2025 IMWG Summit Slides Wednesday V9 by International Myeloma Foundation

Thank you to

2025 IMWG Summit Sponsors

SESSION 5: WORKING COMMITTEE REPORTS

SMOLDERING MULTIPLE MYELOMA COMMITTEE

BONE DISEASE COMMITTEE

Bone Disease Sub-Committee of the International Myeloma Working Group

IMWG Summit 2025

Evangelos Terpos, Jens Hillengass

Updates from Projects discussed during IMWG Summit 2024

Project 1. Retrospective Study on the Safety of Denosumab in patients with CrCl<30 ml/min

• No data on denosumab in this setting of Myeloma patients

• Collect the data focusing on safety, but also in efficacy

• Group decides to go on for an IMWG paper and abstract for IMS/ASH 2024 based on the patients’ data we collect within the next year

Evaluation of the safety

and efficacy

of denosumab

in patients with multiple myeloma and severe renal impairment

Data sent from 6 IMWG centers

1. Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, Athens, Greece (E. Terpos, I. Ntanasis-Stathopoulos)

2. Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA (S. Usmani, Carlyn Rose Tan)

3. University College London, London, UK (C. Kyriakou)

4. Department of Haematology, Odense University Hospital, Odense, Denmark (N. Abildgaard)

5. Universitaire Ziekenhuizen Leuven, Leuven, Belgium (M. Delforge)

6. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (D. Fantl)

IMWG Bone Subcommittee designed a retrospective study to evaluate denosumab efficacy and safety in MM patients with severe RI (eGFR based on CKD-EPI <30 ml/min/1.73m2).

A multi-institutional chart review was performed and data from patients diagnosed with symptomatic MM and RI, under active antimyeloma treatment and concurrent denosumab, were analyzed.

BONE SUBCOMMITTEE STUDY

E. TERPOS1, I. NTANASIS-STATHOPOULOS1, C. KYRIAKOU2, C. TAN3, N. ABILDGAARD4, M. DELFORGE5, D. FANTL6, C.

SEEHAUS6, E. CAMEIRO7, C. JOAO8,9, S. USMANI3

1. Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

2. Department of Haematology, University College London Hospital, London, UK

3. Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

4. Department of Haematology, Odense University Hospital, Odense, Denmark

5. Universitaire Ziekenhuizen Leuven, Leuven, Belgium ;

6. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

7. Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal

8. NOVA Medical School, Universidade Nova de Lisboa, Lisboa, Portugal; Hemato-Oncology Unit, Champalimaud Foundation, Portugal

 Best response to MM treatment for the whole cohort was as follows:

• 8 (8.2%) patients achieved ≥CR,

• 35 (35.7%) VGPR and

• 24 (24.5%) PR.

• Median time to response was 42 (28-90) days.  Regarding best renal response:

• 9 (9.2%) patients achieved CRrenal, • 12 (12.2%) PRrenal and 31 (31.6%) MRrenal.

• Median time to renal response was 30 (20-42) days

EVALUATION OF THE SAFETY AND EFFICACY OF DENOSUMAB IN PATIENTS WITH MULTIPLE MYELOMA AND SEVERE RENAL IMPAIRMENT; RESULTS FROM AN IMWG BONE SUBCOMMITTEE STUDY

E. TERPOS1, I. NTANASIS-STATHOPOULOS1, C. KYRIAKOU2, C. TAN3, N. ABILDGAARD4, M. DELFORGE5, D. FANTL6, C.

SEEHAUS6, E. CAMEIRO7, C. JOAO8,9, S. USMANI3

1. Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

2. Department of Haematology, University College London Hospital, London, UK

3. Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

4. Department of Haematology, Odense University Hospital, Odense, Denmark

5. Universitaire Ziekenhuizen Leuven, Leuven, Belgium ;

6. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

7. Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal

8. NOVA Medical School, Universidade Nova de Lisboa, Lisboa, Portugal; Hemato-Oncology Unit, Champalimaud Foundation, Portugal

• Fifty-one (52.0%) patients in our cohort developed hypocalcemia:

• 18 grade 1 (35.3%),

• 13 grade 2 (25.5%),

• 17 grade 3 (33.3%) and

• 3 grade 4 (5.9%) almost four times higher than the reported incidence for patients with normal renal function or mild/moderate RI.

• Lower baseline calcium levels and higher denosumab dose (120 vs. 60 mg) were associated with hypocalcemia.

• There were 3 (3.1%) cases of osteonecrosis of the jaw and no case of new skeletal-related events (SREs).

• Overall,ourfindingssuggestthat denosumab is effective and safe for MM patients with severe RI, provided that proactive measures are taken to mitigate hypocalcemia.

• Possibly 60 mg, monthly, is sufficient for these patients to prevent both SREsandhypocalcemia.

• However, further prospective research with larger cohort and longer follow-up period will confirm these results and refine treatment guidelines.

Project 1. Retrospective Study on the Safety of Denosumab in patients with CrCl<30 ml/min - Plan

• Anyone who is interested in this study can send us data

• Aim to publish the paper by the end of this year (hope to have acceptance by the IMWG breakfast meeting at ASH 2025)

Project 2. Building a platform for collaborative imaging studies

Concept Developmen t of Online Platform

Obtain IRB approval/ data share agreement Beta-testing Platform Upload images and clinical data

Image evaluation by radiologists

Data analysis

Publication

Background

Utility of 18FDG-PET/CT for Risk Prediction in Relapsed/Refractory Multiple

Myeloma Patients Undergoing

CAR-T Cell Therapy: An Analysis of Baseline and Early Assessment Scans After One and Three Months

Tamariz-Amador, L.E; Alfonso-Piérola, A; Palacios-Berraquero, M.L; Huerga-Domínguez, S; Panizo-Inogés, M; Rifón, JJ; Villar, S; Marcos-Jubilar, E, Valencia-Espinoza; M; Prósper, F; Betech-Antar, V; San-Miguel, JF; GarcíaVelloso, MJ; Rodríguez-Otero, P.

