On Tuesday, June 17, the International Myeloma Foundation (IMF) conducted its annual webinar on the 2025 IMWG Conference Series: Making Sense of Treatment.  
 

The webinar was hosted by IMF Chief Medical Officer Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO (TGen at the City of Hope — Phoenix), along with myeloma experts, IMF Nurse Leadership Board Member Beth Faiman, PhD, MSN, APRN-BC, AOCN, FAAN (Cleveland Clinic, Taussig Cancer Institute — Cleveland); and member of the IMF Scientific Advisory Board and IMF Board of Directors, Sagar Lonial, MD, FACP (Winship Cancer Institute, Emory University School of Medicine — Atlanta).  
 
In part one of this two-part series, the speakers presented on Screening for Myeloma, Smoldering Multiple Myeloma, and Frontline Therapy.  
 
Here are some of the top takeaways from the topics mentioned above. We have gathered some of the key insights from this informative and insightful webinar. (EDITOR’S NOTE: Topics of discussion and panelist views have been edited for conciseness and clarity.) 
 

Screening for Myeloma: The iStopMM Project 

The iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) Project is a massive and critical study — the first large-scale screening trial in the field of myeloma, with over 80,000 Icelanders aged 40 and above participating.  
 
The goal of the iStopMM Project is to screen Iceland’s population for the presence of monoclonal gammopathy of undetermined significance (MGUS) — the precursor state of smoldering multiple myeloma—and to assess whether early detection and follow-up can prevent disease progression, allow for early intervention and importantly prolong survival.  
 
The panelists shared their views about the iStopMM study: 
 
Dr. Mikhael: Is it worth screening for myeloma? We currently screen for cancers like breast and colon cancer—decisions that took years to validate. Now, based on early insights from the iStopMM study, we may know within the next two years whether screening for myeloma can actually save lives. 
 
In the study, individuals diagnosed with MGUS were randomized into three groups: no follow-up, guideline-based follow-up, or intensive monitoring. This large-scale effort is critical in determining whether routine screening for myeloma is justified. 
 
Biologically, we’re learning that events leading to myeloma may begin much earlier in life. Just as colon cancer screening is shaped by age, gender, and family history, similar personalized approaches may be needed for myeloma—especially considering factors like ancestry. For example, I began colon cancer screening early due to my father's diagnosis. Will we eventually do the same for people at higher risk of myeloma? 
 
These are the kinds of questions we’re exploring, and our colleagues in Iceland believe they may soon have answers.  
 
Dr. Lonial: I think the iStopMM study is going to be really important in helping us make that determination. I think from a practical perspective, the incidence of plasma cell disorders is far less frequent than breast cancer, colon cancer, or even lung cancer among smokers. However, I don't know if it's going to be a universal recommendation for everybody. But I do think that there are pockets of patients who might benefit, particularly first-degree relatives of patients who have myeloma—it may be worth considering. 
 
I think the case for screening is even stronger in Black patients with a first-degree relative who has myeloma. Unfortunately, the study doesn’t address this, as it includes only white Northern Europeans. I think we'll learn something about who may benefit from early screening, but I think the definitive answer is going to come from studies in the U.S. or Africa, specifically looking at the incidents in large populations and whether screening is justified. 
 
Dr. Mikhael: Actually, our colleagues in the IMF sponsor and support the CHAAMP study—a screening study in the Charlotte region where we’re beginning to test the feasibility of screening within the African American population. I also received a request recently from our colleagues in Africa to conduct a similar study in one of the larger countries in the region. 
 
Beth Faiman: I do appreciate that the iStopMM study is also assessing the psychological burden of screening, not just clinical outcomes. However, to Dr. Lonial’s point, the study only includes Northern Europeans, which limits its relevance to the diverse U.S. population.  
 
We conducted a small screening study in Cleveland with about 100 participants, focusing on African American and diverse populations. The MGUS incidence was around 4–6%, and while few required treatment, we did identify a couple with smoldering myeloma. 
 
More data will emerge, but for now, I recommend that first-degree relatives of myeloma patients inform their primary care providers and for providers—including internists, nurse practitioners, and physician assistants—to maintain a high level of awareness. Early recognition is key while we await data from future studies. 
 

