Episode Summary: The Fellow on Call – Episode 142

Myeloma Series, Pt.3: Management of Smoldering Multiple Myeloma (2025)

Podcast: The Fellow on Call: The Heme/Onc Podcast
Host: Rouleaux University Medical Center
Guests: Roanok (A), Vivek (B), Dan (C), Sean (D – new Malignant Hematology Attending)
Date: December 17, 2025

Episode Overview

This episode continues the podcast’s deep dive into plasma cell dyscrasias, zooming in on smoldering multiple myeloma (SMM). The team welcomes Dr. Sean, whose clinical expertise in myeloma guides a lively discussion on diagnostic criteria, risk stratification, and evolving treatment decisions, especially in light of new clinical trial data and recent FDA approval for daratumumab in high-risk SMM. The conversation balances historical perspective, current best practices, and the controversies that still exist.

Key Discussion Points & Insights

1. Defining Smoldering Multiple Myeloma and Its Place Between MGUS and Myeloma

• Case Introduction (04:10): 63F with M spike 2.2, κ:λ = 10, 20% marrow plasma cells, no CRAB criteria, positive Bence Jones protein, whole body MRI negative for lytic lesions – a classic high-risk SMM case.
• MGUS vs SMM vs Myeloma (06:01):
  • MGUS: M spike or abnormal free light chains, but not meeting SMM or myeloma criteria. Progression risk ~1%/year.
  • SMM: Either 10–60% marrow plasma cells, M spike >3 g/dL, or 24-hr urine monoclonal protein >500 mg — and no myeloma-defining (SLiM-CRAB) events.
  • Myeloma: >10% marrow plasma cells (or proven plasmacytoma) plus myeloma-defining event (SLiM-CRAB: >60% marrow plasma cells, light chain ratio >100 or <0.01, MRI with >1 focal lesion, or classic CRAB: hypercalcemia, renal, anemia, bone disease).
  • Quote (Dan, 07:15):

    “Smoldering multiple myeloma… is kind of this middle ground. MGUS being the lowest risk generally, smoldering myeloma being this intermediate category...”

2. Historical and Clinical Context

• Natural History:
  • MGUS is common (~5–10% adults). SMM was first described in the 1980s (Bob Kyle, NEJM), with some patients never progressing and others quickly becoming symptomatic myeloma (10:20).
• Risk Stratification:
  • 2220 Rule (10:45):

    • 20% marrow plasma cells

    • M spike >2 g/dL
    • Involved/uninvolved light chain ratio >20
    • Two or more = high-risk SMM (~50% risk of conversion in 2 years)
  • Quote (Sean, 10:58):

    “Smoldering myeloma itself is actually a very heterogeneous entity. Some patients behave like MGUS… others have a very high risk of progressing.”

3. Evolving Definitions & Controversies

• The addition of “SLiM” criteria in 2014 reclassified some SMM as myeloma, affecting treatment thresholds and research cohorts (12:30).
• Analogy: Comparing MGUS/SMM/myeloma to colon polyps of variable malignant potential (12:30).

4. High-Risk SMM: To Treat or Not To Treat?

• Who is “high-risk SMM”?
  2220 rule, adverse cytogenetics (e.g., t(14;16), del17p), and genomics are increasingly used (15:18).
• Debate: Whether all high-risk SMM warrants upfront therapy, given not all will progress rapidly and considering treatment toxicity.

5. Clinical Trials Shaping Practice

a) QuiRedex Trial (Spain/Portugal, published 2016) (17:15)

• Design: High-risk SMM, Lendex (lenalidomide+dexamethasone) vs observation.
• Results:
  • Median time to progression: not reached (tx) vs. 23 months (obs)
  • OS: Not reached (tx) vs 117.6 months (obs)
• Limitations: Possible misclassification (did all have SMM?), lack of modern imaging, and uncertain post-progression salvage therapy.
• Quote (Dan, 17:15):

  “Perhaps in these higher risk patients there may be a role for treatment early on to try to prevent overt signs of myeloma.”

b) ECOG E3A06 Study (JCO 2019) (19:49)

• Design: Intermediate/high-risk SMM, lenalidomide vs observation.
• Results:
  • PFS at 1/2/3 years (lenalidomide): 98/93/91% vs obs 89/76/66%
  • OS: No significant difference
  • Adverse Events: 28% had grade 3/4 (rash, fatigue, infection)
• FDA declined approval (no OS difference, and endpoints like fracture/renal failure not reported)
• Quote (Vivek, 21:26):

  “If a third of them… are going to get a grade three, four adverse event… we have to think about the cost of treating these patients.”

c) AQUILA Trial (NEJM 2025, led to FDA approval) (22:24)