2.A. Image Analysis in Patients on Immunotherapies

=> Background

The presence of FL, PMD, EMD, and bone marrow uptake was assessed at different time points

2.A. Image Analysis in Patients on Immunotherapies

=> Background

At baseline EMD was the only variable associated with inferior PFS and OS

2.A. Image Analysis in Patients on Immunotherapies

=> Background

A negative scan at month 1 had no significant impact on PFS, but did have on OS

A negative scan at 3 months was associated with both improved PFS and OS

The presence of EMD at 3 months was still associated with worse PFS and OS

Conversely to basal scans, persistent hypermetabolic PMD at month 3 was associated with inferior PFS and OS

2.A. Image Analysis in Patients on Immunotherapies

=> Participating Centers

University of Bologna, Italy

German Cancer Research Center, Heidelberg, Germany

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

University of Navarra, Spain

University of Nantes, France

Columbia University New York, NY, USA

University College, London, UK

University of Calgary, Canada

Shanghai Jiaotong University, China

Champalimaud Foundation, Lisbon, Portugal

Memorial Sloan Kettering Cancer Center, New York, NY, USA

University of San Francisco, CA, USA

University of Oslo, Norway

Icahn School of Medicine at Mount Sinai, NY, USA

MD Anderson CCC, Houston, TX, USA

University of Athens, Greece

University of Dresden, Germany

2.A. Image Analysis in Patients on Immunotherapies

OBJECTIVES

Primary:

• To collect imaging and serological data from patients on immunotherapy to assess patterns of response (remission versus progression versus suspected pseudoprogression) and frequency of these patterns

Secondary:

• To analyze the prognostic significance of the different response patterns for PFS and OS

• To define new criteria for imaging response in patients with multiple myeloma on immunotherapies

Exploratory:

• To apply computer-based image analysis to identify additional characteristics of focal lesions in patients with different response patterns

• To compare different imaging techniques (PET versus MRI (including DWI) versus CT)

PET/CT/DWI-MRI

response

CR (MRD)

2.B. Updated definitions of imaging response

Definition

Uptake ≤ liver pool (Deauville scale < 4) by PET or RAC-1 by DWI-MRI in ALL localizations BM/FL/PSD/EMD, irrespective of the reduction of soft-tissue plasmacytomas size.

Decrease of EITHER NUMBER OF FLs/PSD/EMD, WITH STABLE SUV (DS 4-5), OR ACTIVITY (SUV reduction at least 25%), WITH STABLE NUMBER of FLs/PMD/EMD, OR BOTH or RAC-2 at MRI, compared to baseline, irrespective of the reduction of soft-tissue plasmacytomas size.

No significant modification of BM/FL/EMD/PSD uptake or at MRI (RAC-3) compared with baseline, irrespective of soft-tissue plasmacytoma size

New lesion (FL/EMD/PSD) compared with baseline imaging, both in the functional part (PET DS > 4 or MRI RAC 4 or 5) or at CT if different technique applied caution recommended

• First evaluation after 3 months from the end of therapy (to avoid as much as possible background influence/tumor flare after CART/ bone regeneration). Once CR established, no other evaluation requested until suspect of progression, unless high risk context (i.e. EMD, post CART…)

• If persistent metabolic/MRI lesion or doubtful evaluation, repeat after 3-6 months, until CMR/RAC-1 or PD

New Projects

CTCs in patients with Solitary Bone Plasmacytoma

• CTCs have prognostic value in NDMM patients

• No data on CTCs kinetics before and after radiotherapy

• Better definition of the disease – possible exclusion from definition the entity of solitary plasmacytoma with minimal marrow involvement

• NGFC? or NGS?

Phase 2 Randomised Trial: Romosozumab in Newly Diagnosed Multiple Myeloma

Dr

Georgia McCaughan, Prof Peter Croucher & Prof Evangelos Terpos

The Challenge for Patients:

Patients continue to experience skeletal related events

• 45% of patients on anti-resorptive therapy will have a skeletal related event

• Anti-resorptive treatments only stop further bone loss

• Treatments that build new bone are required

• Romosozumab, an antibody against sclerostin, is a new bone anabolic drug

Raje et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncology. Volume 19, Issue 3, March 2018, Pages 370-381

Sclerostin: A

Pivotal Regulator of Bone Formation

Mutations in sclerostin lead to heavier bones

Inhibiting sclerostin leads to increased bone mass

et al 2014

McClung

Romosozumab in Post-Menopausal Women

with Osteoporosis and Fracture: BMD and Turnover Markers

KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, Maddox J, Fan M, Meisner PD, Grauer A. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med. 2017 Oct 12;377(15):1417-1427. doi: 10.1056/NEJMoa1708322. Epub 2017 Sep 11. PMID: 28892457.

Saag

Romosozumab in Post-Menopausal Women with Osteoporosis

and Fracture: BMD and Turnover Markers

Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, Maddox J, Fan M, Meisner PD, Grauer A. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med. 2017 Oct 12;377(15):1417-1427. doi: 10.1056/NEJMoa1708322. Epub 2017 Sep 11. PMID: 28892457.

Anti-Sclerostin Antibody Treatment in Models of Myeloma:

Improved Efficacy in Combination with Zoledronate

In pre-clinical models of myeloma bone disease antisclerostin treatment:

• Increases bone formation

• Stops myeloma bone disease

• Increase resistance to fracture

• Improves efficacy when combined with zoledronic acid

Addressing the Challenge for Patients:

A Trial of the Anti-Sclerostin Antibody – Romosozumab – in Myeloma

• Pilot trial of romosozumab in Myeloma

• St Vincent’s Hospital Sydney/Garvan partnership

• 12 patients with skeletal related event who have received prior zoledronic acid

• Romosozumab 210mg subcutaneously for 12 months

• Primary endpoints – safety and bone turnover markers

• Secondary endpoints - bone mineral density at 6 and 12 months, skeletal related events, progression free survival

• Tertiary endpoints – Single cell analysis, CT analysis of bone lesions

Interim Analysis of Pilot Study

Characteristic

Preliminary analysis of first 8 patients: • BMD decreased at baseline • No adverse events

• Formation markers increased

• Resorption markers decreased

• BMD increased at 6/12 months

• No new skeletal events

Bone Mineral Density T Score (IQR)

Interim Analysis of Pilot Study

Preliminary analysis of first 8

patients:

• BMD decreased at baseline

• No adverse events

• Formation markers increased

• Resorption markers decreased

• BMD increased at 6/12 months

• No new skeletal events

Change in P1NP and β-CTX Levels

Interim Analysis of Pilot Study

Preliminary analysis of first 8

patients:

• BMD decreased at baseline

• No adverse events

• Formation markers increased

• Resorption markers decreased

• BMD increased at 6/12 months

• No new skeletal events

A Proposal for a Randomized Phase II Study of Romosozumab

• Patients with newly diagnosed multiple myeloma with bony disease

• Randomised to 12 months of:

• Zoledronic acid and romosozumab vs.

