One of the most relevant sessions for those interested in smoldering myeloma was a Spotlight Session called “Smoldering Myeloma: A Case for Early Intervention?” presented by Maria-Victoria Mateos, MD, PhD, and Karthik Ramasamy, MD, PhD. The seventy-five-minute session featured a two-sided debate on whether early intervention is appropriate for smoldering myeloma. Dr. Mateos argued in favor of early intervention, while Dr. Ramasamy presented the opposing perspective.
Before presenting their arguments, important points about diagnosing and monitoring SMM were emphasized:
Rule out other conditions: Diseases like diabetes, hypertension, and vitamin deficiencies can mimic signs of myeloma.
Confirm the diagnosis: Doctors should check for the presence of the M-protein. They should also ensure there is no anemia, kidney issues, or high calcium levels, and repeat these tests at least once to confirm stability.
Conduct a full evaluation: Tests like free light chain (FLC) assessment, MRI, and bone marrow biopsy help ensure no active myeloma-defining events (MDEs) are present.
Assessing the risk of SMM progressing to active myeloma is critical for providing the right care. Risk models estimate the chance of progression, typically identifying patients with a 50% risk of developing myeloma within two years. Ideal models combine clinical, biological, and dynamic markers. Examples include:
The Pethema model
Bence Jones proteinuria (protein in urine)
Evolving M-spike patterns or changes in M-spike and hemoglobin levels
PET-CT imaging
The PANGEA model
(Note: The “20-2-20” model, widely used in the U.S., was not presented.)
Dr. Mateos began with the question, “Smoldering Myeloma: A case for early intervention?” Her position was clear: early treatment offers the best chance to cure myeloma. However, she noted that “cure” must be carefully defined. She referenced a 1963 definition of cure: after a decade or two, patients are disease-free and have a similar life expectancy to the general population.
She outlined the challenges of achieving a cure:
Myeloma is a complex and diverse disease, not a single condition.
Treatment should be personalized: frail patients or those with high-risk features need different approaches than fit, low-risk, or asymptomatic individuals.
Dr. Mateos supported her argument with studies showing promising results for early treatment:
Aquila study
GEM-CESAR trial
ASCENT trial
Immuno-PRISM and CAR-PRISM studies
She concluded:
Results from these studies are encouraging, but they need longer follow-up to confirm if early treatment leads to a lasting cure.
Treating high-risk SMM (HR-SMM) with therapies used in active myeloma may offer a curative option.
Patients with newly diagnosed myeloma (NDMM) and no high-risk features may also achieve cure-like outcomes.
A key point here is that the main difference between HR-SMM and NDMM is the absence of myeloma-defining events (MDEs) in HRSMM.
Dr. Ramasamy countered Dr. Mateos’ position by stating: “Early intervention only adds costs and toxicity unless we treat the right patient, at the right time, with the right goal.”
He highlighted the complexities of SMM:
Myeloma remains incurable despite advances.
SMM is a heterogeneous disease—not all patients progress in the same way.
Patients have different priorities and expectations for treatment.
Effective therapies already exist to treat active myeloma, and earlier use can be studied further.
SMM is a large population—how many patients would truly benefit from early treatment?
Dr. Ramasamy then asked: “Under what conditions is early intervention valid?” He proposed five criteria:
SMM cells are sensitive to treatment.
Treatment happens before the disease evolves further.
Treatment is tailored to individual patients.
Early intervention prevents life-altering complications during monitoring.
Early treatment improves survival.
He compared SMM and NDMM studies to examine treatment response:
In transplant-eligible patients, response rates (VGPR or better) were similar for SMM and NDMM.
In transplant-ineligible patients, NDMM studies showed better responses than SMM studies.
Dr. Ramasamy then laid out the pros and cons of treatment approaches in SMM. The following table is a reproduction of one of his slides:
Prevent/Delay Active Myeloma
Functionality Cure Myeloma
Pros
Low-intensity approach Relatively fewer side effects Applicable to the majority of SMM patients
High potential for treatment-free period Deep responses
Cons
May require further therapy Lower response rate Lack of deep responses
High-intensity approach Higher risk of adverse events Applicable for a smaller proportion of patients Risk of multidrug resistant clones
Dr. Ramasamy pointed out challenges with current SMM trials:
Changing definitions of high-risk SMM (HRSMM) and NDMM complicate results (e.g., SLiM CRAB criteria, Mayo “20-2-20,” and IMWG criteria).