Smoldering Multiple Myeloma (SMM): Identifying High-Risk Cases 

Multiple myeloma often begins as smoldering myeloma, and significant work has gone into identifying high-risk cases.  
 
Discussed at the IMWG Summit, the 20-2-20 model defines high-risk smoldering myeloma as having at least two of the following: 

• 20% plasma cells in the marrow 
• M-spike ≥2 g/dL 
• Free light chain ratio of involved or uninvolved light chains >20 

 
Patients with two or more of these markers are considered high-risk. This model helps place smoldering myeloma along the spectrum—with MGUS on one end, and active myeloma on the other—though definitions are still evolving. 
 
The pivotal study AQUILA trial (presented at ASH in December 2024) compared early treatment with daratumumab to close observation in high-risk smoldering patients. After five years, 63% of those treated had not progressed, versus 40% in the observation group. Active monitoring had a median time to progression of around three years, but that wasn’t yet reached in the treatment arm. 
 
The key takeaway is that early intervention may delay progression, though not necessarily prevent myeloma. This opens the door to multiple treatment strategies—some patients may benefit from early therapy, while others may do well with close observation. 
 
Dr. Mikhael: My quick take on SMM is that I really think the AQUILA trial was critical in helping us prove that we are delaying progression in the right patient, albeit not necessarily preventing myeloma. I recently had a conversation with an 83-year-old patient who said: "If this kicks the can down the road and I never have to have myeloma; I'm still golfing four times a week here in Scottsdale. I want to be able to do that. I'm not too keen on going on to full therapy, but I feel like we need to do something." For this patient, daratumumab monotherapy made sense. However, it’s not one-size-fits-all. 
 
Dr. Lonial: After surviving the ODAC meeting on Darzalex® (daratumumab) as monotherapy for high-risk SMM, I think it’s important for us to finally have something that the FDA will approve, so patients can have a potential option. I think we really need to make sure that risk stratification is happening—because it is a totally different discussion for those who have high-risk SMM as opposed to patients who are low-risk or no-risk. 
 
At the ODAC meeting, there was considerable discussion around whether the 20-2-20 model or the AQUILA criteria are the best definitions for high-risk smoldering myeloma. The control arm in the AQUILA trial showed a median time to progression of 2–3 years, aligning well with high-risk SMM patients. 
 
Daratumumab may be a reasonable option, but I still strongly encourage patients to consider clinical trials. We currently have two open, exploring whether more intensive therapy provides added benefit. 
 
Another key factor is the patient’s mindset. When I meet a new patient with intermediate or high-risk smoldering, I ask, "Does knowing something is there—but not treating it—make you anxious?" 
 
If yes, I lean toward discussing early treatment options. Others may prefer to wait, understanding that even with high-risk features, they might remain stable for years. For them, a watchful waiting approach may be more appropriate. 
 
Ultimately, the best strategy combines the patient’s perspective with clear data to guide truly individualized care. 
 
Beth Faiman: Dr. Lonial made an excellent point about the importance of shared decision-making—balancing patient preferences with clinical data to determine the best approach. 

The AQUILA study used broader criteria, particularly around the free light chain ratio, whereas I prefer the Mayo 20-2-20 model when discussing whether to treat smoldering myeloma. That said, clinical trials are essential—they’ve brought us this far, and they’re how we continue to move forward. 
 
We now have several innovative trials, including DETER-SMM — a national study available at many institutions. You may have a patient who qualifies, so it’s always worth asking if they’re open to participating. 
 
For me, a well-designed clinical trial is the first choice, followed by a discussion on whether to treat or not—because that remains the central question. 
 

Frontline Therapy: Quadruplets, Dual Therapy, and MRD Negativity 

In the frontline setting, Dr. Mikhael elaborates why he picked these key studies and mentions a few other developments: 
 

MIDAS Study 

This complex but important study explored the role of transplant in the era of potent quadruplets. Patients received Isa-KRd — Sarclisa® (isatuximab), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), and dexamethasone — for six cycles and were then stratified by MRD status: 

• MRD-negative patients were randomized to more Isa-KRd with or without transplant. 
• MRD-positive patients received either Isa-KRd + transplant or Isa-KRd + tandem transplant. 

