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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

#MMSM #MultipleMyeloma ⚡️#MedSky join me & my friend Dr. Krina Patel In a #CME 🧵exploring efficacy of quad tx in #NDMM 🔬PERSEUS, GMMG-HD7 & CONCEPT, CEPHEUS, IMROZ, ADVANCE, MIDAS +++ 🆓 CME from @bonumce.bsky.social 🔗 to CME ℹ️ 👉🏼 bonumce.short.gy/NDMM-TW1-CME Supported by an edu grant from Janssen

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

2/ Before we jump in, a few disclosures & important links🔗 1️⃣📖#CME info bonumce.short.gy/NDMM-TW1-CME 2️⃣Take the pre-survey 👉bonumce.short.gy/NDMM-TW1-Pre 3️⃣Get the latest NDMM quad tx efficacy data w/ 🧵👇 4️⃣🏆Claim🆓CME bonumce.short.gy/NDMM-TW1-Post Now, let's get started!

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

3/🥼In your practice, which regimen are you using most often for 1L therapy in pts w/ transplant eligible (TE) #NDMM? ☎️ #MedSky #HemeSky 💬 reply and let us know what you do in your practice? 1️⃣ DVRd quad 2️⃣ IsaVRd quad 3️⃣ DKRd or IsaKRd quad 4️⃣ VRd 5️⃣ other triplet

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

4/💃Quads are taking center stage in NDMM Let’s look @ the📈 on quad tx PERSEUS ~🔑 trial: SQ dara➕VRd ➡️ ↑outcomes in TE pts 👉↑PFS @ 48m 84.3 v 67.7%; HR: 0.42; P<0.001 👉↑MRD- rate 75.2 v 47.5%; P<0.001 👉↑CR rate 87.9 v 70.1%; P<0.001 🎉 🆕 SOC ~ quad instead of triplet 🎉

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

5/ PERSEUS #ASCO25: sustained MRD- in pts on quad maintenance median follow-up of 47.5m 👉 ↑ sustMRD- at ≥24m w DVRd v VRd: 55.8 v 22.6% 👉 Pts w ≥12m sustMRD-: ↑ 48m PFS, regardless of tx 👉 Only 3.1% progression at 18m w DVRd v 6.8% VRd 🔑 DVRd ➡️ 2.5x ⬆️ ≥24m sustMRD- & ½ progression risk at ≤18m tx

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

6/🙋🏻What about replacing dara- with isa- in a quad? GMMG-HD7: IsaVRd v VRd induction ➡️ isa-len v len maintenance in TE NDMM 👉↑ MRD- rate 50% v 36%; p =0.00017 👉IsaVRd had ↓AE rates & ↓d/c rates v RVd 🎉🆕 SOC 👉Results ➡️ addition of IsaVRd as induction regimen for TE NDMM

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

7/⚡️GMMG-HD7 #ASCO25 update w/ PFS benefit in all quad recipients ↑CR 43.5% w IsaVRd v 34% w VRd ↑MRD- rate 66.2% w quad v 47.7% w triplet 👉PFS at 3yr benefit: 83% v 75% w/IsaVRd v VRd ↑MRD- regardless of maint v MRD+ (HR 0.61; P=0.002) 🔮Maintenance w Isa-len v len is on-going

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

8/🔬Exciting news for #mmsm Quad tx as🆕SOC for #NDMM Current EHA-EMN (1st optn) & NCCN (pref,cat 1) regimens for TE pts w/NDMM: 🎯DaraVRd➡️SCT➡️len maint 🎯IsaVRd SCT➡️len maint 👏to quad as 1L for TE pts👏 …but what about pts who are TIE /SCT-deferred?

