The Fellow on Call: The Heme/Onc Podcast

Episode 144: Myeloma Series, Pt. 5 – Myeloma Risk Stratification and Response Criteria (2026)
January 7, 2026 – Rouleaux University Medical Center
Hosts: Vivek (A), Dan (C), Sean (B, guest host)

Episode Overview

This episode serves as a pivotal transition in the Myeloma series, diving into the fundamentals of risk stratification and response assessment in multiple myeloma. With a focus on updated diagnostic criteria, risk markers, and the emerging role of MRD (measurable residual disease), the hosts provide practical insight for fellows, residents, and practitioners preparing for treatment decisions. The discussion unpacks complex concepts, recent updates from major hematology societies, and pragmatic approaches to evaluating patients—grounding everything in "need-to-know" knowledge before moving into myeloma treatment regimens in future episodes.

Key Discussion Points & Insights

1. Real-world Case & Diagnostic Approach (02:26 – 07:48)

Case Introduction: 63-year-old female with IGG kappa M spike, abnormal light chain ratio, and lytic bone lesions—classic presentation escalating from high-risk MGUS toward symptomatic multiple myeloma (02:26).
Diagnostic Process:
- Bone Marrow Biopsy: Aspirate for smears, flow cytometry, cytogenetics, molecular testing; core biopsy for architecture and immunohistochemistry (IHC).
- Flow Cytometry vs. IHC:
  - Flow helpful for detecting aberrant immunophenotype and light chain restriction but can underrepresent plasma cells (06:06).
  - IHC (e.g., CD138 staining) preferred for quantifying plasma cell percentage.
- Importance of Kappa/Lambda Restriction: "If they're all choosing kappa or all choosing lambda, that's suggestive of clonality." – Vivek (07:48).
- Baseline Labs: Serum beta-2 microglobulin, albumin, LDH essential for staging and risk (09:33).

2. Cytogenetics & Risk Stratification in Myeloma (07:48 – 13:11)

FISH Testing and Plasma Cell Enrichment: Essential to specifically enrich for plasma cells before cytogenetic analysis.
Key Cytogenetic Abnormalities:
- High Risk:
  - t(4;14), t(14;16), t(14;20), deletion 17p, amplification 1q (≥4 copies), and biallelic deletion 1p.
  - Special Note: t(11;14) associated with venetoclax sensitivity (09:33).
- Updated Criteria (2025 IMS/IMWG): Combination of cytogenetic hits—interaction between mutations now recognized as the real driver of risk (11:07).
- Beta-2 Microglobulin: >5.5 mg/L (with normal creatinine) is a powerful high-risk marker.
Remember: Definitions are evolving; always check trial-specific criteria (13:11).

"Look up these criteria. Super important." – Vivek (13:11).

3. Response Criteria in Myeloma (14:55 – 18:58)

IMWG Response Categories:
- Partial Response (PR): ≥50% reduction in M-spike.
- Very Good Partial Response (VGPR): ≥90% reduction in M-spike.
- Complete Response (CR): Disappearance of M-spike.
- MRD Negative/Positive CR: Adds molecular depth to remission status.
- Disease Progression:
  - 25% increase from nadir in M-spike or free light chains, plus absolute value thresholds.
  - New/plasma cytomas or bone lesions also constitute progression (14:55).
Clinical Pearls:

"It's always best to get to at least a VGPR prior to transplant." – Vivek (16:36).
Stringent CR: Outmoded by the use of MRD testing (16:36).

4. MRD (Measurable/Minimal Residual Disease): Deep Dive (18:58 – 25:57)

Why MRD Matters:
- Detects disease below morphologic thresholds; growing evidence for improved PFS and potentially OS (25:57).
- MRD negativity now a surrogate endpoint for drug approval (FDA/ODAC 2025).
Techniques:
- Next Generation Flow (NGF): Standardized, sensitive to 1 in a million cells, requires live cells processed quickly; won’t detect clonal evolution (18:58–21:19).
- Next Generation Sequencing (NGS): Highly sensitive (down to 1 in 10 million), based on VDJ recombination as "barcode"; requires baseline clone identification, more expensive and slower (21:19–23:44).
Clinical Implications:

"Patients with multiple myeloma inevitably relapse... If we can't detect this at a one in a million threshold, obviously that patient's gonna have a better prognosis." – Vivek (24:03).
- MRD will likely guide therapy de-escalation (not escalation) in the future (27:33).

5. Future Directions & Takeaways (25:57 – End)

MRD-Guided Management:
- Ongoing trials exploring if sustained MRD negativity can justify stopping maintenance therapy.
"We may be able to identify patients that might be lower risk for progression and can be closely monitored." – Sean (25:57).
- De-escalation parallels with other cancers (e.g., response-adapted therapy in Hodgkin lymphoma—RATHL study).
"If we're making patients live longer, let's make them live as best as possible during that time period." – Vivek (27:33).
Upcoming Episodes: Focus on frontline treatment strategies and practical application of these criteria and tools.

