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Myeloma Masterclass on Applying the Latest Guidelines for Evidence-Based, Equitable Care: Experts Answer Your Questions

Released: July 11, 2025

Expiration: July 10, 2026

Natalie S. Callander
Natalie S. Callander, MD
Carol Ann Huff
Carol Ann Huff, MD
Shaji K. Kumar
Shaji K. Kumar, MD
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Key Takeaways
  • Patients with high-risk smoldering multiple myeloma should consider the benefits and risks of treatment or clinical trial participation.
  • Median PFS is projected to be ≥15 years for patients with newly diagnosed multiple myeloma using modern quadruplet regimens.
  • Combination regimens including the investigational CELMoDs iberdomide and mezigdomide have demonstrated high response rates in heavily pretreated patients with multiple myeloma.

In this commentary, myeloma experts Natalie S. Callander, MD; Shaji K. Kumar, MD; and Carol Ann Huff, MD, answer questions posed by an audience of healthcare professionals (HCPs) at a live satellite symposium on applying the latest guidelines for evidence-based, equitable care of patients with multiple myeloma (MM).

Smoldering Multiple Myeloma

Given the changing definitions of high-risk smoldering multiple myeloma (SMM), how can we apply current definitions to the clinical trial definitions made 5-10 years ago? 

Natalie S. Callander, MD:
This is an excellent question, and indeed SMM as an entity has been controversial for quite some time. For me, there are a few things that appear to be consistent regarding the definitions of low risk and high risk. First, patients with low-risk or intermediate-risk disease do not appear to benefit as much from treatment (HR: 0.37; 95% CI: 0.14-0.97) whereas those with high-risk disease per Mayo 2008 high-risk criteria benefited much more from lenalidomide treatment vs observation (HR: 0.09; 05% CI: 0.02-0.44). Second, high-risk SMM always appears to benefit from therapy as demonstrated by the phase III QUIRIDEX study of lenalidomide plus dexamethasone for 9 cycles followed by lenalidomide maintenance vs observation showing improvement in progression-free survival (PFS) (HR: 0.24; 95% CI: 0.14-0.41; P <.0001) and overall survival (HR: 0.43; 95% CI: 0.21-0.92; P <.024) benefit. Similar findings were reported from the randomized phase II/III E3A06 trial of lenalidomide plus aspirin vs observation regarding PFS (HR: 0.28; 95% CI: 0.12-0.62; P <.002).

More recently, the randomized phase III AQUILA study of daratumumab vs active monitoring further explored this question in adults who had SMM for ≤5 years and had ≥10% clonal bone marrow plasma cells and ≥1 other risk factor for progression to multiple myeloma (MM) including serum M-protein ≥30 g/L, IgA SMM, and immunoparesis with reduction of 2 uninvolved Ig isotypes. The AQUILA study showed that daratumumab, compared with active monitoring, yielded a superior 5-year PFS of 63.1% vs 40.8% (HR for progressive disease or death: 0.49; 95% CI: 0.36-0.67; P <.001) per independent review committee using the International Myeloma Working Group SLiM-CRAB criteria. At the time of that report, the median PFS in the daratumumab arm had not been reached and was 41.5 months in the active monitoring arm. Based on the results from the AQUILA trial, the FDA Oncologic Drugs Advisory Committee shared a positive opinion on the benefit–risk profile of daratumumab as single-agent therapy for patients with high-risk SMM.

How would you incorporate patient’s age and risk stratification factors into daily practice? 

Natalie S. Callander, MD:
A common theme for the trials conducted in SMM to date is that patients are mostly in their 60s. But based on the SEER database, the median age of patients with SMM is approximately 75 years. I personally have not enrolled any patient in their 70s in the ongoing Eastern Cooperative Oncology Group phase III EAA173 trial of subcutaneous daratumumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone for patients with asymptomatic, high-risk SMM (N = 288) (NCT03937635). We tend to follow the trial criteria very strictly, including the fact that the patient is still at risk of developing MM.  