• Zoledronic acid

• Primary endpoint:

• % Change from baseline in bone mineral density at the lumbar spine at 12 months

• Secondary endpoints:

• P1NP and beta-CTX at cycle 1, 2, 3, 6 and 12 months (median % change)

• Skeletal related events

• Myeloma progression free survival

• Improvement in lytic disease on CT

• Quality of life: BPI-SF, EORTC QLQ-C30 and QLQ-MY20

Trial Design

Key eligibility Newly diagnosed MM

Bony disease Planned induction

Romosozumab 210mg every 28 days

Zoledronic acid 4mg every 28 days

Primary endpoint

• % Improvement in BMD at Lumbar spine at 12 months

Zoledronic acid 4mg every 28 days

Secondary endpoints

• Change in P1NP and betaCTX

• Skeletal related events

• Progression free survival

• Improvement in lytic disease on CT imaging

• Quality of life

Statistical Assumptions

• Sample size: 100 patients, 50 patients in each arm

• Assumption of an increase in lumbar spine BMD of 4.1% (Muchtar et al, McClung et al) with bisphosphonate therapy

• Numbers based on a 90% power to detect a >5% increase of lumbar spine BMD at 12 months with addition of romosozumab with a significance level of 0.05

• Assumed compliance rate 85%

Thank you

BONE DISEASE COMMITTEE

IMMUNE THERAPY COMMITTEE

https:// myelomafoundation.share point.com/:p:/s/

IMFMeetingProgramResou rceHub/

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IMWG Working Committee:

IMWG Meeting, Milan June 10, 2025

Hira Mian, MD

Yi Lin, MD PhD

Tom Martin, MD

IMWG Immune Therapy Committee

• Quarterly Committee Meetings

• March 21, 2025 (virtual)

• June 10, 2025 (IMWG Summit)

• September at IMS

• November 7, 2025 (virtual)

• IMF Database meetings

• Virtual Tissue bank meetings

IMF Database update

May 22, 2025

New Sites

Sites

Lead PI

Mount Sinai C.Rodriguez

University of Chicago

B. Derman

Emory J, Kaufman N.Joseph

University of Edmonton: university of Alberta I.Sandhu M. Chu

U Alabama S.Bal

Princess Margaret K.Stewart

U Pamplona P. Otero

Huntsman, Utah D. Sbovov

Univ of Kansas L.Shune

France P. Moreau

France M. Mohty

Germany H. Einsele

University of Ottawa A. McCurdy

Samsung Medical Center, Sungkyunkwan University School of Medicine

Utrecht, Netherlands

Dr. Kim

Rimke Oostvogels, Monique Minnema

DFCI-Harvard O. Nadeem

Brazil V. hungria

China Dr. Du

Australia A. Spencer

U of Calgary N. Bahlis

Manuscript Updates

Manuscripts Published

1. Mian, H., Martin, T.G., Pond, G.R. et al. Outcomes of frailty subgroups of older adults (age ≥ 70) treated with teclistamab: an International Myeloma Foundation immunotherapy database real-world analysis. Leukemia 39, 1252–1255 (2025). https://doi.org/10.1038/s41375-025-02552-3

2. Tan, C.R., Asoori, S., Huang, CY. et al. Real-world evaluation of teclistamab for the treatment of relapsed/refractory multiple myeloma (RRMM): an International Myeloma Working Group Study. Blood Cancer J. 15, 53 (2025). https://doi.org/10.1038/s41408-025-01259-z

Ongoing projects

Data being compiled

1. Hira Mian/Carlyn Tan: Early mortality and causes with immunotherapy

• Data being collected, plan for manuscript

2. Rakesh Popat - Real World Elranatamab Outcomes

• ASH submission planned

• Hoping to combine with IFM dataset

• Data cut off July 1st

Ongoing projects

Manuscripts currently being written

1. Carlyn Tan: Long-term Follow-up of Real-World Teclistamab for the Treatment of Relapsed/Refractory Multiple Myeloma (N=210)

• Will try to combine Data from Germany and Czech Republic +/- IFM

2. Murali Janakiram: Real world evidence with Talquetamab in a heavily pretreated population with MM (N= 118)

• 118 patients @ ASH = additional patients being added– excelspreadsheet being finalized end of May

3. Anupuma Kumar: Delayed neurotoxicity after CAR-T in multiple myeloma: (N=78)

New Proposals

1. Murali Janakiram/Darren Pan: Sequencing of ≥ 2 Immunotherapy

• Car-bispecific; Bispecific=>CAR; BCMA to GPRC5D; GPRC5D=>BCMA

2. Susan Bal/Hira Mian: Prophylactic Dexamethasone in CART

• Retrospective study: Can we look at database to see what is currently being done

3. Outcomes with Bela based combination therapy

IMWG Immune Therapy Committee Guidelines

Written

guidelines completed/planned

• Manuscript completed

• Costa, L.J., Banerjee, R., Mian, H. et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia 39, 543–554 (2025).

https://doi.org/10.1038/s41375-024-02482-6

• Manuscript planned

• Nooka, Terpos: Sequencing paper with belamaf incorporated and potentially strategies to think of with regards to dosing of drug, management of toxicity

• Rodriguez Otero, Chari, Usmani: T-cell engagers dosing.

IMWG Online Living Guidelines

• T-cell engagers outpatient management best practices

• Led by RN, APP, Pharmacist (Emory, UCSF, Mayo, UCL, others)

• CAR-T, T-cell Engagers updates

• IEC-late neurotoxicities: cranial nerve palsies, Guillaine Barre Syndrome, Parkinsonism, cerebellar toxicities

• IEC-enterocolitis

• Pre-emptive and alternative CRS management for T-cell engagers

Online Guideline: Prophylactic CRS management with T cell engagers

Preemptive Tocilizumab

 Consider in patients with severe comorbidities, outpatient dosing per physician discretion, high tumor burden, or other conditions.

 Single dose of IV Tocilizumab 8mg/kg 3h-4h hours prior to the first step-up dose of any bispecific antibody.

 Other conventional premedication with dexamethasone, paracethamol and antihistamines remained unchanged.

Preemptive Dexamethasone

 Consider in centers with limited access to tocilizumab.

 Dexamethasone can be use to prevent CRS as a post-treatment drug. Dose range between 1020mg per physician discretion

 24 and 48 hours after first step up dose

Online Guideline: Alternative T-cell engager CRS management

Dexamethasone treatment in low-grade CRS

 Dexamethasone can be use for the management of grade 1 CRS, dose ranging from 10-20mg.

 Consider in centers with limited access to tocilizumab or outpatient capability to manage CRS.

