IMF Virtual Regional Community Workshop (RCW) - New England by International Myeloma Foundation

Welcome and Announcements Kelly Cox Director Support Groups & Senior Director Regional Community Workshops 1

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IMF REGIONAL COMMUNITY WORKSHOP Saturday June 18 , 2022- Agenda 10:00 AM - Welcome and Announcements Kelly Cox, Director Support Groups & Senior Director of Regional Community Workshops 10:05 AM - Myeloma 101 and Frontline Therapy Rafat Abonour, MD, Indiana University, Indianapolis, IN 10:40 AM - Q & A with Panel 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials Raymond Comenzo, MD, Tufts Medical Center, Boston, MA 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Kimberly Noonan, DNP, ANP-BC, AOCN, Dana-Farber Cancer Center, Boston, MA , IMF Nurse Leadership Board 12:05 PM - Q&A with Panel

Myeloma 101 and Frontline Therapy Rafat Abonour, MD, Indiana University, Indianapolis, IN 5

Multiple Myeloma Rafat Abonour, M.D.

Multiple Myeloma: The First Recognized Case • A 39 year old woman developed severe back pain in 1840. • Two years later she developed severe pain while her husband was carrying her from the fireplace area to the bed. • A bitter infusion for her poor appetite was given, but the patient refused it. • Two years later she was admitted to St. Thomas Hospital and was allowed wine, mutton chop, and a pint of porter daily.

The First Recognized Patient

Sara Newberry first published pt in 1844, by Dr. S. Solly, termed condition Mollities Ossium

Multiple Myeloma in 1844

• Despite the infusion of orange peel and giving rhubarb pills, she died five days later and autopsy was performed. • Section of the bones revealed marked destruction. The majority of the nucleated cells had a clear oval outline with 1-2 nucleoli. • Solly believed the process to be inflammatory and that it has begun with a morbid action of blood vessels in which an earthy matter of the bone is absorbed and thrown out by the kidneys and the urine.

•

Solly, 1844:Remarks on the pathology of mollities ossium with cases. Medical and Chirurgical Transaction of London, 27, 435-61.

The Cells seen by Sir Solly

CP1123175-2

Detecting the monoclonal protein in the serum of Multiple Myeloma Patients Serum Protein electrophoresis (sPEP) Normal profile

Monoclonal protein = M-spike

Myeloma Bone Disease

Myeloma in hand

Myeloma in the orbit

MRI (with contrast or STR images) very useful to delineate problems

MRI and FDG-PET in Multiple Myeloma •

> 3 focal lesions or SUV > 4.2 at diagnosis results in shorter PFS and OS[1] 65% of pts PET/CT negative 3 mos after ASCT with longer PFS and OS vs PET positive[1] Complete FDG suppression associated with durable disease control and prolonged OS[1]

•

Imaging Techniques [4]

MRI

•

FDG PET

Skeletal survey recommended in cases of plasmacytoma, extramedullary disease, suspected spinal cord compression as well as with new symptoms or progression [2] MRI and/or PET/CT indicated when symptomatic areas show no abnormality on radiograph [3]

1. Zamagni E, et al. Blood. 2011;118:5989-5995. 2. Ludwig H, et al. Leukemia. 2014;28:981-992. 3. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 4. Boot M, et al. Novel prognostic modalities in multiple myeloma.