Lack of survival data: Only the DETER-SMM trial measures overall survival as an outcome.
Toxicity concerns: Some trials report side effects and reduced quality of life for patients receiving early treatment.
Dr. Ramasamy suggested next steps:
Better monitoring tools: Improve risk models, use whole-body MRI for imaging, and follow care standards.
Patient involvement: Include patient preferences in research, explore barriers to treatment, and set toxicity limits in trials.
Refine treatment approaches: Develop personalized treatments tailored to individual patients.
Cost-effective therapies: Recognize the financial burden on patients, including treatment costs, managing side effects, and lost productivity.
Dr. Ramasamy’s final points included the following:
Enhance monitoring tools alongside early treatment models.
Prioritize patient involvement in research.
Focus early treatment trials on patients at the highest risk of progression.
Design trials to reduce short- and long-term side effects.
Develop affordable treatment strategies to maximize accessibility.
Conclusion
The debate between Drs. Mateos and Ramasamy highlighted the uncertainties surrounding early intervention for SMM. Mateos argued that early treatment offers hope for a cure, especially for high-risk patients, while Ramasamy emphasized caution, patient priorities, and the need for refined, cost-effective approaches.
For those with SMM, it’s essential to carefully consider the risks and benefits of early treatment. Discuss all options with your doctor, evaluate your personal risk tolerance, and consider your long-term goals before making a decision. Research is advancing, but there are still more questions than answers in this complex space.
I am traveling today and then a very busy treatment day, so I’m going to do a quick post-ASH blog. Yet, if you want to hear more in-depth, check back because I promise another blog within a week.
First off, one of my fellow patients who follows me asked, “it must be hard listening to all this information.” Honestly, it was not; it was encouraging and hopeful. As I’ve mentioned before, my Myeloma Specialist told me on my first visit; “The longer I keep you alive, the longer I can keep you alive.” That sentiment stayed with me throughout ASH. It was palpable as I listened to the latest research and advances in treatment…hopeful progress everywhere!
It was heartening to see how dedicated these physicians and scientists are. So many brilliant minds sharing, questioning, and learning from each other! Sure, at times I felt like they were talking about me and us, but I’ve long come to terms with the reality of living with a serious disease. I follow that up with: I have these incredibly serious people working on controlling, and ultimately, curing it! That gives me hope, and that’s what keeps me going.
I’d also like to reiterate another mantra of mine here; see a Multiple Myeloma (MM) Specialist—it really matters!
Okay, Days 2 & 3 Quick Synopsis
Dara, Dara, Dara, Isa!
It is a big deal when a treatment changes the standard of care, and the anti-CD38 antibodies have done just that! Quadruplet therapy as a standard of care in induction therapy has shown amazing results! Even more exciting? Darzalex (daratumumab) has also been shown to prolong progression-free survival (PFS) when used in maintenance therapy. But…wait…there’s more!
Dara is showing incredible promise in high-risk smoldering multiple myeloma (HR SMM). And although Dara took up a lot of space, Sarclisa (isatuximab) showed promising results in induction therapy as well! Isa “might” change the microenvironment, which “might” slow down the rate of progression. It will be interesting to see if this theory plays out and how it plays out!
Next up: Bispecific Antibodies!
Tecvayli (teclistamab) took the center stage in a phase two study, showing promise in induction therapy as both a safe and highly effective treatment. On to phase 3, but it looks very promising. All evaluable patients achieved Minimal Residual Disease (MRD) negativity during maintenance. Patient note: Here’s where the hope keeps sneaking back in!!
Teclistamab is also being looked at in maintenance therapy and early results are positive as well as relapsed/refractory multiple myeloma (RRMM). Elrexfio (elranatamab), Kyprolis (carfilzomib) with dexamethasone are being studied as well.
SO much in the pipeline for Bispecific Antibodies! AND…as if that weren’t enough a bispecific antibody with a new target, Cevostamab is being studied in a phase one clinical trial in heavily pretreated patients and has shown meaningful activity and manageable safety in this patient population at the 160mg TD level given once every 3 weeks.
Studies with Talvey (talquetamab) and Blenrep (belantamab mafodotin) are also showing promise. Though they are sometimes considered harder to tolerate due to the negative side effects, there’s good news here: With adjustments in timing and dosage, these treatments are still effective in managing disease while keeping side effects under control.