Newly Diagnosed Multiple Myeloma

Why is treatment of newly diagnosed MM so important and for how long can the disease be controlled?

Shaji K. Kumar, MD:
Treatment of newly diagnosed MM is key because we need to address the rapidly growing disease burden and attempt to reverse the associated disease-related complications—particularly the renal insufficiency with which many of these patients can present—and with the minimal toxicity possible in the short and long term. We must also attempt the collection of stem cells for transplant if feasible and desired. That being said, the biggest achievement in the treatment of newly diagnosed MM in the past decade or so has been improvement in PFS from approximately 2-3 years with bortezomib, lenalidomide, and dexamethasone vs now projected to be ≥15 years with the use of anti-CD38 antibodies as triplet/quadruplet combinations. Studies evaluating quadruplets in newly diagnosed MM such as CASSIOPEIA (daratumumab, bortezomib, thalidomide and dexamethasone), PERSEUS (daratumumab, bortezomib, lenalidomide, and dexamethasone), and GMMG-HD7 (ixazomib, lenalidomide, bortezomib, and dexamethasone) have all contributed to the improvement in PFS we can achieve now.

In addition to prolonging PFS, we also want to achieve the deepest response that we can in the form of measurable residual disease (MRD), which may provide us with insight into which patients respond best to a given therapy and could be used as a tool or potential surrogate for those who might be eligible for de-escalation of therapy—and potentially even be cured. One study that we are looking at closely is the phase III AURIGA trial of daratumumab plus lenalidomide vs lenalidomide as posttransplant maintenance therapy for newly diagnosed MM who received ≥4 cycles of induction followed by autologous stem cell transplant and a very good partial response and MRD-positive (10-5 threshold). In a recent report, MRD-negative status (10-5) from baseline to 12 months of maintenance treatment was 50.5% (50 of 99 patients) in the daratumumab and lenalidomide arm and 18.8% (19 of 101 patients) for the lenalidomide alone arm.

Relapsed/Refractory MM

How will cereblon (CRBN) E3 ligase modulators (CELMoDs) be used and how will iberdomide be sequenced vs mezigdomide? 

Carol Ann Huff, MD:
Based on the data we currently have, we do not yet know exactly how these agents will be sequenced. Mezigdomide is an oral CELMoD that has shown improved antitumor efficacy and immune stimulatory effects in patients with relapsed/refractory MM when combined with agents often used in that setting. In an early phase I/II study, mezigdomide was combined with dexamethasone, achieving an overall response rate (ORR) of 41% in patients with ≥3 prior lines of therapy (a median of 6 previous lines of therapy including glucocorticoid, immunomodulatory agent [IMiD], proteasome inhibitor [PI], a CD38 antibody, and refractory to the last 3) (n = 101); in combination with daratumumab and dexamethasone, mezigdomide yielded an ORR of 78% for patients who had received 2-4 previous regimens with a median of 2 previous lines of therapy (n = 59); and in combination with dexamethasone and elotuzumab, mezigdomide yielded an ORR of 45% in patients with 2 previous regimens and median of 3 previous lines of therapy (n = 20). The safety profile of mezigdomide in combination with dexamethasone was promising with only 6% of patients discontinuing treatment because of adverse events (AEs).

Iberdomide is another novel CELMoD that co-opts CRBN to enable enhanced degradation of target proteins, including Ikaros and Aiolos. Iberdomide has also shown activity in lenalidomide-resistant and pomalidomide-resistant MM preclinical models. In a phase I/II study of iberdomide conducted in patients with heavily pretreated MM (ie, with ≥3 prior lines of therapy and refractory to IMiD, PI, and CD38 antibody), iberdomide in combination with dexamethasone achieved an ORR of 26% (n = 107). In another phase I/II trial of iberdomide with dexamethasone and daratumumab conducted in patients with ≥2 previous lines of therapy (including lenalidomide/pomalidomide and a PI), this combination yielded an ORR of 42% (n = 27), whereas a combination of iberdomide and dexamethasone and bortezomib yielded an ORR of 61% in patients with ≥1 prior line of therapy (including lenalidomide/pomalidomide and PI) (n = 23).