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

9/CEPHEUS compared induction/consolidation w VRd ± daratumumab (D) followed by maintenance in transplant-ineligible (TIE) #NDMM The DVRd arm demonstrated which of the following outcomes? 💬 REPLY👇 1️⃣ Deep, more durable MRD- 2️⃣ ⬆️MRD- rates. No🔺in PFS 3️⃣ Similar efficacy, ⬆️VTE 4️⃣ ⬆️ D/C rate in DVRd arm

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

10/ CEPHEUS🔑 trial in TIE & SCT-deferrd pts DVRd ➡️ deeper, more durable MRD- rate TIE cohort: 👉Overall MRD- 63.2 v 41.4% 👉Sustained MRD @ ≥12m 48.7 v 26.3%; P<0.0001 👉CR 81.2 v 61.6%; P<0.0001 👉HR 0.57, 95% CI 0.41-0.79; P=0.0005 ↓D/C rate w quad 🎉DVRd new SOC for TIE NDMM🎉

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

11/Do results w isa show similar trends? IMROZ🔑trial IsaVRd ➡️ IsaRd v VRd ➡️ Rd in TIE pts w NDMM 👉IsaVRd ➡️↓time to MRD-: 14.7 v 32.8m 👉↑ PFS @ 60m: 63.2 v 45.2%; HR: 0.60; P<0.001 👉↑ CR: 74.7% v 64.1%; P=0.01 IMROZ results support IsaVRd as 🎉 🆕 SOC for TIE #NDMM pts

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

12/BENEFIT eval'd wkly bortezomib (V) in TIE NDMM IsaVRd➡️IsaVR➡️IsaR v IsaRd➡️IsaR➡️IsaR ↑MRD- rate @ 12mo 51% v 21%; OR: 3.88; 95%CI: 2.27-6.62;P<0.0001 18mo 53% v 26%; OR: 3.16; 95%CI: 1.89-5.28;P<0.0001 🔑Wkly V in IsaRd=deep responses Supports IsaVRd as🆕SOC for TIE NDMM

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

13/🆕SOC for pts w SCT-deferred or TIE #NDMM🎉 NCCN (preferred, cat 1) & EHA-EMN (1st optn) regimens: 🎯DRd ‘til progression; de-escalate prn 🎯DVRd ‘til progression; de-escalate prn(<80 yr old, not frail) 🎯IsaVRd ‘til progression; de-escalate prn(<80 yr old, not frail) #MMSM

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

14/Unfortunately, pts w high-risk (HR) #NDMM have 👎poorer prognosis & shorter survival rates vs standard-risk

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

15/ Based on results of GMMG-CONCEPT presented @ #ASCO2025, which treatment strategy should be used for pts w/ HR NDMM? 💬 reply/comment w/ your answer 💬 1️⃣ Initiate allogeneic SCT 2️⃣ Choose IV instead of subQ 3️⃣ Treat to MRD- then d/c tx 4️⃣ Treat to MRD- & cont maintenance

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

16/👏if you chose to treat to MRD- & cont maint GMMG-CONCEPT, largest cohort to eval MRD- in TE & TIE HRNDMM IsaKRd inductn & consolidatn➡️IsaKR maint➡️ ↑MRD- rate: 67.7% in TE & 54.2% in TIE Sustained ≥1yr: 62.6% in TE & 46.2% in TIE 🎉IsaKRd➡️↑deep remissions

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

17/📣GMMG-CONCEPT ASCO2025 update, TE pts: 73.2% MRD- post-consolidatn; p=1.91x10-13 86.8% MRD- @ any time 58.4% MRD- ≥CR 40.6% retained ≥2yr sust MRD- Med follow-up: 43m(0-90.2m) mPFS: 72.8m 5yr OS: 72% 6yr OS: 69% ⬆️2yr sustMRD-, ⬆️PFS, 69% OS @ 6yr IsaKRd:🆕SOC for HRNDMM

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

18/ADVANCE🔑trial demonstrating dara+ standard KRd ➡️↑outcomes in NDMM independent of TE ↑MRD- rate: 59% v 36%, adjOR = 2.5; P<0.0007➡️ 2.5x ↑MRD- rate w/DKRd 👉No new safety concerns ❓Impact on EFS, PFS & OS TBD DKRd👉1L for all pts on KRd backbone regardless of TE status

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

19/ Looking across trials... e.g. 🔬CEPHEUS 🔬IMROZ 🔬GMMG-CONCEPT 🔬ADVANCE… 🥅 MRD negativity emerges as benchmark to create a level playing field Across🔬, regimens, & now✅ FDA approved as clinical trial endpoint April ‘25

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

20/MIDAS eval’d MRD-guided consolidatn post 1L IsaKRd in TE NDMM Post 1L, no 🔼 in MRD- rates for all pts Tailoring tx to MRD post 1L may not ➡️ MRD- If respond to 1L tx may not need tandem SCT to reach MRD-; cont anti-CD38 &PI 🤔High # pts w t(11;14): impact time to MRD- results?