• Design: High-risk SMM, daratumumab (single agent, q4 weeks up to 3 yrs) vs monitoring. PET CT & MRI required to prove absence of overt myeloma.
• Criteria: Marrow >10% plus either M spike >3, IgA, FLC ratio 8–99, or marrow 50–60% — not perfectly matching 2220 “high risk.”
• Results:
  • 5-year PFS: 63.1% (dara) vs 40.8% (monitor)
  • OS at 5y: 93% (dara) vs 86.9% (monitor), HR 0.52
  • Deaths: 7.5% (dara) vs 13.3% (monitor)
  • Notable: Over 40% of monitored patients did NOT progress at 5 years—implies potential overtreatment.
  • Only about 25% of “progressors” received modern MM therapy.
• FDA Approval (Nov 2025): Dara now level 1 per NCCN for SMM.
• Quote (Dan, 24:08):

  “Based on this data, the NCCN does now list daratumumab as level 1 indication for smoldering myeloma. But additional clinical trials were still recommended…”

6. Practical Implications: Surveillance and Shared Decision-Making

• Lab and Imaging Follow-Up (Sean, 27:28):

  • CBC, CMP, SPEP, FLC every 3–4 months for SMM (esp first 5 years)
  • Reimaging (WBMRI, PET) mainly if symptoms or high risk, not routine
  • Quote:

    “This is really most important in the first five years. If stable… might be reasonable to space that out further…”

• Who to Treat? (Sean, 28:20):

  • Benefit for some, but concerns linger about overtreatment and study limitations.
  • Shared decision-making emphasized; some may want therapy due to anxiety/risk; especially considered if progression is particularly dangerous (e.g., pre-existing CKD).
  • Quote, Sean (29:22):

    “The main area where I think that this approval may be particularly helpful is as part of a shared decision making.”

• Balancing Act – Notable Perspective (Vivek, 30:32):

  • “Remember, 40% of patients didn’t need that treatment… do all 85-year-old patients need to get daratumumab? … Remember, that’s definitely a risk here for these patients.”
  • “Don’t hang your hat always on an overall survival benefit that wasn’t powered for it…”

Memorable Quotes & Moments

• Dan (03:48): "I also want to be clear…when Vivek said chips, he was referring to Lays, Pringles, Ruffles—not clonal hematopoiesis."
• Sean (10:58): "Smoldering myeloma itself is actually a very heterogeneous entity… some behave more like MGUS… some are more likely to be active myeloma."
• Dan (24:08):
  “Based on this data, the NCCN does now list daratumumab as level 1 indication for smoldering myeloma. But additional clinical trials were still recommended…”
• Vivek (30:32):
  “Remember, 40% of patients didn’t need that treatment… do all 85-year-old patients need to get daratumumab?"
• Sean (29:22):
  “The main area where I think that this approval may be particularly helpful is as part of a shared decision making.”

Segment Timestamps

• Introductions & Welcome Sean: 00:37 – 02:57
• Clinical Case & Workup: 04:10 – 06:00
• SMM, MGUS, Myeloma Definitions: 06:01 – 08:20
• History, Natural History of MGUS/SMM: 08:41 – 10:20
• SMM Facts & Heterogeneity: 10:20 – 12:30
• Controversies (“SLiM-CRAB”, treatment philosophy): 12:30 – 15:18
• How to Risk Stratify & Who to Treat: 15:18 – 18:05
• Key Trials:
  • QuiRedex: 17:15 – 19:49
  • ECOG E3A06: 19:49 – 21:26
  • AQUILA: 22:24 – 25:06
• Interpreting the Data, Practical Implications: 25:06 – 29:34
• How to Monitor SMM/Initiate Treatment: 27:28 – 29:34
• Wrap-Up Discussion: 29:34 – 32:39

Takeaways for Clinicians

• Diagnosis & Risk Stratification is Nuanced:
  Use bone marrow %, M spike, FLC, cytogenetics, and the 2220 rule. Imaging (WBMRI, PET) is essential for accurate staging.
• Trial Data Must Be Interpreted Carefully:
  Cohort definitions and post-progression therapies matter; not all labeled “high risk” are equivalent.
• Daratumumab is FDA-approved for SMM—but treatment is NOT for all.
  Individualize by balancing risk, adverse events, life expectancy, and patient preferences.
• Surveillance Remains Key:
  Most SMM patients progress, if at all, within first 5 years. Labs q3–4 months, focused reimaging.
• Shared Decision-Making is Crucial.
  Some patients value action, others prefer to defer. Decision should be collaborative.

Conclusion

The field of SMM is shifting rapidly: where once all were monitored, now a subset may benefit from early therapy. Trials like AQUILA have ushered in new options, but inclusion criteria, study design, and the practicalities of treatment must guide individualized patient care. The team emphasizes a measured, evidence-based but patient-centered approach in this area of evolving practice.

[Ads, show intros, and outros have been omitted. For specific study tables or guideline visuals, refer to the show notes cited in the episode.]