Screening for Monoclonal Gammopathy of Undetermined Significance: A Population-Based Randomized Clinical Trial. First Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study (abstract 156) S i gurdur Y Kristinsson, MD, PhD 1,2, Sæmundur Rögnvaldsson, MD 3*, Sigrun Thorsteinsdottir, MD, PhD 1,4, Elin Ruth Reed 5*, Jon Thorir Thorir O s kar sson 1*, Iris Petursdottir 1*, Gudrun Asta Sigurdardottir 1*, Brynjar Vidarsson, MD6, P all Torfi Onundarson, MD6, Bjarni Agnar Agnarsson, MD 6*, M a r gret Sigurdardottir, MD 6*, Ingunn Thorsteinsdottir, MD, PhD 6*, Signy Vala Sveinsdottir, MD PhD 7*, Robert Palmason, MD 7*, Isleifur Olafsson, 1*, Elias Yngvi Kristinsson, M D , PhD 6*, Fridbjorn Sigurdsson, MD8*, Asdis Sigurður Rosa Thordardottir Eythorsson, MD,MD, PhD 6*,PhD Asbjorn Jonsson, MD 6*, Runolfur Palsson, MD6*, 1*, Jon Kristinn Sigurdsson 1*, Ingigerdur Solveig Sverrisdottir, O l a fur Skuli Indridason, MD, MHS2*, Gauti Kjartan Gislason, MSc1*, Andriof Olafsson Professor Hematology 5*, Hlif Steingrimsdottir, MD 10*, Ragnar Danielsen7*, Petros Kampanis, PhD 11*, M D , BSc 5*, Maria Soffia Juliusdottir 9*, Gudlaug Katrin Hakonardottir University of Iceland M a lin Hultcrantz, MD PhD 12, Brian G.M. Durie, MD 13, Stephen Harding, PhD 14, Ola Landgren, MD 15 and Thorvardur Jon Love, MD, PhD 1*

Email: sigyngvi@hi.is Twitter: @sykristinsson @iStopMM

The iStopMM study

Rögnvaldsson S et al. Blood Cancer Journal 2021

Recruitment • November 2016 to October 2018 • 148 708 Icelanders were eligible to participate

• 80 759 (54.3%) agreed to participate • 75 422 (93.4%) of these participants have since been sampled Rögnvaldsson S et al. Blood Cancer Journal 2021

Active myeloma* N=28 *FLC ratio >100 or M-protein >30 g/L

No further work-up N=1,164 • •

•

3,725 with MGUS

Previously known MGUS excluded N=237

R IMWG Recommendation s N=1,159

Arm 1 – Traditional health care Arms 2 and 3 – Medical history and clinicial examination – Blood work-up in all individuals Arm 3 – Extensive blood work, bone-marrow, low-dose CT in all patients – Annual follow-up – More intense bone marrow evaluations

Intensive arm N=1,164

RCT of MGUS screening, work-up, and follow-up

133

p<0.001

Conclusions • In this large prospective population-based screening study, the iStopMM study, including >75,000 screened persons, we have identified 3,725 individuals with monoclonal gammopathy • In the RCT, after 3 years of follow-up, we show that active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease • Our findings illustrate the fact that early detection and intervention is achievable • Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals

High prevalence of monoclonal gammopathy using mass spectrometry in a population at risk: The early results from the PROMISE study

Habib El-Khoury, MD, David J Lee, MD, MPH, Jean-Baptiste Alberge, PhD, Hadley Barr, Ciara Murphy, Christian J. Cea-Curry, BS, D.J. Sakrikar, PhD, Tara Krause, MSc, David Barnidge, PhD, Mark Bustoros, MD, Houry Leblebjian, PharmD, Annie Cowan, BS, Maya I Davis, BA, Julia Amstutz, BA, Jacqueline Perry, MPH, Cody J. Boehner, BS, Elizabeth D. Lightbody, PhD, Tarek H Mouhieddine, MD, Romanos Sklavenitis-Pistofidis, MD, Mark C Perkins, PhD, Stephen Harding, PhD, Prashant Kapoor, MD, Clifton C. Mo, MD, David L. Murray, MD, PhD, Ivan M. Borrello, MD, Gad Getz, PhD, Timothy R Rebbeck, PhD, Catherine R. Marinac, PhD and Irene M. Ghobrial, MD

Adults aged 40 and above who are: Self-identify as Black

Family history of HM or a precursor condition

Participants 18+ with a strong family history (2 or more 1 st and 2 nd degree relatives) are eligible

Conclusions •

Most precise estimates of MGUS in a high-risk screened population reaching 13 – 17% in highrisk group >50 years

•

Higher detection rates by Mass Spectrometry compared to conventional methods in the same double-tested population around ~2 fold higher

•

Prevalence of low-level MGs that increase with aging and are transient for the most part

•

Clinical significance of monoclonal gammopathies including lower-level MGs and stratification by concentration gradients

MM is Characterized by a Pattern of Remission and Relapse

Asymptomatic

Symptomatic

Relapsing

Refractory

Disease Burden

Remission duration decreases with each line of therapy

Active Myeloma Relapse Remission MGUS or Indolent Myeloma

// Front-line Therapy

// 2nd or 3rd-line Therapy

Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation; 2011/2012 edition; Kumar. Mayo Clin Proc. 2004;79:867.