 While rate of CRS with subsequent dose of T-cell engager step up dose between first treatment of CRS with tocilizumab or dexamethasone has not been formally studied in randomized trial, observation suggest that subsequent rate of CRS may be higher with dexamethasone. However subsequent episodes of CRS has also been managed with dexamethasone alone without the need for tocilizumab.

 In the outpatient setting, consider a complete evaluation of the patient at the ER/hematology/oncology service for patients whose CRS do not respond to dexamethasone

 Neutropenic fever and infection surveillance and management should be performed concurrently per institutional guideline

IMF Immune Therapy Data

Baseline Myeloma History

Subtypes of neurotoxicity (n=52)

• Median 4 prior lines of therapy (range 1-16)

• 67% progressed on last line

• 6% extramedullary disease

Baseline Neurological History

• No history of CNS myeloma or prior IT chemotherapy

• 1 (2%) had prior CNS radiation

• 10 (19%) had pre-existing neurological conditions

IEC-Parkinsonism Treatment –lessons learned

• Demographic trends – patients who developed Parkinsonism were predominantly male and White

• High peak inflammatory markers (ALC, ferritin, CRP) observed in Parkinsonism patients

• Cognitive and personality change may predate movement disorder

• Steroids were insufficient for full recovery

• Dopamine agonists had limited efficacy

• Early intervention with single dose of cyclophosphamide (2g/m2 IV) in the right patients may be key to recovery

• No evidence thus far of early relapse in those who received cyclophosphamide

Proposed Online Guideline Updates: IEC-Neurotoxicity (IEC-NT)

IEC-Parkinsonism (IEC-PKS)

 Be vigilant of new-onset symptoms which can occur most commonly approximately 1-3 months post CAR-T infusion

 Symptoms can be isolated movement, cognitive, and personality changes: stooped posture, bradykinesia, rigidity, paucity of speech, confusion, slowed responses, flat affect, micrographia

 Do not need full presentation of all neurologic domains to prompt evaluation and consideration for management

 Local clinic should contact CAR-T treatment centers to discuss coordination of evaluation and management

 Recommend neurology consultation for comprehensive movement disorder evaluation, including MRI brain, lumbar puncture to rule out infectious etiology, and handwriting assessments for micrographia

 Treatment experiences are limited to retrospective reports and case series

 Symptoms resolution with IVIG, steroid, with and without dopamine agonist are limited and can be tried with initial presentation

 Morbidity and mortality is high with severe cases, therefore alternative treatment should be considered when no improvement is seen in 1-2 weeks

 Intrathecal chemotherapy and systemic high dose cyclophosphamide (1–2 g/m²) use have been reported with some patients having symptoms improvement and or resolution. High rate of infections have been seen with systemic cyclophosphamide, and antimicrobial prophylaxis and vigilant infection surveillance should be done.

 Mitigating strategies

 Myeloma disease burden reduction, when possible, prior to CAR-T infusion have been found to be associated with decreased incidence

Proposed Online Guideline Updates: IEC-Neurotoxicity (IEC-NT)

IEC-Guillaine Barre Syndrome

 Consider this in the differential in patients with sudden onset of severe back pain after CAR-T infusion. Early signs may be confounded by patient’s history of bone disease from myeloma.

 Prompt evaluation with neurologist consultation is warranted

 Treatment experiences are limited with plasmapheresis, IVIG and steroid.

IEC-Cranial Nerve Palsy (IEC-CP)

 Consider IEC-CP in patients presenting with new-onset cranial neuropathies approximately 35 weeks post CAR-T

 most commonly facial nerve (cranial nerve VII) palsy, although cranial nerve III, V have also been reported

 Can be unilateral or bilateral. More than 1 cranial nerve could be involved

 Recommend neurology consultation, MRI brain, and lumbar puncture to rule out infectious etiology

 Treatment experience from real world data, IMF Immunotherapy Data Registry and U.S. Myeloma Immunotherapy Consortium, suggest good response with steroid and IVIG

 Median time to partial resolution was approximately 11 days, with full resolution typically achieved by 2 months.

Proposed Online Guideline update: Other Non-ICANS

Neurotoxicities

Bulbar and Cerebellar Toxicity associated with GPRC5d-targeted agents

Diagnosis

 Consider in patients with unexplained ataxia, gait instability, dysmetria, bulbar aphasia or other bulbar or cerebellar symptoms occurred after the start of GPRC5D-targeting T-cell engager or CAR-T therapy.

 Time to onset around 1st month but can be identified at a later time depending on the severity of the symptoms.

 Recommend neurology consultation for comprehensive evaluation, including contrasted enhanced brain MRI, lumbar puncture to rule out infectious etiology, EEG. Other exams as deemed necessary.

Management

 Pathogenesis is poorly understood

 Recommended management includes:

 Permanent interruption of the GPRC5d-targeting T-cell engager if grade 2 or higher

 Consider early implementation of corticosteroids or IVIG, although no formal treatment has shown efficacy for symptom resolution

IEC-associated enterocolitis

Mayo Clinic Experience with Longer Follow-up

US MM Immunotherapy Consortium

• 14 cases across 10 U.S. Centers (2-4%)

• 13 cilta-cel; 1 ide-cel

• Likely not BCMA specific, 3 case reports with CD19 CAR-T

• Median time to onset 79 (22-210) days

• Median duration 76 (17-113) days

• Response to steroid (4/10); infliximab (3/6); vedolizumab (1/3)

• 5 deaths due to colitis or infection complications

• Important to escalate treatment early and monitor for C. Diff and CMV

Fortuna G et al. BCJ 2024.

• No patients had a durable response to systemic corticosteroids.

• Three patients (Case 1, 2 and 3) received infliximab of which one (Case 2) achieved a durable response after 16 months.

• Two patients (Case 4 and 6) received Vedolizumab of which both achieved a durable response after 5 and 6 months.

• Two patients (Case 1 and 8) received high-dose Cyclophosphamide; both are yet to respond after 2 months.

• One patient (Case 3, with CD4+ LPD changes on duodenal biopsy) had highly refractory disease failing to respond to multiple lines.

• Myeloma response rate, 1-yr PFS and OS rate not different.

T-cell lymphoproliferative disorder with IECenterocolitis

Case Report after Cilta-Cel

Harrison SJ et al. NEJM 2025.

Ozdermilini G et al. NEJM 2024.

mSMART Management of IEC-

Enterocolitis

• Typical onset 1-6 months after CAR-T infusion

• Can be severe and require hospitalization for IVF, electrolyte replacement and TPN

• Communicate with CAR-T treatment center to coordinate evaluation and management. Multi-disciplinary care with GI and ID.

• Recommended evaluations

• Stool: c. diff PCR, GI pathogen panel, calprotectin, (outpatient, less severe presentations: bile acids, pancreatic elastase)

• Blood: CMV PCR, TCR clonal rearrangement

• Imaging: CT abdomen and pelvis with contrast

• EGD and colonoscopy with biopsies

• Check on pathology for presence of T cells. Check TCR clonal rearrangement on biopsy specimen

mSMART Management of Severe IECEnterocolitis

Proposed Online Living Guideline Update: IEC-Enterocolitis

IEC-Enterocolitis

Diagnosis

 Consider in patients with unexplained, non-bloody diarrhea with negative infectious work-up occurring 1-3 months post-CAR-T. This may also be seen post T-cell engagers.

 Evaluation to include GI and ID specialists:

 Perform endoscopic evaluation with biopsies that are specifically reviewed by a hematopathologist, as inflammation often resembles patterns seen in GVHD following allogeneic transplantation

 Infections are common preceding or concurrent, should be evaluated and treated if identified

 Perform T-cell receptor clonal rearrangement on GI biopsy as part of evaluation to identify T-cell lymphoproliferative disorder

 Collaborate with product manufacturers to test for CAR-T presence on enteral biopsies

Management

 Treatment experience are limited to retrospective reports & case series. Morbidity and mortality is high with severe cases. Consider TPN support early in severe cases.

 IVIG and steroid, +/- budesonide can be trialed first. If lack of improvement in 1-2 weeks, consider stopping systemic steroid, and try infliximab or vedolizumab.

 Consider T-cell modulating or lymphotoxic drug such as high dose cyclophosphamide in refractory cases or in cases of T-cell lymphoproliferative disorder

 Remain vigilant of antimicrobial prophylaxis and infection surveillance during treatment

Virtual Tissue Bank Projects Resistance to immunotherapy

Resistance to IT Agents

Francesco Maura and Holy Lee

- Discussion

Post-BCMA therapy

Multiple Hot spots on BCMA

F, et al ASH 2024; Lee H, et al Nature Medicine 2023;29:2295-2306

Maura

Key point 7. Effector-to-target ratio (tumor burden) and baseline soluble BCMA levels

predict upfront anti-BCMA TCE response

Key questions guiding clinical and translational strategies in TCE resistance

• What is the optimal clinical method to detect emerging antigen escape clones in real time before clinical relapse - ctDNA, soluble antigen levels, WGS, targeted panels, flow/ IHC antigen expression

• How should longitudinal tissue collection protocols be designed to capture clonal evolution and emerging resistance - what should trigger sampling?

• Can baseline tumor burden/ heterogeneity/ T cell profile predict the likelihood or timing of relapse?

• Can rationally designed multi-specific TCEs, combinational strategies, or fixed duration therapies prevent functional antigen-loss?

Next steps – Virtual tissue bank

• Share sequencing and immune phenotyping data, linked to the IMF

Immune Therapy Data Registry

• Timepoints and archiving samples to enable near future sequencing studies - BM

• Pre-CART or TCE treatment, at time of PD/next treatment

• At fixed interval such as after 4 cycles of TCE

• When stopping TCE or going to maintenance

• Type of sequencing studies

• WGS at pre-treatment and PD/next treatment

• Targeted panels during surveillance

• Need for funding. Use testing that is CLIA to enable future use for clinical decision making

• Some lab may have cfDNA capability

• BM/PB immune panel

Prospective/Retrospective Database project –

IEC late neurotoxicities mitigating strategies

ALC peak as biomarkers to predict risk for delayed neurotoxicity (Mayo Clinic analysis)

*<0.05;

• Mayo Clinic 3 sites data (cases included in IMF Database Registry)

• Controls n=208

• IEC-NP (nerve palsies) n=15

• IEC-PKS (Parkinsonism) n=9

• Other risk factors by MVA

• Older age, ICANS, >1 dose tocilizumab, increased month 1 ferritin

10 mg PO twice daily for 3 days

ROC analysis identified ALCpeak ≥3.0 x 10^9/L as a viable threshold value (AUC=0.838)

ALCpeak ≥3.0 x 10^9/L has 21% AR for IEC-NP vs 1% if ALCpeak

<3.0x10^9/L

ALCpeak ≥3.0 x 10^9/L has 12% AR for IEC-PKS vs 1% if ALCpeak

<3.0x10^9/L

Thank you! Questions and Comments

IMMUNE THERAPY COMMITTEE

https:// myelomafoundation.share point.com/:p:/s/

IMFMeetingProgramResou rceHub/

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IBxEBsx2hvN8kZTiWq2G

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COMBINED MASS SPECTROMETRY &

MRD COMMITTEE

Mass Spectrometry – Mayo Clinic Update

Curated by

Dr. David Murray, MD, PhD

Presented by Maria Alice Willrich, PhD

Associate Professor of Laboratory Medicine and Pathology

Co-director, Protein Immunology Laboratory

International Myeloma Working Group Summit 2025 | Milan, Italy June 10 &11

IgG, IgA , IgM, κ, λ Spectra

2D Spectra with Peaks highlighted Automated Analysis

Peak Analyzer Isotyper Interpreter Analyzer System

Current Detected M-Proteins

M-Protein, FLC and Ig Quant History

3D Spectra History

Lab Tech and Lab Director Review Manual regating if

TIMELINE OF MASS-FIX

Initial development of MALDI-TOF method

2014

2018 Clinical test go-live for serum IFE replacement

2016 Clinical Chemistry method publication

2024 Mass-fix quantitation SPEP replacement

2023 Clinical test go-live for urine IFE replacement

Performed >475,000 tests

1+ year course of MM treatment

EXAMPLE OF DYNAMIC RANGE IN AN IGG LAMBDA

M-protein slowly decreasing

IMPLICATIONS OF LOWER LOQ FOR M-PROTEIN

SPEP and IFE

• 65% of M-protein positive samples were below the LOQ of SPEP

• The range of IFE positive samples below the SPEP LOQ was 0.05 g/L to 40 g/dL by Mass-Fix

Mass-Fix

• 0.03% of M-protein samples had values below LOQ of Mass-Fix

MASS-FIX PROVIDES A LOT OF INFORMATION

ONGOING PROJECTS

DO LOW LEVEL M-PROTEINS PERSIST?

EXAMPLE OF LOW-LEVEL IGG KAPPA PERSISTENCE

4 years IgG kappa persisting at 0.04 g/L to 0.10 g/L

CAN MASS-FIX DETECT EARLY RELAPSE?

EARLY RELAPSE DETECTION IN AN OLIGO-SECRETORY IGG LAMBDA MM PATIENT

M-Protein 0.58 g/L

CAN HIGH RESOLUTION MASS-FIX ENHANCE MPROTEIN DETECTION

PLANNED WORKFLOW

MM diagnosed

MASS-FIX performed

• Isotype determined

• One sample used as baseline for accurate mass of M-protein determination

Treatment initiated

• MASS-FIX follow-up samples

• Identifies tmabs

MRD ASSAY CHARACTERISTICS AND PLAN FOR TESTING

Follow-up MASS-FIX

MALDI-TOF method

LOQ = 10 mg/dL

About 1/3 of MASS-FIX negatives are positive by hi-res MASS-FIX

Reflex to HiRes MASSFIX

High-resolution liquid chromatography MS on 7600 QTOF Qualitative only LOD = 0.3 mg/dL

BENEFITS

• Benefits of MASS-FIX are in the negatives

• Benefit of MRD testing in bone marrow are in the positives

• This approach is relatively simple

• Blood mass spectrometry, as an easier specimen type, can offer more information over time to understand the course of disease

• Go-live of MM MRD test is planned for Q1 2026 for Mayo Clinic patients

SOFTWARE TO COMBINE MASS-FIX AND HIGH-RESOLUTION MASS-FIX

High-Resolution Mass-Fix LOD ~ 0.003 g/L

ACKNOWLEDGMENTS

+ Protein Immunology Lab Technologists and Lab Assistants

David Murray, MD PhD Prot & Ab Imm Co-Director

Melissa Derksen PIL Assistant Supervisor

Stephanie Kalass PIL Technical Specialist

Laura Eckelkamp PIL Technical Specialist

Brandon Copet PIL Technical Specialist

Mark Martinez PIL Technical Specialist

Cana Straub PIL Quality Specialist

Amy Ennis Laboratory Technologist Resource Coordinator

Grant Spears Biostatistician

Vanessa Pazdernik Biostatistician

Dirk Larson Biostatistician

Mindy Kohlhagen Principal Developer

John R. Mills, Ph.D. Neuroimmunology Co-Director

Jon Coker, PhD Signal Processing Engineer

Tyler Nienaber PIL Supervisor

Angela Dispenzieri, MD Hematology Professor

Jody Smith PIL Quality Specialist

Ashley Thompson PIL Technical Specialist

Danelle Moonen Research Technologist

Jamie Shulman PIL Education Specialist

Combined Mass Spectrometry and MRD Committee

Flow Cytometry - CIMA LAB Diagnostics

Hematology Department - Clinica and CIMA Universidad de Navarra

Spanish Myeloma Group (GEM)

EuroFlow Consortium

Bruno Paiva

Additional thoughts

• Complementarity across different techniques: more studies are needed to identify optimal combination of methods, time points, treatment scenarios, making it cost-efficient and improving patients’ QoL.

• Mass spec is the future of M-component assessment: need studies comparing different methodologies for optimal use in different applications, and develop consensus/guidelines.

• MRD/PRD criteria to stop treatment and to define operational cure (as in the new response criteria): need to collect more data in ongoing and future studies.

• EMA questionnaire about MRD negative CR endpoint: EHA-EMA Joint Symposium session at 15.45 CEST, Friday 13.

• Further development of NGF MM-MRD: There are extensive requirements for analytical validation and clinical validation for an IVD cleared MRD test (as achieved for NGS). To support continued clinical validation of NGF, we propose a meta-analysis of existing high quality trial and real world data including MM MRD by NGF.

Possible algorithm to combine different methods and to monitor MRD/PRD

The assessment of MRD in BM should probably be the standard approach during the first year of treatment:

• Aligned with the MRD-negative CR end point

• Aligned with the time of best response achieved in different disease settings and treatment scenarios

• PRD using NGF/NGS will be often negative during the early and more intensive stages of treatment

• The use of MS may lead to some false-positive results owing to the long half-life of the M component

Monitoring PRD using NGF and MS

BloodFlow outperforms NGF and has independent prognostic value together with MRD assessment in BM

Complementarity between BloodFlow and MS

Double-negative MRD detection in PB and serum using BloodFlow and QIP-MS achieved a NPV of 84% (ie, MRD negativity in BM using NGF)

Improving PRD with dynamic monitoring using MS

Additional thoughts

• Mass spec is the future of M-component assessment: need studies comparing different methodologies for optimal use in different applications, and develop consensus/guidelines.

• MRD/PRD criteria to stop treatment and to define operational cure (as in the new response criteria): need to collect more data in ongoing and future studies.

• EMA questionnaire about MRD negative CR endpoint: EHA-EMA Joint Symposium session at 15.45 CEST, Friday 13.

COMBINED MASS SPECTROMETRY &

MRD COMMITTEE

QUALITY OF LIFE COMMITTEE

QoL Sub-Committee Meeting

June 10, 2025

Sonja Zweegman, MD, PhD

Surbhi Sidana, MD

Collaborative Effort!

Myeloma Experts and Researchers

1. Nadine Abdallah, Mayo Clinic, Rochester, MN

2. Rahul Banerjee, University of Washington, Seattle

3. Natalie Callandar, University of Wisconsin

4. Donna Catamero, Mount Sinai, NY

5. Rajshekhar Chakraborty, Columbia University

6. Gordon Cook, University of Leeds, UK

7. David Cucchi, Amsterdam UMC, Netherlands

8. Edvan Crusoe, Brazil

9. Michel Delforge, UZ Leuven, Belgium

10. Beth Faiman, Cleveland Clinic, OH

11. Doris Hansen, Moffitt Cancer Center

12. Jens Hillengass, Roswell Park Cancer Center

13. Murali Janakiram, City of Hope

14. Artur Jurczyszyn, Krakow, Poland

15. Charalampia Kyriakou, University College of London, UK

16. Hira Mian, McMaster University, Hamilton, Ontario

17. Roberto Mina, Italy

18. Simone Oerlemans, Netherlands

19. Charlotte Pawlyn, The Institute of Cancer Research, London, UK

20. Aurore Perrot, France

21. Borja Puertas Martinez, Spain <borjapuertas@usal.es>

22. Joshua Richter, Mount Sinai

23. Katja Weisel, Germany

24. Tanya Wildes, University of Nebraska

25. Christine Ye, MD Anderson Cancer Center

Statistical PRO Experts

Amylou Dueck, PhD Mayo Clinic, Arizona

Birgit Lissenberg, PhD, Netherlands

Regulatory Experts:

Vishal Bhatnagar, US FDA

Bindu Kanapuru, US FDA

Francesco Pignatti, EMA

Patient Advocates:

Eilidh Duncan, Myeloma Patient Europe

Poornima Parmesawaran, IMF Patient Board, US

PROPOSAL FOR GUIDELINES ON INVESTIGATING, ANALYSES AND REPORTING OF QOL IN MM CLINICAL TRIALS

1. INTRODUCTION - WHY TO MEASURE QOL?

 SURBHI SIDANA AND SONJA ZWEEGMAN

2. QOL TOOLS IN CLINICAL MM TRIALS – THE PRO’S AND CON’S – WHICH TO USE?

 RAHUL BANERJEE, CHARALAMPIA KYRIAKOU, MICHEL DELFORGE, DORIS HANSEN, ROBERTO MINA

3. STATISTICAL ANALYSES OF QOL, AND HOW TO DEFINE CLINICAL MEANINGFUL DIFFERENCES IN PRO DOMAINS

 NADINE ABDALLAH, HIRA MIAN, DAVID CUCCHI, SIMONE OERLEMANS, BIRGIT LISSENBERG-WITTE, AMYLOU DUECK

4. PROS AS ENDPOINTS IN MYELOMA CLINICAL TRIALS – UNDER WHICH CONDITIONS

 MURALI JANAKIRAM, NATALIE CALLANDER, BIRGIT LISSENBERG, VISHAL BHATNAGAR, BINDU KANAPURU, AMYLOU DUECK, FRANCESCO PIGNATTI

5. CONCLUSIONS AND GUIDELINES FOR INVESTIGATING, ANALYSES AND REPORTING OF QOL IN MM CLINICAL TRIALS

 SURBHI SIDANA AND SONJA ZWEEGMAN

PROPOSAL FOR GUIDELINES ON INVESTIGATING, ANALYSES AND REPORTING OF QOL IN MM CLINICAL TRIALS

WHAT & WHEN

QOL TOOLS IN CLINICAL MM TRIALS – THE PRO’S AND CON’S – WHICH TO USE?

RAHUL BANERJEE, CHARALAMPIA KYRIAKOU, MICHEL DELFORGE, DORIS HANSEN, ROBERTO MINA

DESCRIPTION OF PRO AND QOL TOOLS IN CLINICAL MM TRIALS

 Review of key trials in the last 15 years – leading to registration

 2 SMM trials

 12 NDMM trials

 10 RRMM trial

 Heterogeneous questionnaires – EORTC-QLQ C30 and MY20, EQ 5D 5L, FACT-G, FACT-MM and timepoints

 Most used tool EORTC-QLQ C30 in combination with EORTC-MY20

 However, in the US the NIH supports PROMISE-29

DIFFERENCES BETWEEN THE PROMIS-29 AND EORTC QLQ-30

Item/Domain

Pain Interference

Pain Intensity

Fatigue

Sleep Disturbance

Physical Function

Anxiety

Depression

Social Roles & Activities

Cognitive Function

Nausea / Vomiting

Dyspnea

Appetite Loss

Constipation / Diarrhea

Financial Impact

Global Health Status / QoL

(1 item)

(4 items)

(within scale)

(3 items)

(1 item only)

(indirect)

(less detailed)

WHAT

IS NOT CAPTURED?

• Specific side effects with novel immune therapies

• CRS, ICANS, late motor-neurotoxicity

• On-target, off-tumor symptoms

• GPRC5D – skin – nail – oral – GI

• BCMA – eye toxicity with ADC, severe and mild but chronic upper respiratory tract infections

WHAT & WHEN?

EORTC MY20 or specific PRO-CTCAE for myeloma-related symptoms? 3. Development of specific PRO-CTCAEs for what is not captured with certain therapies?

HOW?

STATISTICAL ANALYSES OF QOL, AND HOW TO DEFINE CLINICAL MEANINGFUL DIFFERENCES IN PRO DOMAINS

NADINE ABDALLAH, HIRA MIAN, DAVID CUCCHI, SIMONE OERLEMANS, BIRGIT

LISSENBERG-WITTE, AMYLOU DUECK

IT IS NOT ABOUT STATISTICS, BUT ABOUT CLINICAL MEANINGFUL DIFFERENCES

 Minimal Important Difference (MID)

 the smallest group-level difference in a score that patients or proxies perceive as meaningful, and that could prompt a change in clinical management

 Responder Thresholds (RTs)/responder definitions (RDs)

 to define individual-level changes considered meaningful

MORE THAN 1 METHOD TO DEFINE

CLINICALLY IMPORTANT DIFFERENCES

Method Description

Anchorbased Links PRO score changes to external criteria (e.g. patient-reported global ratingof change).

Distributionbased Uses statistical characteristics of the score distribution (e.g., 0.5SD, SEM) to estimate MID or RT.

Qualitative Derives thresholds through patient interviews or surveys identifyingwhat magnitude of change is personallymeaningful.

Triangulation Integrates all three methods to derive robust estimates of MIDs and RTs.

Strengths

Patient-centered; Directlylinks the score to a meaningful change in health perception

Easyto compute; no need for external anchor

Limitations

Requires valid and sensitive anchor; subject to recall bias or interpretation differences

Lacks patient input; Risk of over- or underestimatingclinical relevance as purely based on statistics; context-dependent

Deep insight into patients’ experiences; Can reveal differences across disease context or cultures

Maximizes validity; balances statistical, clinical, and patient-centered evidence

Resource-intensive; maylack generalizability

Requires integration of diverse methodologies and expertise

ANCHOR BASED

A patient rates their pain improvement as "a little better" on a 7-point global impression of change scale.

The average score change in those who said “a little better” becomes the MID

DISTRIBUTION BASED

0.5 SD: Half a standard deviation of the baseline scores or Standard Error of Measurement (SEM)

MORE THAN 1 METHOD TO DEFINE

CLINICALLY IMPORTANT DIFFERENCES

• And they all have been used – but not consistent

• All using different cutt offs

HOW?

MIDs or RTs?

Anchor or distribution-based or both?

And more in general – which statistical methods to use, how to report, how to handle missing data

Can we endorse consistent MIDs/RTs for EORTC QLQ-C30/MY20, PROMIS-29, and PRO-CTCAE?

10-point RT (within group) for EORTC scales – Coon et al., 2022

5-point MID (between groups) for EORTC scales

2-6 point RT (within group) for T-score PROMIS scales – Terwee et al., 2021

3-point MID (between groups) for T-score PROMIS scales – consensus meeting of PROMIS Leadership*

1-point RT (within group) for PRO-CTCAE – Lee et al., 2025

*https://www.healthmeasures.net/score-and-interpret/interpret-scores/promis/meaningful-change

TO FINALLY COME TO A(N) (END)POINT

PROS AS ENDPOINTS IN MYELOMA CLINICAL TRIALS

MURALI JANAKIRAM, NATALIE CALLANDER, BIRGIT LISSENBERG-WITTE, VISHAL BHATNAGAR, BINDU KANAPURU, FRANCESCO PIGNATTI, AMYLOU DUECK

1. When as a co-primary endpoints when as a secondary endpoint

2. Which requirements when included as an endpoint

3. How to check for bias in reporting

4. Endorse SISAQOL recommendations for statistical analysis of PROs

Proposed Guidelines

What to measure

1. Disease-related symptoms

2. Symptomatic adverse events (key AEs of interest based on trial)

3. Physical function

4. Role function

5. Overall side effect impact summary measure

6. Overall quality of life – dependent on many factors and may not solely represent treatment impact

1-5 are consistent with FDA Core Guidance

Key Recommended Instruments

Domain PRO Measures

1. Disease related symptoms: Pain, fatigue

2. Symptomatic AEs

3. Physical function

4. Role function (work, home, leisure)

5. Side effect summary score

EORTC QLQC30 or PROMIS-29

• PRO-CTCAE: Pick from item library

• EORTC QLQ-30 (nausea, vomiting, diarrhea, sleep)

• Specific symptom modules (vision, taste)

EORTC QLQC30 or PROMIS-29

EORTC QLQ-30 (No direct measure in PROMIS)

6. Overall QoL

EORTC library question 168 or GP-5 (FACIT library)

EORTC QLQC30

Note for PROMIS measures: not standalone question for overall QoL but available as summary measure

How often to measure: Active MM

Frequency:

On continuous Therapy

 First 3-6 months during induction: Once a month

Month 6-24 months: Every 3 months  2 years: Every 6 months

 At progression, and if feasible 1 additional timepoint soon after

Response adapted treatment stopping or escalation

 More often: Monthly for at least 3 months after treatment change

 QoL may improve after stopping and worsen with increased treatment burden

Special Considerations: BsAb and CAR-T

Frequency:

Bispecific Antibodies

In the step- up phase: consider more often in the first cycle (weekly)

CAR-T Cell Therapy

• At enrollment/apheresis (if significant interval in between, enrollment should be baseline)

• Prior to lymphodepletion

• Day 0, Day 14

• Month 1-6: Monthly

• Month 6-2 years: Every 3 months

• Beyond 2 years: Every 6 months

Extended bridging/induction approach: refer to continuous therapy .

Both enrollment/apheresis and pre-lymphodepletion are important timepoints as bridging represents a critical period with rapidly changing disease and symptom burden. Change should be described from apheresis to pre-LD and compared to both timepoints

Special Considerations: RCTs

• In a RCT with different types of treatment (Eg. CAR-T vs continuous, limited vs continuous duration BsAb), measurement frequency should align to the more intense arm.

• If two arms differ in unique toxicity, specific symptomatic AEs should be included to determine tolerability.

• Eg. In a hypothetical trial for DaraKRd vs DaraVRd, neuropathy and dyspnea/chest pain should be included as patient reported AEs

Special Considerations: Smoldering MM

• Important to measure more frequently and for longer

• Include PRO-CTCAEs and instruments to evaluate overall side effect bother

• Current measures for cancer population (EORTC) may not be appropriate

• Measures validated in general populations (PROMIS) may be more appropriate

• Consider development of additional measures

Regulatory Considerations

• In certain areas, regulatory requirements may necessitate the use of additional PROs

• Eg. Use of EQ5D in registrational trials for EMA

• Include as required by regional regulatory guidelines

Responder

Thresholds and Minimally Important Difference (MID)

Responder Threshold: Individual level change, MID: Group level change

Various methods to define: Anchor, distribution, qualitative

• For EORTC scale (100-point scale)

• Responder threshold: 10-point change

• MID: 5-point difference is clinically significant, as long as statistically significant

• For PROMIS T-score scales:

• Responder threshold: 5-point change is meaningful (literature reported 2-6 points)

• MID: 3-point difference to be clinically significant on T-score scale, as long as statistically signifcant

Working on consensus on subdomains

PRO-CTCAE: Descriptive analysis, but 1-point change is meaningful (like grade 2 vs

Special Considerations in Data Analysis

Report PRO change by key sub-groups of interest:

• Age group

• Baseline function/frailty

• Disease symptoms

• Consideration for Race/Ethnicity

PROs as Endpoints

• Limited ability to use PROs as a primary endpoint

• Key secondary or co-primary endpoint with traditional efficacy measures to define tolerability of treatment

• Pre-planned, with hypothesis and statistical analysis plan and plan for missing data (aligned with FDA guidance)

• Endpoints should include specific domains or symptoms, not overall QoL

• Examples: NDMM: Improvement in pain and fatigue can be an endpoint

Largely asymptomatic patients (smoldering MM, biochemical relapse, maintenance studies): Side effects/tolerability as endpoint

Pre-planned Robust Framework to Handle Missing Data

• Use Estimand framework to clearly specify components of analysis including handling intercurrent events (missing data, crossover)

• Prefer mixed modelling when estimating means at a fixed time point – plus sensitivity/supplemental data analysis varying assumptions around intercurrent events and missing data

• Other analysis possible depending on the endpoint selected (eg, responder definition)

• Efforts to include reporting of amount and reasons for missingness

• Awaiting updated SISAQOL guidelines and will align SISAQOL 2020 report. Coens et al.

Future Directions

Focus Planned Action

Comparison/correlation of scores b/w

EORTC QLQC30 and PROMIS-29

Validate in large datasets

Certain future studies in MM to include both and develop statistical approaches to compare

Surrogate endpoint analysis:

Optimal timepoints, degree of expected change and relationship between PRO change and efficacy measures

Consensus for responder thresholds/MID for subscales of EORTC and PROMIS-29

Evaluation in smoldering MM

Effort to evaluate individual patient level PRO data from large clinical trials (~ MRD effort)

As above

Review applicability of current measures and consider development of additional measures