Is there an age limit for CAR T-cell therapy? Which CAR T-cell therapy do you use?

Carol Ann Huff, MD:
At our institution, we do not tend to apply absolute age limits and we have certainly administered CAR T-cell therapy to patients in their late 80s. We have found that those patients, at least at our institution, tolerate autologous transplants well. Regarding which CAR T-cell therapy, we predominantly use ciltacabtagene autoleucel (cilta-cel).

Natalie S. Callander, MD:
Some of us are looking at the safety profiles of the various CAR T-cell therapies to better determine which agent might be best for our patient.

Cilta-cel is available to patients with relapsed/refractory MM after ≥1 previous lines of therapy which include a PI and an IMiD and who are refractory to lenalidomide. In the phase III CARTITUDE-4 trial, treatment with cilta-cel in patients who had received 1-3 previous lines of therapy and who were refractory to lenalidomide (n = 208) yielded an ORR of 84.6% and a median PFS that was not reached at the time of that report (95% CI: 22.8 months to note estimable). Regarding safety, any-grade cytokine release syndrome (CRS) was seen in 76.1% of patients and neurotoxicity was seen in 20.5% of patients (immune effector cell–associated neurotoxicity syndrome [ICANS]: 4.5%). Idecabtagene vicleucel (ide-cel) is also available to patients with relapsed/refractory MM after ≥2 prior lines of therapy including an IMiD agent, a PI, and an anti-CD38 monoclonal antibody. Results from the phase III KarMMa-3 trial of ide-cel in patients with relapsed/refractory MM and 2-4 previous lines of therapy—and who were refractory to their last regimen—yielded an ORR of 71% and a median PFS of 13.8 months (95% CI: 11.8-16.1). Regarding safety, any-grade CRS with ide-cel was seen in 88% of patients with neurotoxicity observed in 15%.

Based on the data we have thus far, cilta-cel appears to be less well tolerated. Thus, for an olde or frail individual, I will use ide-cel instead. In patients with higher-risk disease, I might consider cilta-cel even for patients aged in their 80s based on the better response data with this agent. We must definitely weigh the pros and cons of our options including for things like renal insufficiency, you can modify the fludarabine, use low-dose chemotherapy, and in particular for a patient where it might be challenging to use high-dose melphalan.

What is the optimal bridging therapy for CAR T-cells? 

Carol Ann Huff, MD:
I personally do not think there is an optimal bridging therapy. I think this decision is informed by patient and disease factors that may vary from one patient to another. For a patient who had received carfilzomib or pomalidomide or was receiving daratumumab, we certainly have agents that we could use as a bridge to CAR T-cell therapy vs a patient who has had all 5 of the major drugs for MM. In that scenario, we will often try pheresis and then use talquetamab as a bridging therapy. In a patient with rapid disease progression, we might opt for cytotoxic therapies.

Shaji K. Kumar, MD:
I agree that there is not really an optimal bridge therapy for all patients. My question for you is what is your experience managing the talquetamab-associated toxicities, particularly neurologic toxicity? And how long does it take for the skin, nails, taste, or disease symptoms to stop during talquetamab treatment?

Carol Ann Huff, MD:
In my experience, these AEs are most intense in the first few months. What we have found to be most beneficial for patients is applying supportive care and increasing the time between doses.

What are you thoughts on bispecific antibodies as short-term bridging for CAR T-cell therapy?

Natalie S. Callander, MD:
At our institution, we just “step-up-dose” talquetamab dosing and stop. Patients still get the nail, skin, and dysgeusia AEs, but fortunately, they do not last more than 3 or 4 months. That said, these AEs can be quite severe in the short term but the overall outcomes for patients makes it worth it.

Your Thoughts
What are your thoughts or questions on the current treatment landscape of smoldering, newly diagnosed, or relapsed/recurrent MM? Answer the polling question and leave us a comment.

Visit the program page to access the slides associated with this program and watch an on-demand webcast from the live event.

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