 
Key takeaways

• In MRD-negative patients, adding a transplant did not appear to deepen response. 
• In MRD-positive patients, tandem transplant offered no clear advantage over a single transplant.          

This has potential implications for de-escalating therapy in select patients. 
 

PERSEUS Trial 

This study added daratumumab to Velcade® (bortezomib) + lenalidomide + dexamethasone (VRd) as D-VRd, followed by transplant, consolidation, and maintenance with daratumumab + lenalidomide for up to two years, adjusted by MRD status. 
 

Highlights 

• >50% of patients in the D-VRd arm achieved sustained MRD negativity for over 2 years. 
• Only 3% of patients in the D-VRd group progressed in the first 18 months, compared to 7% in the VRd group. 


This supports the move toward quadruplet induction and dual maintenance as a new standard, especially in centers already leading in this area. 

 

GMMG-CONCEPT Trial 

This study focused on high-risk myeloma, using aggressive Isa-KRD induction, transplant, consolidation, and continuous maintenance. 
 

Notable outcome

• 6-year overall survival exceeded 66%, a significant improvement in a historically poor-risk population. 
• MRD-negative patients had notably better outcomes, reinforcing MRD as a critical therapeutic marker. 

 
Dr. Mikhael: There were a few other studies we didn’t have time to dive into today, but I want to highlight a couple. Blenrep® (belantamab mafodotin), which is likely to return to clinical use, is being explored in the frontline setting—though we’ll mostly be discussing it in relapsed disease. Similarly, bispecific antibodies, like Elrexfio® (elranatamab) (which we’ve mainly used in heavily pretreated patients), had an interesting update in the MagnetisMM-6 trial. This looked at combining elranatamab with daratumumab and lenalidomide in patients ineligible for transplant—a promising approach in the frontline setting. 
 
We're also seeing quadruplet regimens becoming more of a standard for many newly diagnosed patients. I'm curious to hear the group’s take on that, especially in the context of dual maintenance post-transplant and the push for sustained MRD negativity. Most of us agree that MRD is becoming a key tool for guiding therapy. I asked about this at ASCO—specifically, whether MRD negativity might one day mean skipping transplant. The response was cautious: we're not there yet, and we need longer follow-up to know how durable MRD responses really are. 
 
Still, MRD is clearly shaping the direction of treatment. High-risk myeloma remains a tough area but using MRD as a treatment goal could improve outcomes. 
 
I didn’t get to cover all the studies, but I found it striking how often carfilzomib is now being used in the frontline setting—we saw that in the MIDAS study, for example. And looking ahead, it seems clear that agents like belantamab and the bispecifics will play an even bigger role. 
 
What was your take home in the frontline world? 
 
Beth Faiman: One of the first things I look at when reviewing a study is whether it’s well-designed—Is it randomized? Phase 1, 2, or 3? Then I dig into the results, which are often complex. 
 
Take the MIDAS study. It was well-constructed and suggested that we likely don’t need tandem transplants anymore. But in the U.S., second transplants weren’t common to begin with, so that answered a narrow question. 
 
The bigger, still-unanswered question is: if a patient achieves MRD negativity, do they need a transplant at all? With all the innovative therapies we now have, that’s a real conversation. 
 
In frontline treatment, I usually start patients on a four-drug regimen, depending on age, frailty, and performance status. If they're not in a clinical trial, we reassess after 4–6 cycles, look at MRD status, and talk through options. 
 
Transplant isn’t going away anytime soon, but for some patients who reach MRD negativity, we may consider de-escalating and continuing therapy without transplant. That’s why ongoing trials like Isa-KRd vs. Dara-VRd are so exciting. 
 
And now with CAR-T being tested in frontline settings, it’s more important than ever to connect patients with clinical trials. We’re entering a really exciting era. 
 
