The Fellow on Call: The Heme/Onc Podcast

Episode 145: Myeloma Series, Pt. 6 – First Line Treatment of Multiple Myeloma (2026)
Date: January 21, 2026
Hosts: Ronak (A), Vivek (B), Sean (C)
Rouleaux University Medical Center

Episode Overview

This high-yield episode continues the updated Myeloma Series, focusing on the evolving landscape of first-line treatment for Multiple Myeloma as of 2025–2026. The hosts break down the latest evidence and expert consensus for both transplant-eligible and ineligible patients, clarify new terminology (quadruplet vs. triplet induction), and provide guidance on risk stratification, regimen selection, and major clinical trial data influencing modern practice. The discussion is accessible for trainees, providers, and anyone interested in hematology–oncology fundamentals.

Key Discussion Points & Insights

1. Case-Based Introduction: Setting the Stage

[02:35]

• A 63-year-old, newly diagnosed with IgG Lambda multiple myeloma—standard risk, involved bones, anemia, PET-CT and pathology reviewed.
• Entry question: How do we approach first-line multiple myeloma treatment in 2025?

2. Treatment Phases and Modern Strategy

[04:05 - 07:40]

Standard Treatment Phases:

• Induction: “Debulk the disease”—typically 4–6 months aiming for deep responses (VGPR or better).
• Stem Cell Collection: Maximized after induction, before marrow compromise.
• Consolidation: Deepen response, often with high-dose melphalan + autologous stem cell rescue (“high-dose chemotherapy with stem cell rescue”—not an ‘immune’ transplant).
• Maintenance: Prolong remission with lower-intensity therapy, commonly oral lenalidomide, sometimes combined with daratumumab or bortezomib.

Notable Quote [06:04], Sean:

“You can think of stem cell transplant for myeloma as really high-dose chemotherapy with a stem cell rescue. That’s why we use a patient’s own stem cells—it’s not about the immune system, but the chemo intensity.”

3. Evolving Eligibility: Transplant & Quadruplet Therapy

[08:09 - 10:02]

• Transplant eligibility: More physiologic than chronologic (generally <75 years, good functional status, minimal comorbidities).
• Melphalan dose adjustment: MEL140 for older/renal-impaired; MEL200 standard for most.
• Quadruplet eligibility: No strict guideline—tailored to fitness, comorbidities; ongoing research to define benefit/risk in older/frailer populations.

Quote [09:28], Ronak:

“If you want to think about it, patients eligible for a major surgery are probably the same ones who may be eligible for transplant.”

4. Modern Induction: Triplet vs. Quadruplet Regimens

[10:47 - 13:18]

Key Drug Classes:

• Anti-CD38 monoclonal antibody: Daratumumab or isatuximab (always included if available)
• Steroid: Dexamethasone
• IMIDs: Lenalidomide (Revlimid), pomalidomide
• Proteasome inhibitors: Bortezomib (Velcade, “V”), carfilzomib (Kyprolis, “K”)
• Alkylators (less common in induction): Cyclophosphamide

Regimen Nomenclature:

• “VRD” = Velcade (bortezomib), Revlimid (lenalidomide), Dexamethasone
• “KRD” = Kyprolis (carfilzomib), Revlimid, Dexamethasone
• “Dara-VRD” = Daratumumab + VRD

Notable Quote [13:18], Vivek:

“It sounds complicated, but with our chart you’ll see — lenalidomide is R, bortezomib is V, carfilzomib is K. That alphabet soup starts to make sense after a while.”

5. Risk Stratification: High-Risk Myeloma Features

[14:57 - 16:26]

High risk defined by cytogenetics:

• Del(17p) / TP53 mutation
• Translocations: t(4;14), t(14;16), t(14;20)
• del(1p), gain(1q) (biallelic or both)
• β2-microglobulin >5.5 with normal creatinine
• Check show notes for full criteria.

Quote [15:30], Ronak:

“Always remember 17p is where P53 exists. So a deletion here is high risk, just like in other blood cancers.”

6. Historical Perspective: How We Got Here

[17:43 - 21:04]

• 1960s-80s: Low-dose melphalan (+ prednisone) was standard, then high-dose + transplant developed.
• IMIDs/proteasome inhibitors: Replaced chemotherapy, established efficacy of combinations (e.g., CyBorD, VCD).
• Pivotal trials:
  • SWOG S0777: VRD superior to RD (triplet > doublet), became standard.
  • Endurance trial: KRD vs VRD — no difference, VRD remained standard.

Quote [20:36], Vivek:

“VRD remained king for a while. That triplet was the gold standard, setting the stage for today’s pivotal quadruplet trials.”

7. Pivotal Trials: Quadruplet Induction in 2025

[21:04 - 29:41]

Perseus (Phase 3) & Griffin (Phase 2) Trials

• Compared Dara-VRD vs. VRD (quadruplet vs. triplet)
• Results:
  • 4-year PFS: 84% (Dara-VRD) vs. 68% (VRD)
  • MRD-negativity: 58% (quad) vs. 33% (triplet)
• Takeaway: Dara-VRD is new standard for eligible patients

Quote [22:25], Sean:

“These are great numbers for PFS—just 15, 20 years ago, that was unimaginable.”

Surrogate Endpoints: MRD Negativity

• Evidence Meta-analysis: Established MRD negativity as a surrogate for PFS in clinical trials, supporting faster drug approvals.

Quote [24:03], Vivek:

“If we improve MRD-negativity rates, we’re likely going to get a significant PFS improvement, and that’s why it’s now an acceptable FDA approval target.”

MASTER & IsKia Trials

• MASTER: DARA-KRD, MRD-adapted phase II; careful de-escalation if MRD-negative.
• IsKia: Isatuximab-KRD vs. KRD (phase III); again, quadruplet improves MRD-negativity, but watch for cross-trial comparison errors.

