Podcast Summary: The Fellow on Call: The Heme/Onc Podcast

Episode 141: Myeloma Series, Pt.2 – Intro to MGUS and Smoldering Myeloma (2025)

Date: December 10, 2025
Hosts: Ronuk (A), Vivek (B), Dan (C)
Podcast: Rouleaux University Medical Center

Episode Overview

This episode continues the myeloma series by exploring the spectrum of plasma cell dyscrasias, focusing primarily on Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering multiple myeloma (SMM). The hosts offer a detailed, evidence-based approach to risk stratification, monitoring, and diagnostic criteria—translating recent research and expert guidelines into pragmatic clinical pearls for trainees and practicing clinicians. Case examples, memorable mnemonics, and practical decision points make it an essential listen for those encountering monoclonal gammopathies in clinic.

Key Discussion Points & Insights

1. Case Introduction and Core Laboratory Interpretation

• Case Discussion (01:25): 63-year-old woman with hypertension, hyperlipidemia, diabetes, presenting with normocytic anemia and an M spike of 1.2 g/dL found on SPEP.
• Lab Workup: Importance of ordering SPEP, immunofixation, and free light chain assays together. Immunofixation helps determine the immunoglobulin type and light chain involved.
• Quote:

  “If you order the SPEP, you always want to order those free light chains with it…that would change our management in approach to this patient.” – Ronuk (01:33-01:50)

2. Understanding SPEP & Light Chain Physiology

• SPEP as Quantitative Tool (02:50):
  SPEP differentiates between protein types and quantifies monoclonal protein.
• Role of Immunofixation: Identifies M protein type (IgG, IgA, etc.) and light chain (kappa vs lambda).
• Physiology of Light Chains and Renal Clearance (07:41):

  “Your body, in general, produces more kappa than lambda...lambda forms dimers and has a higher molecular weight...in normal situations, the kappa/lambda ratio is often less than 1.” – Vivek (07:48-08:34)

• Renal Dysfunction Nuance: In AKI or CKD, normal ratio can rise up to 3.1 – don’t misdiagnose myeloma in these patients!

  “In renal dysfunction, kappa is higher than lambda and the normal ratio goes all the way up to 3.1.” – Vivek (10:18)

3. MGUS: Definition, Risk Stratification, and Monitoring

• Defining MGUS (05:54, 07:19):

  • M spike < 3 g/dL
  • <10% bone marrow plasma cells
  • No myeloma-defining events (SLiM CRAB criteria)

• High-Risk MGUS Features:

  • Non-IgG M protein
  • M spike >1.5 g/dL
  • Abnormal free light chain ratio (<0.26 or >1.65)

• Workup for High-Risk Features: Bone marrow biopsy, full-body imaging (PET/CT or MRI), 24-hour urine protein electrophoresis (not spot UPEP!)

  “Don't get a spot UPEP...Always get a 24-hour UPEP.” – Vivek (04:43, 18:21)

• Clinical Impact of Risk Stratification:

  “If you have all three risk factors...at 20 years your risk of progression to myeloma was 58%. If none...the risk was only 2%.” – Vivek (11:13)

• Monitoring Recommendations:

  • All MGUS: Repeat labs at 6 months after diagnosis
  • Low-risk: No further routine testing unless symptoms emerge
  • Non-low-risk: Annual labs (CBC, creatinine, calcium, SPEP, FLC)
  • Rationale: Higher risk of progression in the first year post-diagnosis

4. Indicators for Additional Testing in MGUS Tracking

• When to Escalate Evaluation:
  • Rising M spike (by ≥0.5 g/dL per year)
  • Decreasing hemoglobin (by ≥0.5 g/dL in a year)
  • Symptom onset (bone pain, hypercalcemia, renal dysfunction)
• Memorable Moment:

  “Even if a patient has progressive rise in their M spike...only half will develop multiple myeloma at 10 years. The biggest predictor is an M spike rising by 0.5 with a hemoglobin drop by 0.5 in a year.” – Dan (15:09)

5. Transition: Defining Smoldering Multiple Myeloma (SMM)

• Smoldering Myeloma Criteria (17:10, 17:54):

  1. M protein >3 g/dL or >500 mg/24h monoclonal protein in urine or 10-60% clonal plasma cells in marrow
  2. No myeloma-defining events (per SLiM CRAB)
  • PET/CT, MRI, marrow always necessary in suspected SMM

• Essence of 24-hour Urine Collection:

  “You could have a patient who has a 24-hour UPEP >500mg...that patient could still be defined as having smoldering multiple myeloma.” – Vivek (18:21)

6. Myeloma-Defining Events (SLiM CRAB Criteria)

• Classic CRAB: Hypercalcemia, Renal dysfunction, Anemia, Bone lesions

• SLiM Additions: (19:19-22:06)

  • S: ≥60% clonal plasma cells in marrow
  • Li: FLC ratio ≥100 or ≤0.1
  • M: >1 focal lesion (>5mm) on MRI

• Key Point: Diagnosis requires new or worsening findings not explained by alternative causes

  “You’re really looking for things that you can’t otherwise explain...things that have developed in suspiciously close correlation in time.” – Dan (21:51)

• Urine Protein Modification: FLC difference ≥100 + urine monoclonal protein >200 mg/24h may be required.

7. Smoldering Myeloma: Natural History, Risk Stratification & Surveillance

• Risk of Progression:

  “At 20 years, the risk of progression to myeloma [with SMM] was 80%...versus 20% for MGUS.” – Vivek (24:09)

  • Highest risk first 5 years (≈10%/year), then risk declines
  • Disease entity is heterogeneous and definition is evolving

• Risk Models:

  • Mayo 2018 Criteria - “2220 Rule” (26:42):
    • FLC ratio >20
    • M spike >2 g/dL
    • Bone marrow plasma cells >20%
    • 2 or more = high risk SMM: 50% chance of progression to MM in 2 years

• Monitoring Strategy:

  • Low-risk SMM: Labs every 3-4 months for first 5 years, then every 6 months
  • High-risk: Increased monitoring, consider therapeutic trials

8. Additional Risk Factors & Imaging

• Beyond “2220”:
  • M spike rises by 0.5 + hemoglobin drop by 0.5 in 12 months → ~90% risk of progression (30:22)
  • Decreasing uninvolved immunoglobulin levels is a bad sign
  • Focal/diffuse PET scan uptake or a single MRI lesion = high risk, mandates serial imaging (every 6 months first, then less frequently)
• Cytogenetics:
  • FISH and chromosomal analysis from marrow can further risk stratify; details to be covered in the next episode

Notable Quotes & Memorable Moments

• On MGUS Counseling:

  “It’s scary for them...knowing there’s some abnormality in their blood...and it’s so reassuring because you can put a number to it. Right. 2% progression is pretty low.” – Ronuk (12:27)

• On Testing Strategy:

  “Don't get a spot, get a 24-hour.” – Ronuk and Vivek (19:04–19:06)

• Concluding the SMM Monitoring Plan:

  “For smoldering myeloma, we monitor labs every 3-4 months in these low-risk patients for the first five years...Once you get beyond that five year mark, you space it out to every six months thereafter.” – Ronuk (28:08)

• On Clinical Intuition:

  “...if you know your SLiM CRAB criteria...all you’re saying is if you know those, smoldering myeloma patients who don’t quite meet them are approaching the threshold.” – Ronuk (32:53)

Key Timestamps for Reference

• Case Introduction: 01:25
• Explaining SPEP/Light Chains: 02:50–05:05
• Defining and Risk-Stratifying MGUS: 05:54–07:19
• Light Chains, Physiology & Renal Nuance: 07:41–11:13
• Long-Term Progression Risks (MGUS): 11:13–12:27
• Monitoring MGUS: 13:05–14:52
• When to Escalate Evaluation: 15:09, 16:23
• Smoldering Myeloma Definitions: 17:10–18:21
• SLiM-CRAB Criteria Explained: 19:19–22:06
• SMM Risk, “2220 Rule,” and Monitoring: 24:09, 26:42–29:12
• Other High-Risk Features: 30:22–32:53
• Cytogenetics Preview: 33:41–34:36
• Episode Wrap-Up: 35:17–35:49

Final Thoughts

The hosts synthesize a complex field into actionable, memorable frameworks (e.g., the “2220 rule,” SLiM CRAB criteria, monitoring intervals). They encourage a dynamic, patient-specific approach, always contextualizing lab findings with clinical events, and emphasizing shared decision-making in gray zones. The episode effectively arms listeners with both foundational knowledge and nuanced clinical pearls—essential as the landscape of plasma cell disorders continues to rapidly evolve.

Recommended For:
Medical students, residents, hematology/oncology fellows, APPs, and attendings managing monoclonal gammopathies.

Next Up:
Frontline treatment strategies for smoldering and overt multiple myeloma—including cytogenetic prognostication!