduce quickly if not tolerated - the starting dose is not the destiny dose
Think of dosing as a staircase: find where the patient can start, and adjust from there
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