Quote [28:23], Ronak:

“This adds credibility to MRD as our guide for future management—but it’s not so simple. High risk still needs tailored approaches.”

8. First-Line Options for Quadruplet-Ineligible or Frail Patients

[29:41 - 32:39]

Triplet Regimens

• MAYA Trial: Dara-RD (daratumumab, lenalidomide, dexamethasone) vs. RD
  • 5-year PFS: 60% (triplet) vs. 30% (doublet)
  • Still strong for frailer/non-transplant patients

Quadruplet in Transplant-Ineligible

• CEPHOUS, IMROZ trials: Quadruplets (Dara/Isa-VRD) vs. triplet in older or non-transplant candidates
• Improved MRD-negativity, higher 5-year PFS—but also higher infections (grade 3+)

Quote [32:15], Sean:

“There’s a significant increase in how well we treat myeloma with these regimens, but also an increased risk of infection. So patient selection is absolutely critical.”

9. Head-to-Head of Triplet vs Quadruplet (with anti-CD38)

[34:10 - 36:41]

• BENEFIT Study: Isa-VRD vs Isa-RD (quad vs triplet, both with anti-CD38)
  • Showed improved MRD-negativity in quadruplet
  • No mature PFS or OS difference yet; infection data incomplete, especially for severe events
  • Caution: Excluded patients over 79 years

Quote [35:24], Ronak:

“They didn’t really publish the grade 3 infection rates, which is crucial—so that’s a flaw in the available data so far.”

10. Practical Pearls & Final Thoughts

[36:41 - 40:13]

Summary of Key Takeaways

• Quadruplet induction (anti-CD38 + IMID + PI + Dex) offers longest PFS but increases infection risk—especially in frail patients.
• Don’t feel pressured to always use quadruplet; triplet regimens (especially with anti-CD38) are still excellent in less fit populations.
• MRD-negativity is an important surrogate, but nuanced approaches still needed for high-risk or older patients.
• Early referral to a transplant center is key; as a generalist, focus on picking the most effective regimen for the patient’s fitness level.

Quote [37:37], Sean:

“If you’re a fellow or practicing in the community, pick the regimen that’s most effective for your patient, and refer early for transplant eval. That decision is very nuanced.”

Quote [38:57], Vivek:

“You’re not wrong by doing a triplet with an anti-CD38 agent. That’s a very good regimen... but the decision point is not easy.”

Practical Tips

• Familiarize with regimen abbreviations (“alphabet soup”).
• Monitor for and proactively prevent infections.
• Adjust maintenance/intensity based on MRD and individual risk.
• Watch for upcoming trial data and updates on whether maintenance or shorter/fixed-duration therapies become new standard.

Notable Quotes & Memorable Moments

| Timestamp | Speaker | Quote | |-----------|---------|-------| | 06:04 | Sean | “You can think of stem cell transplant for myeloma as really high-dose chemotherapy with a stem cell rescue.” | | 09:28 | Ronak | “Patients eligible for a major surgery are probably the same ones who may be eligible for transplant.” | | 13:18 | Vivek | “It sounds complicated, but with our chart you’ll see — lenalidomide is R, bortezomib is V, carfilzomib is K. That alphabet soup starts to make sense after a while.” | | 15:30 | Ronak | “Always remember 17p is where P53 exists. So a deletion here is high risk, just like in other blood cancers.” | | 20:36 | Vivek | “VRD remained king for a while. That triplet was the gold standard, setting the stage for today’s pivotal quadruplet trials.” | | 22:25 | Sean | “These are great numbers for PFS—just 15, 20 years ago, that was unimaginable.” | | 24:03 | Vivek | “If we improve MRD-negativity rates, we’re likely going to get a significant PFS improvement, and that’s why it’s now an acceptable FDA approval target.” | | 28:23 | Ronak | “This adds credibility to MRD as our guide for future management—but it’s not so simple. High risk still needs tailored approaches.” | | 32:15 | Sean | “There’s a significant increase in how well we treat myeloma with these regimens, but also an increased risk of infection. So patient selection is absolutely critical.” | | 35:24 | Ronak | “They didn’t really publish the grade 3 infection rates, which is crucial—so that’s a flaw in the available data so far.” | | 37:37 | Sean | “If you’re a fellow or practicing in the community, pick the regimen that’s most effective for your patient, and refer early for transplant eval. That decision is very nuanced.” | | 38:57 | Vivek | “You’re not wrong by doing a triplet with an anti-CD38 agent. That’s a very good regimen... but the decision point is not easy.” |

Important Timestamps

• [02:35] – Case introduction and treatment approach
• [04:05] – Review of treatment phases (induction, consolidation, maintenance)
• [10:47] – Modern induction: triplet vs. quadruplet regimens explained
• [14:57] – Risk stratification in 2025
• [17:43] – Historical evolution of myeloma therapy
• [21:04] – Key trials for quadruplet regimens (Perseus, Griffin)
• [25:58] – MRD-adapted strategies (MASTER, IsKia)
• [29:41] – First-line therapy for quadruplet-ineligible/frail patients
• [34:10] – BENEFIT study (quadruplet vs. triplet with anti-CD38)
• [36:41] – Recap and clinical pearls

Wrap-up

This episode provides a cogent, up-to-date roadmap for first-line myeloma therapy, blending practical clinical reasoning, clear explanations of trial data, and wisdom for tailoring regimens to individual patient risks and goals. The hosts emphasize nuanced decision-making, high expectations for modern therapies, and the need for ongoing learning as data continue to emerge.

Pro tip: Check the episode show notes for regimen charts and full risk stratification criteria!