Dr. Lonial: I agree with Beth—tandem transplants aren’t commonly done anymore, so the added benefit seems pretty limited. For me, the key questions are: When is the best time to assess MRD to guide therapy? And what do we actually do with that information? 
 
At the IMWG meeting, I emphasized that early MRD (within the first 9 months) is most helpful for escalating therapy, not for de-escalating. That’s especially relevant in MIDAS, where a large portion of early MRD-negative patients randomized to de-escalation were high-risk. We know those high-risk patients can reach a deep response, but they don’t tend to stay there. I’m concerned about what the PFS will look like, especially in groups like t(4;14) or other high-risk groups. 
 
What I usually tell patients is this: if you compare the projected PFS in PERSEUS (dara-VRd with transplant) to CEPHEUS (dara-VRd without transplant), the transplant group’s PFS is almost double. That first remission matters—some patients may never need second-line therapy, or other health issues may prevent it. You want to maximize that first shot. 
 
Also, if you’re planning to let MRD guide the decision to transplant or not, keep in mind that in MIDAS, they had trouble collecting stem cells after six cycles. You’ve got to commit to stem cell collection early—ideally after 3–4 cycles, maybe 6 at most—if you want to preserve that option. I’m not necessarily advocating for that approach, but if you're considering it, make sure stem cell collection happens early, so patients don’t lose access to transplant down the road. 
 
Dr. Mikhael:  I really worry about people jumping to conclusions—thinking, “Okay, you're MRD-negative, so you can skip transplant.” I appreciate how you framed it as escalation versus de-escalation. The paradox is that high-risk patients often hit MRD negativity early, but they can’t sustain it. We've known this since the early Arkansas trials—high-risk patients may respond well up front but relapse faster. It’s not just about achieving MRD negativity, it’s about sustaining it. 
 
I’m sure you all see this too—we definitely do at the IMF—people calling in with a kind of “MRD or bust” mindset. But it's too simplistic to think that one early MRD-negative result guarantees long-term success. 
 
As Beth mentioned, the trials are ongoing. And I can’t believe we’re doing a frontline talk without even touching on whether CAR T will move up—though the data’s not mature yet. So that’s a bit of a teaser for our next IMWG conference, where we’ll dive into bispecifics and CAR T in the upfront setting. 
 
Dr. Lonial: Two quick points before we get to early relapse. You're absolutely right—there's almost an obsession with MRD negativity, and patients who don’t achieve it by day 100 can feel discouraged. But I have plenty of patients who never reached complete remission and, eight or nine years later, are still doing well—on lenalidomide maintenance, with a small, stable M protein. 
 
We have to be careful not to overhype the downside of not hitting MRD negativity. It really depends on the context—the patient’s risk level, the therapy they're on, and how stable their disease is. Sometimes MRD negativity is a win, sometimes it's not critical, and sometimes we just need more time to know what it means. 
 
On the flip side, we just finished analyzing our carfilzomib, Pomalyst® (pomalidomide), and dexamethasone (KPd) maintenance trial for high-risk patients. Many didn’t reach MRD negativity until 12 to 18 months into maintenance, yet the median PFS was 65 months—for high-risk myeloma. That’s not the final answer, but it tells us you don’t always need to chase MRD aggressively from day one. Sometimes the key is knowing when to be patient and allowing the treatment to play out. 
 
Beth Faiman: If I could just jump in—that’s a great point. In some studies, about a third of patients never achieve MRD negativity. I have patients who’ve never been on maintenance after transplant—going back to before 2010—who are still doing well with a stable M protein of 0.3. So, taking MRD recommendations with a grain of salt is definitely a wise approach. 

Final Thoughts on Frontline Therapy 

• Quadruplet regimens are increasingly becoming the standard. 
• Dual maintenance post-transplant is gaining traction, especially for sustaining MRD negativity. 
• MRD status is emerging as a treatment guide, though it's still too early to abandon transplant based on MRD alone. 
• High-risk myeloma remains a challenge, but with MRD-guided strategies, outcomes are improving. 
• Expect more carfilzomib use, as seen in MIDAS and other trials, and frontline integration of novel agents like belantamab and bispecifics. 

 
(To be continued next week)