Notable Quotes & Moments

On Cytogenetics:

"If you’re seeing deletion 17p or loss of p53, you’re in kind of a high-risk territory." – Dan (08:34)
On MRD Value:

"MRD negativity is going to be a surrogate for improved overall survival and potentially opening the door towards determining whether or not someone's really been cured of this disease." – Dan (18:58)
On Evolving Criteria:

"Definitions are changing over time. Always check what the study actually used." – Sean (13:11)
On Real-World Practice:

"Early referral to transplant is very important in these patients with multiple myeloma." – Vivek (16:36)
On Therapy Strategy:

"Let's de-escalate therapy... That is likely the patient you're okay with de-escalating that therapy for." – Vivek (27:33)
On the Purpose of Risk Stratification:

"The whole idea...is to get a better sense of which patients are at highest risk for progression and be able to tailor our treatments." – Sean (11:07)

Timestamps for Major Segments

[02:26] Introduction of Real-World Case & Initial Diagnostics
[04:10] Bone Marrow Biopsy Workup Explained
[06:06] Plasma Cell Enumeration: Flow vs. IHC
[07:48] Clonality, Kappa/Lambda Restriction, and Role of FISH
[08:34] Cytogenetic Features and Their Clinical Impact
[11:07] 2025 IMS/IMWG Risk Definition Updates
[13:11] Pathophysiology of Myeloma Progression
[14:55] Response Criteria: PR, VGPR, CR, MRD Negative
[18:58] MRD Assessment Techniques and Clinical Implications
[24:03] Prognostic Value of MRD
[25:57] MRD as Surrogate Endpoint; Future of Therapy De-escalation

Final Thoughts

The episode masterfully demystifies the evolving landscape of risk assessment and response evaluation in multiple myeloma. The hosts blend foundational principles with up-to-the-minute clinical updates—emphasizing that risk stratification is dynamic, diagnostic tools are rapidly improving, and the role of MRD is ascendant in both research and care. The take-home message: always look up the latest criteria, tailor treatment to individual risk, and watch this space for new evidence to inform real-world decision-making.

Next episode: Practical Applications—Frontline Treatment of Myeloma, broken down and fully updated for 2026.

The Fellow on Call: The Heme/Onc Podcast

Episode Overview

Key Discussion Points & Insights

1. Real-world Case & Diagnostic Approach (02:26 – 07:48)

Case Introduction: 63-year-old female with IGG kappa M spike, abnormal light chain ratio, and lytic bone lesions—classic presentation escalating from high-risk MGUS toward symptomatic multiple myeloma (02:26).
Diagnostic Process:
- Bone Marrow Biopsy: Aspirate for smears, flow cytometry, cytogenetics, molecular testing; core biopsy for architecture and immunohistochemistry (IHC).
- Flow Cytometry vs. IHC:
  - Flow helpful for detecting aberrant immunophenotype and light chain restriction but can underrepresent plasma cells (06:06).
  - IHC (e.g., CD138 staining) preferred for quantifying plasma cell percentage.
- Importance of Kappa/Lambda Restriction: "If they're all choosing kappa or all choosing lambda, that's suggestive of clonality." – Vivek (07:48).
- Baseline Labs: Serum beta-2 microglobulin, albumin, LDH essential for staging and risk (09:33).

2. Cytogenetics & Risk Stratification in Myeloma (07:48 – 13:11)

FISH Testing and Plasma Cell Enrichment: Essential to specifically enrich for plasma cells before cytogenetic analysis.
Key Cytogenetic Abnormalities:
- High Risk:
  - t(4;14), t(14;16), t(14;20), deletion 17p, amplification 1q (≥4 copies), and biallelic deletion 1p.
  - Special Note: t(11;14) associated with venetoclax sensitivity (09:33).
- Updated Criteria (2025 IMS/IMWG): Combination of cytogenetic hits—interaction between mutations now recognized as the real driver of risk (11:07).
- Beta-2 Microglobulin: >5.5 mg/L (with normal creatinine) is a powerful high-risk marker.
Remember: Definitions are evolving; always check trial-specific criteria (13:11).

"Look up these criteria. Super important." – Vivek (13:11).

3. Response Criteria in Myeloma (14:55 – 18:58)

IMWG Response Categories:
- Partial Response (PR): ≥50% reduction in M-spike.
- Very Good Partial Response (VGPR): ≥90% reduction in M-spike.
- Complete Response (CR): Disappearance of M-spike.
- MRD Negative/Positive CR: Adds molecular depth to remission status.
- Disease Progression:
  - 25% increase from nadir in M-spike or free light chains, plus absolute value thresholds.
  - New/plasma cytomas or bone lesions also constitute progression (14:55).
Clinical Pearls:

"It's always best to get to at least a VGPR prior to transplant." – Vivek (16:36).
Stringent CR: Outmoded by the use of MRD testing (16:36).