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Joseph Mikhael MD @jmikhaelmd.bsky.social · 24/09/2025

21/ 1L in TE & TIE for NDMM 🔑 SUMMARY🔑 🎯Triplet WAS standard approach, but quad is🆕SOC 🎉Quad is preferred 1L for TE NDMM v triplet 🆕SOC: IsaRVd for TIE NDMM🎉 🎯MRD- emerging as a benchmark in🔬 & clin decision making 👏Great news for pts & Don't forget to claim #CME > bonumce.short.gy/NDMM-TW1-Post

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NDMM ~ Tweetorial #1: Efficacy of Quad Therapies ***Post-Survey & Application for Credit***

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

1/ Best practices for 2L+ tx #MetastaticUrothelialCarcinoma 🧵 w🌟 @tiansterzhangmd.bsky.social & me ...assuming EV+P 1L ✅FGFR3 alts: THOR/erda 🎯Trop-2: sacituzumab govitecan 🏁HER2 IHC 3+: T-DXd Support by edu grants: Astellas, Gilead Sci, Merck, Seagen #CME from @bonumce.bsky.social ℹ️👇

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

2/ 📸👇COI & CME info👇 Full #CME ℹ️ bit.ly/muc_tw2 1️⃣ Answer Pre-survey 👉 bit.ly/muc_tw2_pre 2️⃣ Review #MedTweetorial👇 3️⃣ claim CME🏆bit.ly/muc_tw2_post #MedTwitter #OncTwitter #gucsm #BladderCancer #MetastaticUrothelialCarcinoma #OncX #CommunityOncology

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

3/Chemo-naive cisplatin eligible pts 👇Post-1L IO monotx👇 💡2L gem+cisplatin (or ddMVAC) pref'd 💡Erda for FGFR3 mut/fusion (THOR level 1 evidence for erda post-IO) 👉Cisplatin ineligible pts can get gem+carbo or EV (or erda if FGFR3+ alt) #OncSky

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

4/Preferred 2L tx for cisplatin-ineligible pts after 1L ICI monoTx ✅EV or ➡️gem + carbo or ➡️erdafitinib (if FGFR alt+) 👉Pembro alone is one of2L tx options for pts who progress after 1L platinum-based chemo and have not received ICI #OncSky

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

5/Other 2L options(depending on prior tx): ✔️Erda for FGFR3 alterations ✔️EV monotx Taxane if no access to☝️ ✔️Nivo or avelumab if no access to pembro + ICI naïve ✔️T-DXd for HER2 3+ IHC (gastric Ca scoring) ✔️Sacituzumab govitecan (FDA indication withdrawn) @pcvblack.bsky.social #OncSky

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

6/Atezolizumab EMA approved as monotx ✓1L in cisplatin-ineligible + PD-L1 +ve Based on IMvigor 210 & 130 trials 🔬IMvigor 130: ✅mPFS significantly longer in atezo+plat/Gem vs plat/Gem alone 🚫mOS not sign. longer in atezo grps vs plat/Gem alone @oncobellmunt.bsky.social @sandysrimd.bsky.social

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

7/ IMvigor130 safety results 👇 🎯 Fewer AEs ➡️ withdrawal of any agent in atezo only group 🎯 Most common TRAEs mainly related to chemo ✓ Anemia ✓ Neutropenia ✓ Thrombocytopenia #OncSky

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

8/Even w pembro➡️24 mo PFS rate in KEYNOTE-045 was 12.4%👉Pts likely to need subsequent line tx 🧐NCCN guidelines RE: next tx? Options (if not given prior): 🔶EV 🔶Erda for FGFR3 alt 🔶T-DXd for HER2 IHC 3+ (gastric Ca scoring) 🔶Saci(indication withdrawn, still in NCCN gdlns)