Depth of Response Influence Time to Progression

The Evolution of Myeloma Therapy

Now

VD Rev/Dex CyBorD VTD VRD KRD

D-VMP DRD Front line treatment

Induction

New

SCT Tandem ASCT (?)

D-VRD Isa-VRD D-KRD Isa-VRD

Nothing Thalidomide? Bortezomib Ixazomib Lenalidomide Combinations Maintenance

Consolidation

Post consolidation

“more” induction?

Daratumumab? Carfilzomib? Lenalidomide + PI

ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; Cy, cyclophosphamide; d- daratumumab; D/dex, dexamethasone; isa, isatuximab; K, carfilzomib; M, melphalan; PD-L1, programmed death ligand-1; PI, proteasome inhibitor; Rev, lenalidomide; V, bortezomib

Bortezomib Panobinostat Lenalidomide Daratumumab Ixazomib Carfilzomib Elotuzumab Pomalidomide Isatuximab Selinexor Belantamab mafodotin Melphalan flufenamide Idecabtagene autoleucel Relapsed

Rescue

CAR T Cell Therapy Bispecific/Trispecific Antibodies Cell Modifying Agents Venetoclax? PD/PDL-1 Inhibition? Multiple small molecules ++++++++

Mechanisms of Action of Novel Agents in MM

Upfront therapy • Combination therapy continues to prove superiority in providing Long remission and long survival. • The patient is at good place as options are becoming more prevalent. • Lenalidomide, bortezomib and dexamethasone continues to be an effective regimen. • Daratumumab in combination with lenalidomide is an excellent option for “frail patient”

• But wait what else can we do?

Frontline Therapy • GRIFFIN • MASTER • GMMG-HD7 • Background – • are we ready for quadruplets in patients going to transplant? • We already have D-VTD but we rarely use it (ie thalidomide) • If we do use 4 drugs together, for how long?

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) With Transplant-eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of GRIFFIN After 24 Months of Maintenance

Presented at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual

*Presenting author.

Additional information can be viewed by scanning the QR code or accessing this link: https://www.oncologysciencehub.com/ ASH2021/Daratumumab/Laubach The QR code is intended to provide scientific information for individual reference, and the information should not be altered or reproduced in any way.

GRIFFIN: Study Design of the Randomized Phase • Phase 2 study of D-RVd versus RVd in transplant-eligible NDMM, 35 sites in the United States with enrollment between December 2016 and April 2018

Key eligibility criteria • Transplanteligible NDMM • 18-70 years of age • ECOG PS score 0-2 • CrCl ≥30 mL/mina

1:1 randomization

Induction: Cycles 1-4 D-RVd D: 16 mg/kg IV Days 1, 8, 15 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

Consolidation: Cycles 5-6c T R

A N

D-RVd D: 16 mg/kg IV Day 1 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

Maintenance: Cycles 7-32d DR D: 16 mg/kg IV Day 1 Q4W or Q8We R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

P RVd R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16 21-day cycles

L A

N T

RVd R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16 21-day cycles

R R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

28-day cycles

Endpoints and statistical assumptions Primary endpoint: sCR rate (by end of consolidation); 1-sided alpha of 0.1 80% power to detect 15% improvement (50% vs 35%), N = 200

Secondary endpoints: Rates of MRD negativity (NGS 10–5), ORR, ≥VGPR, CR, PFS, OS

Stem cell mobilization with G-CSF ± plerixaforb

33 Presented at the 63 rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11 -14, 2021; Atlanta, GA/Virtual

GRIFFIN: Responses Deepened Over Time a

100

Patients, %

sCR, P = 0.0096b ≥CR, P = 0.0013b

12 7

≥CR: 19%

≥CR: 27%

26 End of induction c

12 End of ASCTc

7 6

≥CR: 52%

66 ≥CR: 80%

40 20

14 4

14 3

End of consolidation c

14 5

At After 1 year of 2 years of maintenanced maintenanced

VGPR

≥CR: 42%

End of induction c

End of ASCTc

End of consolidation c

≥CR: 60%

47 ≥CR: 61%

14 7

At After 1 year of 2 years of maintenanced maintenanced

RVd

D-RVd sCR

31 35

≥CR: 20%

≥CR: 82%

≥CR: 13%

SD/PD/NE

sCR

VGPR

SD/PD/NE

• Response rates for sCR and ≥CR were greater for D-RVd versus RVd at all time points, with the deepest responses occurring after 2 years of maintenance therapy

34 Presented at the 63 rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11 -14, 2021; Atlanta, GA/Virtual

GRIFFIN: MRD Negativitya (10–5) After 2 Years of Maintenance Therapy GRIFFIN: MRD-negativitya Rates Improved Throughout the DR Maintenance Period D-RVd (ITT,b n = 104)

Patients with MRD negativity, %

59%

50%

11%

MRD negative 64% 64%

MRD negative and ≥CR 21% 10–6 62% 36%

≥CR (n = 82)

30 20

10–5

MRD negative 78%

22%

RVd (ITT,b n = 103)

MRD evaluabled (n = 83)

0 End of induction

End of consolidation

MRD negative

At 1 year of After 2 years of 81% maintenance maintenance

D-RVd

Patients with MRD negativity, %

P <0.0001c

P = 0.0003c

20% 3%

MRD-negative (10–5) conversion rate • 29% (15/52) of MRD negative and ≥CR D-RVd patients and 27% 12% (10/82) of RVd patients who were ≥CR (n = 59) MRD positive at the 30% 26% end of consolidation MRD negative 10–6 15% became MRD negative 47% 13% after 2 years of DR or 10–5 d maintenance MRD evaluable (n =R71) MRD negative 30%

P <0.0001c

MRD negative

c End of End of At 1 year of After 2 years of P <0.0001 induction consolidation maintenance 44% maintenance

RVd

• Similarly, MRD-negativity (10–6) rates favored D-RVd versus RVd in the ITT population (36% vs 15%, respectively; P = 0.0007), –6 threshold 10–5 threshold 10–5 threshold 10–6 threshold as well as among patients who10achieved ≥CR (43% vs 22%; P = 0.0121) The threshold of MRD negativity was defined as 1 tumor cell per 105 white cells. MRD status is based on the assessment of bone marrow aspirates by NGS in accordance with International Myeloma Working Group criteria. Bone marrow aspirates were assessed at baseline, at first evidence of suspected CR or sCR (including patients with VGPR or better and suspected DARA interference), at the end of induction and consolidation, and after 1 and 2 years of maintenance, regardless of response. Median follow-up was 38.6 months, and MRD-negativity rates are among the ITT population (D-RVd, n = 104; RVd, n = 103). a

Presented at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual

35 Presented at the 63 rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11 -14, 2021; Atlanta, GA/Virtual

GRIFFIN: PFS in the ITT Population 2-year PFS rate

• Median PFS was not reached in either group • There is a positive trend toward improved PFS for DRVd/DR versus RVd/R • The separation of the PFS curves begins beyond 1 year of maintenance and suggests a benefit of prolonged DR therapy

% surviving without progression

100

• Median follow-up: 38.6 months

3-year PFS rate

91.6%

88.9%

89.7%

81.2%

D-RVd

RVd

40 20

No. at risk RVd D-RVd

HR: 0.46 (95% CI: 0.21-1.01)

0 0

103 104

93 97

77 93

72 89

69 89

67 88

62 86

60 85

Months 58 81

52 81

50 79

45 67

34 50

19 29

9 11

2 2

0 0

36 Presented at the 63 rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11 -14, 2021; Atlanta, GA/Virtual

Conclusions • 4 drugs have a deeper response than 3 • Interestingly, it deepens at each step – post induction, transplant, consolidation and maintenance • It is feasible to add dara to lenalidomide for maintenance • The trend seems to improve PFS • We are getting close – need a phase 3 study…

Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Transplantation and MRD Response-Adapted Consolidation and Treatment Cessation-Final Primary Endpoint Analysis of the MASTER Trial

Luciano J. Costa1, Saurabh Chhabra2, Natalie S. Callander, MD3 , Eva Medvedova4, Bhagirathbhai Dholaria5, Rebecca Silbermann4, Kelly Godby 1, Binod Dhakal2, Susan Bal1, Smith Giri1, Anita D’Souza2, Timothy Schmidt3, Aric Hall3, Pamela Hardwick 1, Robert F. Cornell5, Parameswaran Hari2 1- University of Alabama at Birmingham; 2- Medical College of Wisconsin; 3- University of Wisconsin at Madison; 4- Oregon Health and Science University; 5- Vanderbilt University

COMMIT- Academic Consortium to Overcome Multiple Myeloma through Innovative Trials

Treatment Dara-KRd Daratumumab 16 mg/m2 days 1,8,15,22 (days 1,15 C 3-6; day 1 C >6) Carfilzomib (20) 56 mg/m2 Days 1,8,15 Lenalidomide 25 mg Days 1-21 Dexamethasone 40mg PO Days 1,8,15,22

MRD assessment by NGS

AHCT

MRD→

Dara-KRd x 4

Consolidation

Dara-KRd x 4

2nd MRD (-) (<10-5)

MRD→

Induction

MRD→

• • • •

Lenalidomide Maintenance

2nd MRD (-) (<10-5)

”MRD-SURE” -Treatment-free observation and MRD surveillance*

*24 and 72 weeks after completion of therapy

MASTER trial

Best MRD response by phase of therapy

HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)

MASTER trial

Progression-Free and Overall Survival

2-year PFS

0 HRCA

91%

1 HRCA

97%

2+ HRCA

58%

HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)

2-year OS

0 HRCA

96%

1 HRCA

100%

2+ HRCA

76%

MASTER trial

Conclusions • NGS-MRD response-adapted therapy is feasible in ~96% of patients in multi center setting – 72% reaching MRD-SURE. • Patients with standard and high-risk NDMM have similar depth of response and low risk of MRD resurgence or progression when treated with Dara-KRd/AHCT and MRDadapted treatment cessation. • Quadruplet therapy and achievement of confirmed MRD (-) responses enables the exploration of treatment cessation and “MRD-SURE” as alternative to continuous therapy.

Effective novel consolidative strategies should be explored to clear MRD and improve outcomes in patients with ultra-high-risk MM MASTER trial

Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone as Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma: The Phase III GMMG-HD7 Trial

1, Roland Fenk 3, Uta Bertsch 1,2, Diana Tichy4, Britta Besemer 5 , Jan Dürig 6 , Hartmut Goldschmidt 1,2, Elias K. Mai1, EvaGMMG NievergallMM5 trial in newly diagnosed Multiple Myeloma to evaluate PAd vs VCD in 10, Anne Marie Asemissen 11 , Bernhard Heilmeier 12 , Stefanie Huhn1 , Roland Schroers7, Ivana von Metzler8, Mathias Hänel9, Christoph MannLenalidomide consolidation and maintenance – final analysis on 1 1 13 Katharina Kriegsmann , Niels Weinhold , Steffen Luntz , Tobias A. W. Holderried14, Karolin Trautmann-Grill15, Deniz Gezer16, 1, Jan Duerig2, Uta Bertsch1, Christina Kunz3, Thomas Hielscher3, Elias K. Loos1, Mathias Haenel2, Igor W. Blau2, Dirk Hose1, Anna J Hartmut Goldschmidt 18, Cyrus 19 , Wolfgang Knauf20 , Markus Munder 21, Thomas Geer 22 , Maika Klaiber-Hakimi17, Martin Müller Khandanpour 1, Maximilian Merz1, Markus Munder2, Hans-Walter Lindemann2, Matthias Zeis2, Christian Gerecke 2, Ingo G. H. Schmidt-Wolf2 Huegle-Doerr 1, Hans J. Salwender 26 , Katja C. Weisel11 for the 2 Hendrik Riesenberg 23, Jörg Thomalla24, Martin Hoffmann25, Marc-Steffen Raab 1German-Speaking Myeloma Multicenter Group (GMMG) and University Hospital Heidelberg, Germany, GMMG, Germany, 3Division of Biostatistic German-speaking Myeloma Multicenter Group (GMMG) Randomized (n = 504)

GMMG Germany; MM5 Trial 2 National Center for Tumor Diseases Heidelberg, Heidelberg, Germany; Medicine V, University Hospital Heidelberg, Heidelberg, Two patients were excluded from ITT due to 3 Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany; 4 Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, unconfirmed diagnosis Germany; of multiple myeloma Heidelberg, The MM5 phase III trial of the German-Speaking Myeloma Multicenter Group (GMMG) was designed requiring systemic therapy 5 Department of Internal Medicine II, University Hospital Tübingen, 6 Department to address Tübingen, two independent primary objectives: 1.forDemonstration non-inferiority of VCD Germany; Hematologyofand Stem Cell Transplantation, University Hospital Essen, Essen, Germany; 7 Medical Clinic, University Hospital Bochum, Bochum, Germany; 8 Department (bortezomib, cyclophosphamide, dexamethasone) induction compared to PAd (bortezomib, of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; Patients not receiving PAd VCD 9 Department of Internal Medicine III, Clinic Chemnitz, Chemnitz, 10Department adriamycin, dexamethasone) induction with respect to response rate (very goodUniversity partial Germany; fortherapy Hematology, Oncology and Immunology, Hospital Gießen anddue Marburg, Marburg, allocated intervention (n = 251) Germany; (n = 251) to: response (VGPR) or better). 2. Determination of the best 12 ofClinic four treatment strategies respect to Hospital Barmherzige 11 Department of Oncology, Hematology and BMT, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; for Oncology andwith Hematology, Brueder Regensburg, Regensburg, Germany; - myocardial infarction prior Received allocated progression-free survival (PFS). The four treatment strategies are defined by PAd vs. VCD induction Received allocated 13 Coordination Centre for Clinical Trails (KKS) Heidelberg, Heidelberg, to therapy (n = 1) Germany; 14 Department of Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn,(nBonn, intervention = 248) Germany; intervention (n = 249) - death (n = 1) treatment, high dose melphalan followed by autologous stem cell transplantation and maintenance 15 Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany; 16Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, treatment with lenalidomide for 2 years vs. lenalidomide until complete response (CR) (figure 1). randomized PAd and RWTH Aachen University, Aachen, Germany; 17 Clinic for Hematology, Oncology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany; 18 Clinic for Hematology, Oncology and Immunology, treated VCD (n = 1) During the induction phase the patients are treated with 3 cycles of either PAd or VCD. PAd was 19 20 Center for Hematology and Oncology Bethanien, Frankfurt am Main, Germany; Klinikum Siloah Hannover, Hannover, Germany; Medical Clinic University1.3 Hospital Münster, Germany; dosed A, as bortezomib mg/m2, days 1, 4, 8, Münster, 11, doxorubicin 9 mg/m2, days 1-4, dexamethasone 20 21 Department of Internal Medicine III, University Hospital Mainz, Mainz, Germany; 22 Department of Internal Medicine III, Diakoneo Schwäbisch-Hall, Schwäbisch-Hall, Germany; mg, days 1-4, 9-12, 17-20 (repeated every 28 days). VCD consisted of bortezomib 1.3 mg/m2, daysClinic 1, 23 Hematology/Oncology Center, Bielefeld, Germany; cycles n = 234 3 cycles n = 244 Hematology / Oncology Koblenz, Germany; Medical Clinic Clinic Ludwigshafen, Ludwigshafen,3 Germany; 4, 8, 11,24cyclophosphamide 900 mg/m2Center, day 1, dexamethasone 40 mg, 25 days 1-2, 4-5, 8-9,A, 11-12 2 cycles n = 10 2 cycles n=4 26 Asklepios (repeated Tumorzentrum every 21 days). TheHamburg, route of administration bortezomib was changed from intravenously AK Altonafor and AK St. Georg, Hamburg, Germany 1 cycle n=5 1 cycle n=1 1 Department of Internal

to subcutaneously in all study arms by a protocol amendment in February 2012 after inclusion of 314 patients.

ASH 2021; Final Abstract Code: 463

symptomatic MM 1st line treatment 18-70 years

3 x PAd

A1 + B1

Randomization 3 x VCD

ITT Per-Protocol Safety

n = 251 n = 233 n = 249

ITT Per-Protocol Safety

n = 251 n = 240 n = 249

One patient excluded from ITT (due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy) received VCD therapy and was included in safety analysis

Excluded from PP analysis - incomplete induction therapy (n = 5) - missing response assessment (n = 3) - one patient not ITT not PP but Safety (see above)

Figure 2: Consort diagram

A2 + B2

stem cell mobilisation (CAD+G-CSF) + leukapheresis

Excluded from PP analysis - incomplete induction therapy for reasons other than PD (n = 9) - missing response assessment (n = 6) - randomized PAd and treated VCD (n = 1)

Patients not receiving allocated intervention due to: - non-compliance (n = 1) - withdrawal of consent (n = 2)

Standard intensification according to

Baseline characteristics Patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, kidney function and the high-risk cytogenetic abnormalities deletion (17p), translocation t(4;14) and

Primary endpoint: MRD negativity at the end of induction phase nosed Multiple Myeloma to evaluate PAd vs VCD induction prior to HDT followed by HD7

consolidation and maintenance – final analysis on induction therapy

Kunz3, Thomas Hielscher3, Elias K. Loos1, Mathias Haenel2, Igor W. Blau2, Dirk Hose1, Anna Jauch1, Baerbel Schurich1, Kai Neben2, Anja Seckinger1, Barbara nder2, Hans-Walter Lindemann2, Matthias Zeis2, Christian Gerecke2, Ingo G. H. Schmidt-Wolf2, Katja Weisel2, Christof Scheid2, Hans Salwender2 MG) and University Hospital Heidelberg, Germany, 2GMMG, Germany, 3Division of Biostatistics, German Cancer Research Center Heidelberg, Germany

Induction phase (3 x 6-week cycles)

Patients not receiving allocated intervention due to: - myocardial infarction prior to therapy (n = 1) - death (n = 1)

PAd (n = 251)

VCD (n = 251)

Received allocated intervention (n = 248)

Received allocated intervention (n = 249)

randomized PAd and treated VCD (n = 1)

Excluded from PP analysis - incomplete induction therapy for reasons other than PD (n = 9) - missing response assessment (n = 6) - randomized PAd and treated VCD (n = 1)

3 cycles 2 cycles 1 cycle

n = 234 n = 10 n=5

3 cycles 2 cycles 1 cycle

n = 244 n=4 n=1

ITT Per-Protocol Safety

n = 251 n = 233 n = 249

ITT Per-Protocol Safety

n = 251 n = 240 n = 249

One patient excluded from ITT (due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy) received VCD therapy and was included in safety analysis

Excluded from PP analysis - incomplete induction therapy (n = 5) - missing response assessment (n = 3) - one patient not ITT not PP but Safety (see above)

Isa + RVd

In the PAd group 91.2% and in the VCD group 96.0% of the patients completed three planned induction cycles. Applied total bortezomib dose over all three cycles was comparable in both, PAd and VCD arms. Response rates were similar in both induction regimens (PAd vs. VCD) with 34.3% vs. 37.0% of patients achieving VGPR or better. Non-inferiority of VCD compared to PAd was shown (one-sided p=0.0013). Similar results were obtained in the PP analysis. CR rates were 4.4% and 8.4% (PAd vs. VCD) and 21.1% and 22.3% (PAd vs. VCD) for near complete response (nCR) or better. Partial response (PR) or better was reached in 72.1% vs. 78.1% of the patients (PAd vs. VCD) (figure 3). PAd

Patients not receiving allocated intervention due to: - non-compliance (n = 1) - withdrawal of consent (n = 2)

RVd

VCD

Screening

MRD (bone marrow aspirate)