New on the scene is Etentamig (also known as ABBV-383), a monthly dosed bispecific antibody. Early studies are promising, and it’s definitely one to watch. I personally was intrigued by its binding domain and its potential to mitigate cytokine release syndrome (CRS) More to come!
Smoldering Multiple Myeloma (SMM): New Hope on the Horizon
When a person has smoldering multiple myeloma and their myeloma is growing, doctors often consider this a “watch and wait” situation. This can be stressful and anxiety-inducing for patients, but the AQUILA study offers hope. It shows that treatment with Dara can extend time before active treatment is required in the high-risk SMM population.
Frailty
Research was presented that looked into the following: reduced dosing, decreased dexamethasone, and clinical trials including older patients. More to come on that, but I will say Darzalex (daratumumab), Revlimid (lenalidomide), or DR outperformed Revilimid (Lenalidomide) and dexamethasone (Rd) in the frail population…down with Dex!!
I’ll stop here for now with the promise to return and further clarify. I hope to share more information once I stop long enough to look at my notes and absorb the immense amount of information I took in over the past three to four days! This is by NO MEANS a comprehensive review; it’s just what caught my attention. Again, I remind all who are reading, this is the takeaway from me…a humble fellow MM patient, and it is how I personally understood the information presented! I hope it gives you a good starting point to delve deeper into the information yourself and discuss what you find with your care team.
It’s exciting to see all this research across the spectrum of treatment lines. It is a non-ending quest for better, safer, and more effective treatment of MM. I was humbled and honored to be a part of the IMF team, and this nerd can’t wait to look at a few of the presentations I did not get to attend! I did have a focus on High-Risk Multiple Myeloma (HRMM), but I did not find much discussion on this. Yet, many studies did include high-risk patients. I will delve deeper in the coming days and share what I find.
That’s it for now! I’ll be back soon with a more detailed post on what I’ve learned from ASH. Thanks for following along and remember: There is always hope! Stay strong, keep fighting, and always reach out to your specialist and team with any questions you may have! They are working every day for us!
HOPE
Hardworking MM specialists and oncologists.
Optimism SO much research for newly diagnosed and those exposed to many lines.
Patients…the center of it all!
Energy! That is what I saw most at ASH an uncontainable energy to do more, know more, help more!
The theme so far on this last day of #ASH is to treat or not to treat these conditions. Most have heard of the iStopMM study ongoing in Iceland. They invited adults in Iceland who were born before 1975 or earlier to participate in this study to detect the incidence of multiple myeloma in a large population. 148,704 people were offered participation, and in the first month, 50,000 Icelanders signed up. 80,759 in total signed up during the enrollment period, and 75,422 had their blood samples collected. I’m still boggled by the generosity of over half of the target population of Icelandic people willingly signed up to selflessly give of themselves to help the rest of the world. You can read all about the study at https://istopmm.com/
Conclusion: “In this study evaluating the presence of clonal plasma cells in bone marrow samples from IgA and IgG individuals by next-generation flow cytometry, we detected clonal plasma cells more frequently in samples from individuals with IgA MGUS compared to IgG. Additionally, the absence of clonal plasma cells correlated with a higher frequency of transient M protein and an absence of disease progression. These findings provide biological insight into the differences between IgA and IgG MGUS, which may contribute to the lower rate of progression in IgG MGU.”
The other very interesting program was two physicians stating their case for either early intervention in smoldering multiple myeloma (SMM) or active surveillance. Dr. Mateos spoke eloquently about why she believes treatment of high-risk smoldering multiple myeloma (HR SMM) can lead to a cure. Dr. K. Ramasamy says that there are potential downsides to early treatment, along with costs and toxicities.
The DreaMM-7 trial compared bBlenrep (belatamab mafodtin), Velcade (bortezomib), and dexamethasone [BVd] versus Darzalex (daratumumab), Velcade (bortezomib) ,and dexamethasone [DVd] in relapsed refractory multiple myeloma (RRMM). There was an N of 494 patients, randomized into the two arms. I was pleased to see a study with more than the usual N of single-digit patients. The surprising news was that the BVd arm performed better than the DVd arm. The primary reason for individuals who left the study from both groups was disease progression.
The next oral abstract in the session was a multi-site (124 sites in 23 countries) study of Darzalex (daratumumab) monotherapy vs active monitoring in patients with HR SMM, the AQUILA study. The dara arm showed significant improvement in time to disease progression.