4. MRD (Measurable/Minimal Residual Disease): Deep Dive (18:58 – 25:57)

Why MRD Matters:
- Detects disease below morphologic thresholds; growing evidence for improved PFS and potentially OS (25:57).
- MRD negativity now a surrogate endpoint for drug approval (FDA/ODAC 2025).
Techniques:
- Next Generation Flow (NGF): Standardized, sensitive to 1 in a million cells, requires live cells processed quickly; won’t detect clonal evolution (18:58–21:19).
- Next Generation Sequencing (NGS): Highly sensitive (down to 1 in 10 million), based on VDJ recombination as "barcode"; requires baseline clone identification, more expensive and slower (21:19–23:44).
Clinical Implications:

"Patients with multiple myeloma inevitably relapse... If we can't detect this at a one in a million threshold, obviously that patient's gonna have a better prognosis." – Vivek (24:03).
- MRD will likely guide therapy de-escalation (not escalation) in the future (27:33).

5. Future Directions & Takeaways (25:57 – End)

MRD-Guided Management:
- Ongoing trials exploring if sustained MRD negativity can justify stopping maintenance therapy.
"We may be able to identify patients that might be lower risk for progression and can be closely monitored." – Sean (25:57).
- De-escalation parallels with other cancers (e.g., response-adapted therapy in Hodgkin lymphoma—RATHL study).
"If we're making patients live longer, let's make them live as best as possible during that time period." – Vivek (27:33).
Upcoming Episodes: Focus on frontline treatment strategies and practical application of these criteria and tools.

Notable Quotes & Moments

On Cytogenetics:

"If you’re seeing deletion 17p or loss of p53, you’re in kind of a high-risk territory." – Dan (08:34)
On MRD Value:

"MRD negativity is going to be a surrogate for improved overall survival and potentially opening the door towards determining whether or not someone's really been cured of this disease." – Dan (18:58)
On Evolving Criteria:

"Definitions are changing over time. Always check what the study actually used." – Sean (13:11)
On Real-World Practice:

"Early referral to transplant is very important in these patients with multiple myeloma." – Vivek (16:36)
On Therapy Strategy:

"Let's de-escalate therapy... That is likely the patient you're okay with de-escalating that therapy for." – Vivek (27:33)
On the Purpose of Risk Stratification:

"The whole idea...is to get a better sense of which patients are at highest risk for progression and be able to tailor our treatments." – Sean (11:07)

Timestamps for Major Segments

[02:26] Introduction of Real-World Case & Initial Diagnostics
[04:10] Bone Marrow Biopsy Workup Explained
[06:06] Plasma Cell Enumeration: Flow vs. IHC
[07:48] Clonality, Kappa/Lambda Restriction, and Role of FISH
[08:34] Cytogenetic Features and Their Clinical Impact
[11:07] 2025 IMS/IMWG Risk Definition Updates
[13:11] Pathophysiology of Myeloma Progression
[14:55] Response Criteria: PR, VGPR, CR, MRD Negative
[18:58] MRD Assessment Techniques and Clinical Implications
[24:03] Prognostic Value of MRD
[25:57] MRD as Surrogate Endpoint; Future of Therapy De-escalation

Final Thoughts

Next episode: Practical Applications—Frontline Treatment of Myeloma, broken down and fully updated for 2026.

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Episode 144: Myeloma Series, Pt. 5 - Myeloma Risk Stratification and Response Criteria (2026)

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Summary

The Fellow on Call: The Heme/Onc Podcast

Episode Overview

Key Discussion Points & Insights

1. Real-world Case & Diagnostic Approach (02:26 – 07:48)

2. Cytogenetics & Risk Stratification in Myeloma (07:48 – 13:11)

3. Response Criteria in Myeloma (14:55 – 18:58)

4. MRD (Measurable/Minimal Residual Disease): Deep Dive (18:58 – 25:57)

5. Future Directions & Takeaways (25:57 – End)

Notable Quotes & Moments

Timestamps for Major Segments

Final Thoughts

Summary

The Fellow on Call: The Heme/Onc Podcast

Episode Overview

Key Discussion Points & Insights

1. Real-world Case & Diagnostic Approach (02:26 – 07:48)

2. Cytogenetics & Risk Stratification in Myeloma (07:48 – 13:11)

3. Response Criteria in Myeloma (14:55 – 18:58)

4. MRD (Measurable/Minimal Residual Disease): Deep Dive (18:58 – 25:57)

5. Future Directions & Takeaways (25:57 – End)

Notable Quotes & Moments

Timestamps for Major Segments

Final Thoughts