Understanding the Disease: Why Early, Aggressive Intervention Matters

Multiple myeloma is a cancer of plasma cells in the bone marrow, leading to overproduction of abnormal proteins (M-protein), bone destruction, anemia, kidney damage, and immune suppression. It affects about 35,000 new patients annually in the U.S. alone. Risk factors include age (median diagnosis at 65–70), family history, obesity, and monoclonal gammopathy of undetermined significance (MGUS).

In my practice, I start with a comprehensive workup: bone marrow biopsy, PET-CT or whole-body low-dose CT, serum free light chains, cytogenetics/FISH for high-risk features (e.g., del(17p), t(4;14)), and MRD (minimal residual disease) assessment via next-generation sequencing. Staging uses the Revised International Staging System (R-ISS), incorporating lactate dehydrogenase (LDH), albumin, beta-2 microglobulin, and high-risk genetics. Early high-risk identification guides my aggressive stance — because in 2025, we can cure subsets of patients and extend remission for others.

Treating Newly Diagnosed Multiple Myeloma (NDMM): Transplant-Eligible Patients

For younger, fitter patients (under 70–75, good performance status), I always consider autologous stem cell transplant (ASCT) as consolidation.But induction therapy has revolutionized this space.

My Go-To: The Quadruplet Regimen (Daratumumab + VRd) Based on the PERSEUS trial (published 2024, now standard in 2025 NCCN guidelines), I start with four cycles of daratumumab (Dara) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) —the "quad" that's become my default for transplant candidates. This quadruplet achieves deeper responses (up to 88% stringent complete response rate) and superior progression-free survival (PFS) compared to triplet VRd alone. Why? Dara, the anti-CD38 monoclonal antibody, targets myeloma cells directly and boosts immune response.

• Regimen Details: Dara IV/subQ weekly x3 in cycle 1, then biweekly; bortezomib SQ weekly; lenalidomide 25 mg days 1–21; dex 40 mg weekly.
• Response Goal: Achieve MRD negativity (10^-5 sensitivity) before transplant.
• Followed By:Stem cell collection after induction, ASCT with melphalan 200 mg/m², then two cycles of consolidation (same quad), and indefinite maintenance with Dara + lenalidomide. This extends PFS to over 60 months in many.

For high-risk patients (e.g., extramedullary disease or R-ISS III), I might incorporate isatuximab (another anti-CD38) or escalate to clinical trials with bispecifics like teclistamab early. Side effects? Neuropathy from bortezomib (I dose-reduce proactively) and infections (I use acyclovir, levofloxacin prophylaxis).

NDMM in Transplant-Ineligible Patients: Frailty Doesn't Mean Feeble Treatment

For older or frail patients (IMWG frailty score ≥2, common over age 75), I avoid transplant but don't skimp on efficacy. The 2025 EHA-EMN guidelines emphasize doublet or triplet options tailored to comorbidities.

My Preferred: Dara-Rd or Isa-VRd Lite

• Daratumumab + Lenalidomide/Dexamethasone (Dara-Rd): From the MAIA trial, this continuous regimen yields a median PFS of 31+months with low toxicity. Ideal for intermediate-risk; Dara subQ every two weeks after cycle 3.
• For Fitter Ineligible: Isatuximab + VRd (Isa-VRd), per the IMROZ trial — weekly bortezomib only in cycles 1–2 to minimize neuropathy. In the 2025 REST trial, this achieved 80% response in average-age-77 patients.Maintenance?Lenalidomide alone (10 mg days 1–21) for standard-risk; add Dara if high-risk. I monitor every 3 months with labs and imaging, adjusting for cytopenias.

Relapsed/Refractory Multiple Myeloma (RRMM): Sequencing Immunotherapies Wisely

Relapse is inevitable, but 2025's toolkit — CAR-T, bispecifics, ADCs — makes it a new battle each time. I stratify by lines of prior therapy, duration of response, and extramedullary disease.

Early Relapse (1st–2nd Line):

• If prior lenalidomide-exposed: Switch to pomalidomide + Dara + dex (from APOLLO).
• High-risk or short response: CAR-T like idecabtagene vicleucel (Abecma) or ciltacabtagene autoleucel (Carvykti) — real-world data shows 73% overall response rate (ORR) and durable remissions up to 2 years. I reserve for after 1–4 prior lines per updated NCCN.

Later Lines (3rd+):

• Bispecific Antibodies: Teclistamab (BCMA-CD3) or the new linvoseltamab (Lynozyfic, FDA-approved July 2025) — 71% ORR in heavily pretreated patients, now NCCN-preferred. SubQ, outpatient, but watch for CRS (cytokine release syndrome; I premed with tocilizumab).
• ADCs: Belantamab mafodotin (Blenrep) for corneal events (2025 guidance minimizes via lubrication). Or elranatamab.
• Triplet Backbones: Selinexor + pomalidomide/dex for penta-refractory cases.

For CNS involvement (rare but aggressive), I add intrathecal chemo or radiation. Always: Prophylaxis for infections (IVIG if IgG <400), bisphosphonates/denosumab for bones, and erythropoietin for anemia.

Supportive Care: The Unsung Hero of My Treatment Philosophy

I treat the whole patient. Bone health? Zoledronic acid q3–4 months. Kidney failure? Hydration, avoid NSAIDs, consider Dara avoidance if severe. Infections? Vaccinate against COVID, shingles, pneumococcus. Psychosocial support? Integrated palliative care from day one — myeloma's marathon, not sprint.Trials? I enroll 70% of my patients; 2025 hotspots include quadruplets with bispecifics and MRD-driven de-escalation.

The Hopeful Horizon: Toward Cure in Subsets

In my career, I've seen survival double. With quadruplets, MRD-guided therapy, and immunotherapies, 30–40% of standard-risk patients may achieve functional cure. High-risk? We're closing the gap with earlier CAR-T.

If you're facing myeloma, know this: It's not who you are; it's what we treat. Seek a myeloma center (NCCN-listed), ask for quadruplets, demand MRD testing. My patients live longer, fuller lives because we treat smart — and we treat now.

For personalized advice, consult your hematologist. The fight is winnable, one targeted therapy at a time.