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

10/➡️Erdafitinib cont. 👍mOS and mPFS significantly ⬆️in erdafitinib group vs taxane or vinflunine THOR1 trial efficacy results 👇 #OncSky @achoud72.bsky.social @pbarata95.bsky.social @crisbergerot.bsky.social @paulobergerot.bsky.social @alisonbirtle.bsky.social @laurabukavinamd.bsky.social

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

11/Erda. Safety Grade ≥3 TRAEs occurred in 45.9% w erdafitinib & 46.4% w chemo ⚖️Most AEs w erdafitinib manageable w dose modification & best supportive care 🛑Tx d/c rates 8.1% w erdafitinib & 13.4% w chemo #OncSky #BladderCancer

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

14/💡For phosphate of 8.0 mg/dL, withhold erdafitinib & restart once phosphate <5.5 mg/dL 🙌Erdafitinib=good option for pts w susceptible FGFR3 alt ⚖️What about pts who progress after 1L tx & no FGFR3 alt? ⚖️How does the changing 1L tx landscape w EV+P affect choice of 2L tx?

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

15/🏁What about T-DXd in mUC? 1st tumor agnostic ADC w FDA approval for Tx-refractory HER2+ IHC3+ Cas From DESTINY-PanTumor02 16 pts w/ HER2 IHC3+ mUC 56.3% ORR, mPFS 7.4mo, mOS 13.4mo No significant neuropathy 🔑AEs: pneumonitis, neutropenia, N/V, left ventricular dysfunction

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

16/Sacituzumab govitecan(SG) an ADC 🎯Trop-2 An active agent in mUC but failed to show stat. significant longer OS over taxane or vinflunine (VIN) in TROPiCS-04 ✅FDA approval w/drawn~Oct 2024 👉Let’s look @ original approval & possible reasons for a negative P3 trial

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

17/#TROPHYU01 Cohorts 1,2,3👇 1️⃣=113 pts who progrs'd after plat chemo+ICI ✅Notable efficacy compared to hist cntls Led to accel approval 2021 2️⃣=38 cisplatin-inelig pts s/p ICI tx ✅ORR=32% 3️⃣= 41 pts who progrs'd after plat chemo w 2L SG+pembro ✅ORR=41% mPFS=5.3m mOS=12.7m

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

18/🔬TROPHY-U-01 Cohort 3 trial safety of sacituzumab govitecan👇 TRAEs led to➡️ ✋SG interruptions in 46% ⬇️SG dose reduction in 39% 🛑SG d/c in 15% @markuseckstein3.bsky.social @amandanizammd.bsky.social #OncSky

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

19/TROPiCS-04 Ph3 RCT SG vs chemo in pretx mUC 🚫sig. improvmt in OS w/ SG compared to taxane or VIN mOS: SG 10.3 vs chemo 9.0mo (HR:0.86; 95% CI:0.73–1.02; p=0.087) Grade ≥3️ TRAEs (SG): Neutropenia(35%; FN 12%), diarrhea (15%) G5 AEs: SG 7% (16 inf w neutropenia), chemo 2%

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

21/Why TROPiCS4 neg for OS? Hard to est, consider: 🔸Late-line,hvly pretx pop 🔸Ltd primary G-CSF prophy in SG arm(~20%) 🔸~5% pts randomized to control never rec’d tx(~2% in SG arm) 🚫biomarker selection(UGT1A1 gene polym→⬆️tox?) 🔸~20% in each arm rec'd salvage EV(confounding)

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

23/🔑SUMMARY🔑 2L & later line tx in mUC 👉Erdafitinib FDA-approved w/ FGFR3 alt after prior tx 🎉NCCN guidelines updated Jan 2025 🔬Ongoing trials for SG in diff clin scenarios ✔️T-DXd for HER2 IHC3+ (based on gastric cancer scoring algorithm)

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pgrivasmdphd.bsky.social @pgrivasmdphd.bsky.social · 02/04/2025

Don't forget to complete the post-survey & 🏆 Claim #CME 👉bit.ly/muc_tw2_post

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