In this episode, Raj, Ashwin, and Eddie sit down with Dr. Vincent Rajkumar — Professor of Medicine at Mayo Clinic and Chair of the ECOG Myeloma Committee — for a clinically focused conversation on newly diagnosed multiple myeloma. Topics span baseline workup, risk stratification, induction selection, transplant timing, MRD-directed decision-making, and maintenance strategy. The episode closes with a discussion of Open Medicine, a new medical education platform, and Dr. Rajkumar's ongoing advocacy on drug pricing reform. KEY TOPICS DISCUSSED Baseline workup: 24-hour urine protein: It is important to obtain 24-hour urine protein with electrophoresis and immunofixation in all newly diagnosed patients — not for diagnosis, but to establish a baseline for long-term management and to distinguish M-protein from albuminuria. In patients where an FLC ratio ≥100 is the sole myeloma-defining criterion, a 24-hour urine Bence Jones protein ≥200 mg is part of the diagnostic threshold for treatment initiation. Myeloma cast nephropathy: when to biopsy: An involved FLC ≥50 mg/dL supports a presumptive diagnosis of cast nephropathy and treatment can begin without a kidney biopsy. Below this threshold — particularly if renal involvement is the sole myeloma-defining event — kidney biopsy is warranted to exclude light chain deposition disease, MPGN, or other unrelated disorders. It warrants aggressive early treatment (Dara-VCD or Dara-VD), starting even before bone marrow results are available when the diagnosis is clinically clear. Solitary plasmacytoma [with or without minimal bone marrow involvement]: Patients with ~10% clonal plasma cells technically meet criteria for myeloma, but management in this borderline zone warrants shared decision-making. Solitary plasmacytoma as sitting between smoldering myeloma and overt myeloma on the disease spectrum. Risk stratification: revised IMWG criteria: The new revision aimed to keep the high-risk designation to ≤15–20% of patients. Del 17p alone confers high-risk status. TP53 mutation without del 17p is exceedingly rare and FISH alone captures the vast majority of cases. All other cytogenetic abnormalities (t(4;14), t(14;16), t(14;20), 1q gain, 1p deletion, biallelic 1p) require at least one co-occurring abnormality to define high risk. Elevated β2-microglobulin with normal renal function is retained as a proxy for high tumor burden. Emergent indications for treatment initiation: The three situations warranting urgent treatment are acute cast nephropathy (days matter for renal recovery), cord compression (surgery vs. radiation vs. systemic therapy determined by acuity), and hypercalcemia. Induction regimen selection: For fit, transplant-eligible patients, the preferred induction is a quadruplet — Dara-VRd or Isa-VRd — with dose adjustment as needed. Triplets (Dara-Rd or Isa-Rd) are reserved for those unable to tolerate a quadruplet even with dose reduction. Carfilzomib-based induction is not favored: head-to-head data show no benefit of KRd over VRd in NDMM, and the cost differential is substantial. Lenalidomide dosing: Starting dose should be individualized: 15 mg for patients over 75, those with small body habitus (60 kg), or patients of Asian ethnicity. In octogenarians, starting at 5–10 mg is reasonable and allows upward titration based on tolerability and response. The 25 mg starting dose is not appropriate for many real-world patients. Response depth before transplant: Pursuing deeper response before ASCT by switching induction regimens is not supported by evidence and may result in patients never reaching transplant. All randomized trial data use fixed induction cycles regardless of response depth. In partial responders, high-dose melphalan itself delivers the deeper response — transplant is the treatment! MRD-directed transplant decision-making: We discussed MIDAS trial, and the main limitation being short follow-up thus far, but it does show limited utility of ASCT in patients who are MRD-negative post-induction. Maintenance therapy: Doublet maintenance (Dara-len or bortezomib-len) is recommended for high-risk patients and MRD-positive standard-risk patients. Lenalidomide alone is adequate for MRD-negative standard-risk patients. Duration of maintenance is likely more consequential than drug selection — results from the ECOG (len duration) and SWOG (Dara-len vs. len, dara duration) trials are anticipated. The future of induction therapy: Improving on Dara-VRd (85% PFS at 4 years) will require demonstrating either shorter treatment duration, a potential cure signal (plateau), or replacement of transplant with CAR-T or bispecifics. Trispecific antibodies may eventually replace multi-drug regimens. Trial design must account for the fact that studies starting now may not read out for a decade. Trial inclusion of high-risk subgroups: Cast nephropathy and plasma cell leukemia are frequently excluded from industry trials due to financial and regulatory risk to sponsors. Dr. Rajkumar argues that real-world observational studies and NIH/philanthropy-funded investigator-initiated trials are the most viable path to evidence generation for these high-risk, underserved populations. TRIALS & REFERENCES MENTIONED PERSEUS — Dara-VRd induction + Dara-len maintenance in transplant-eligible NDMM [https://pubmed.ncbi.nlm.nih.gov/38084760/]IMROZ — Isa-VRd vs. VRd in transplant-ineligible NDMM [https://pubmed.ncbi.nlm.nih.gov/38832972/]GRIFFIN — Dara-VRd vs. VRd in transplant-eligible NDMM [https://pubmed.ncbi.nlm.nih.gov/37708911/]MIDAS — MRD-directed transplant decision-making after Isa-KRd induction: https://pubmed.ncbi.nlm.nih.gov/40459097/ECOG (ongoing) — CybOrD vs. Dara-VD for frontline acute light chain cast nephropathyECOG (pending readout) — Fixed vs. indefinite lenalidomide maintenance durationSWOG (pending readout; DRAMMATIC Trial) — Dara-len vs. len maintenance; duration of daratumumabCanadian trial — Dara-R(V)D fixed duration vs. indefinite maintenanceRajkumar SV — AJH 2024: https://pubmed.ncbi.nlm.nih.gov/38943315/Rajkumar SV & Leung N — Cast nephropathy management: https://pubmed.ncbi.nlm.nih.gov/36990996/; IMWG consensus MCN management: https://pubmed.ncbi.nlm.nih.gov/37414019/Mayo Clinic series on Solitary plasmacytoma (+/- minimal BM involvement): https://pubmed.ncbi.nlm.nih.gov/42018661/ ABOUT OPEN MEDICINE Open Medicine is an independent, open-access medical education platform co-founded by Dr. Simon Chaudhuri with the goal of bridging the gap between academic expertise and community oncology practice. The platform delivers mobile-first, living clinical algorithms and expert-narrated content — free of paywalls — updated in real time as new data emerge. Dr. Rajkumar serves as a founding circle member, contributing myeloma algorithms and commentary. Follow OpenMedicine on X, LinkedIn and Bluesky:
