NEJM in Review — August 13, 2026

This week’s standout is REPLENISH — secukinumab doubles sustained remission in relapsed polymyalgia rheumatica vs glucocorticoids alone, establishing the second biologic option after sarilumab. The Case Records delivers a textbook walkthrough of methanol toxicity: osmolar gap, fomepizole, and the hemodialysis trigger. Two oncology trials — LIBRETTO-432 (adjuvant selpercatinib for the rare RET+ NSCLC subtype) and MonumenTAL-5 (talquetamab-daratumumab in relapsed myeloma) — are summarized for awareness. VERVE-102 previews one-shot gene editing for LDL cholesterol, but this phase 1 study is not yet practice-changing.

RHEUMATOLOGYREPLENISH✓ HIGH YIELD · IM

Phase 3 Trial of Secukinumab in Polymyalgia Rheumatica

In relapsed PMR, does adding secukinumab (anti-IL-17A) to a glucocorticoid taper vs glucocorticoid taper alone improve sustained remission at 52 weeks?

Population: 381 patients ≥50 yr with relapsed PMR (≥1 relapse while tapering prednisone ≥5 mg/day). Mean age 70, 70% women. Excluded: GCA, RA.
Intervention: Secukinumab 300 mg or 150 mg SC weekly ×4, then q4 wk for 52 wk, plus a 24-wk prednisone taper.
Comparison: Placebo injections + the same 24-wk prednisone taper.
Outcome: Sustained remission at 52 wk: 41% (300 mg) and 41% (150 mg) vs 20% placebo (P<0.001). Complete sustained remission: 28% and 25% vs 5%. Annual GC dose ~20% lower. Rescue Tx needed: 51% vs 76%. One cryptococcal meningitis death (SEC-150 arm).

Clinical takeaway: REPLENISH establishes secukinumab (anti-IL-17A) as the second biologic for relapsed PMR, after sarilumab (anti-IL-6R). The editorial (Tanaka) frames this as a paradigm shift for GC-dependent older patients — but flags important nuance: the companion GCAptAIN trial of secukinumab in giant-cell arteritis was negative, likely because multilayered granulomatous vasculitis resists single-cytokine blockade. Tanaka describes the PMR effect as “relatively modest.” The ~20% reduction in cumulative GC exposure is clinically meaningful in this population (mean age 70; prevalent hypertension, diabetes, osteoporosis).

HEME/ONCLIBRETTO-432⚠ LOWER YIELD · NARROW ONC

Selpercatinib in Early-Stage RET Fusion–Positive NSCLC

In stage IB–IIIA RET fusion+ NSCLC after surgery, does adjuvant selpercatinib vs placebo improve event-free survival?

Population: 151 patients with stage IB–IIIA RET fusion+ NSCLC, post-surgery ± adjuvant chemo. RET fusions occur in 1–2% of NSCLC.
Intervention: Selpercatinib 160 mg BID for up to 3 yr.
Comparison: Placebo.
Outcome: 2-yr EFS: 92% vs 61% (HR 0.17; P<0.001). 3 deaths, all placebo. Grade ≥3 AEs 67% vs 24% (mostly ALT/AST). 17% discontinued for AEs.

Clinical takeaway: Extends the adjuvant targeted-therapy paradigm (ADAURA for EGFR, ALINA for ALK) to RET fusion+ NSCLC with a similarly striking HR. However, RET fusions affect only 1–2% of NSCLC patients — this is a subspecialized thoracic-oncology decision. The practical take-home for the generalist: comprehensive biomarker testing at NSCLC diagnosis matters, because actionable fusions now inform therapy at every stage.

HEME/ONCMonumenTAL-5⚠ LOWER YIELD · NARROW ONC

Talquetamab–Daratumumab in Relapsed or Refractory Myeloma

In R/R multiple myeloma after ≥1 line, does adding talquetamab (anti-GPRC5D bispecific) to daratumumab ± pomalidomide improve PFS vs DPd?

Population: 864 patients with R/R myeloma after ≥1 line (prior lenalidomide + PI). Excluded: anti-CD38–refractory, prior GPRC5D therapy.
Intervention: Tal-DP (talquetamab + daratumumab + pomalidomide) or Tal-D (talquetamab + daratumumab).
Comparison: DPd (daratumumab + pomalidomide + dexamethasone).
Outcome: 24-mo PFS: 81% (Tal-DP), 78% (Tal-D) vs 51% DPd (HR 0.28 and 0.33; P<0.001). CR or better: 71% and 69% vs 35%. MRD-negative CR: 52% and 46% vs 16%. CRS ~58–68% (mostly grade 1). GPRC5D-related: taste changes 73%, weight loss 46%, ataxia 14.5% (late onset, median 292 d).

Clinical takeaway: GPRC5D-targeting with talquetamab offers an alternative to BCMA-directed therapy in earlier myeloma lines, with deep responses and a distinct safety profile (taste changes, weight loss, ataxia rather than cytopenias). The late-onset ataxia signal (median ~10 months) is clinically meaningful and may limit cumulative dosing. A heme-oncology decision — the generalist should know GPRC5D is the new target class alongside BCMA.

Review Article

PREVENTIVE MEDICINE⚠ LOWER YIELD · IM

Evidence-Based Tobacco-Cessation Strategies for Low- and Middle-Income Countries • Only 31 of 195 countries meet WHO best practice for tobacco cessation (behavioral interventions + pharmacotherapy). 80% of the world’s 1.3 billion tobacco users live in LMICs. • The Ask–Advise–Connect model is a feasible, low-burden clinical pathway for routine integration. Cytisine and NRT are on the WHO Model List of Essential Medicines. • Key barriers highlighted through India (smokeless tobacco, ASHA worker integration, free NRT) and Vietnam (quitlines, out-of-pocket NRT costing 20% of monthly income) case studies: pharmacotherapy cost, weak enforcement, tobacco industry influence.

Case Records of the MGH

TEACHING CASE✓ HIGH YIELD · IM

Case 23-2026: A 28-Year-Old Woman with Nausea, Dizziness, and Metabolic Acidosis

Key learning point: The pivot is the osmolar gap. This 28-year-old presented with high anion-gap metabolic acidosis (bicarb 10, AG 21, pH 7.23) and a markedly elevated osmolar gap of 78 (measured 363 vs calculated 285; reference <10). With negative lactate, ketones, salicylates, and acetaminophen, a large osmolar gap points to toxic alcohol ingestion. Methanol was 190 mg/dL. Treatment triad: fomepizole (blocks alcohol dehydrogenase → prevents toxic metabolite formation), IV sodium bicarbonate (corrects acidosis), and emergency hemodialysis (cleared methanol in ~5 hr). Key timing caveat: the osmolar gap is highest early (parent compound present) and normalizes as it is metabolized to toxic acids — a normal gap does NOT rule out toxicity if presentation is delayed. The GOLD MARK mnemonic (Glycols, Oxoproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis) replaces the older MUDPILES. The strongest predictor of death in methanol poisoning is the degree of acidosis.

Also in this issue

In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia (Cardiology) — Phase 1, open-label, single-ascending-dose study of VERVE-102, a GalNAc-LNP–delivered base-editing therapy targeting hepatocyte PCSK9. 35 participants with HeFH or premature CAD; single IV infusion produced dose-dependent reductions in PCSK9 (up to 88%) and LDL cholesterol (up to 62%, absolute −78 mg/dL), durable through ≥1 yr. No dose-limiting toxicities. The editorial (Nordestgaard) states: this “will not have an immediate effect on clinical practice” — larger, longer studies with clinical endpoints are needed. Not an RCT — phase 1, surrogate-only, not yet practice-changing.

DOIs this issue: NEJMoa2602567 (REPLENISH) · NEJMoa2601283 (VERVE-102) · NEJMoa2602628 (LIBRETTO-432) · NEJMoa2604657 (MonumenTAL-5) · NEJMra2507061 (Tobacco Cessation) · NEJMcpc2603175 (Case 23-2026)

Trial registrations: NCT05767034 (REPLENISH) · NCT06164730 (VERVE-102/heart-1) · NCT04819100 (LIBRETTO-432) · NCT05455320 (MonumenTAL-5)

All summaries are original paraphrase for personal study; no publisher text is reproduced. Full articles available at nejm.org via institutional or personal access. Anki cards attached for high-yield items.