After HDT

After 12 m onths

After 24 m onths

End of study



0 CR

nCR

VGPR

missing

Figure 3: Response rates after induction PAd or VCD induction therapy. The proportion of patients with any adverse event was comparable in PAd vs. VCD (61.3% vs. 64.0%,

p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. Primary endpoint: Secondary endpoints: Patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, 24.0%, p=0.04). VCD led to a significantly higher proportion of leukocytopenia and neutropenia kidney function and the high-risk cytogenetic abnormalities• deletion (17p), translocation t(4;14) and at the end MRD negativity after induction CTCAE grade 3 and•4 (PAdCR 11.3% vs. VCD 35.2%, p=<0.001). The number of infections (≥ CTCAE gain 1q21 (>3 copies). There were significant differences in patient age and distribution of WHO grade 2) and infection-related SAE was similar (PAd 24.6% vs. VCD 22.4% for AE, p=0.60 and PAd performance status (table 1). of induction treatment12.9% vs. VCD 10.8%• for SAE, Safety p=0.49). Compared to the infection rate (AE ≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg on days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4Table 1: Patient baseline characteristics (NGF, sensitivity 10-5)trial, a reduction in MM5 during induction was observed. Preliminary data (412 patients) of numbers of Characteristic PAd VCD P value stem cells were comparable (PAd median 9.8x10 vs. VCD median 9.4x10 kg according tocollected R- CD34+ cut-off: No of patients % in PAd arm no stratified of patients % in VCD arm bodyweight, p=0.15).Data In the PAd arm more deaths were observed compared to the VCD arm (5 vs 1). Table 2: Toxicity during induction Sex (male / female) 147 / 104 58.6 / 41.4 153 / 98 61.0 / 39.0 0.65 ISS • April 2021 59.4 (37 - 70)

58.7 (33 - 70)

0.04

27 / 224

10.8 / 88.2

30 / 221

12.0 / 88.0

0.78

ISS stage (I / II / III)

99 / 80 / 72

39.4 / 31.9 / 28.7

94 / 82 / 75

37.5 / 32.7 / 29.9

0.91

WHO performance status (0-1 / 2-3 / unknown)

215 / 30 / 6

85.7 / 11.9 / 2.4

230 / 21 / 0

91.6 / 8.4 / 0.0

0.01

LDH above ULN

18.4

17.5

0.82

Calcium elevation

15.9

12.3

VCD

P value

AE ≥ 3º (or ≥ 2º for infections, cardiac disorders, PNP and thromboembolic events)

152

61.3

ASCT, 160 autologous 64.0 stem cell0.58 transplant; CR, complete response; d, dexamethasone; HDT, high-dose therapy; Isa, isatuximab; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NGF, next-generation flow; PD, progressive disease; R, lenalidomide; R-ISS, Revised International Staging System; Te, transplant eligible; V, bortezomib 60 24.0 0.04 1. ClinicalTrials.gov: NCT03617731 88 35.2 <0.01

32.7

11.3

AE Infections and Infestations ≥ 2º

24.6

22.4

0.60

0.31

SAE Infections and Infestations ≥ 2º

12.9

10.8

0.49

15.1

15.5

1.00

Anemia

124

49.4

138

55.0

0.25

Bone disease

229

91.2

223

88.8

0.46

61 28.5 53 25.0 (26 / 25 / 25) (12.0 / 11.6 / 11.7) (23 / 22 / 19) (10.4 / 10.1 / 8.9)

PAd

No of patients % in PAd arm No of patients % in VCD arm

Any SAE

Renal insufficiency

High-risk cytogenetics (del 17p / t (4;14) / gain 1q21)

Characteristic

Leukocyto-/Neutropenia ≥ 3º

(IMWG).

ene, Chugai ch Funding; chmidt-Wolf: , Honoraria, ssen Cilag:

Response rates (ITT)

Baseline characteristics

Age in years (median, range) Salmon and Durie stage (IA-IIB / IIIA-IIIB)

ponse to

3 years or PD

After Cycle 3

ysis were ses were

HDT + ASCT

Isa + R

Figure 2: Consort diagram

dard ication ding to rotocol MG dard)

Randomization

Two patients were excluded from ITT due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy

Maintenance phase (4-week cycles)

Results

Randomization 1:1

designed of VCD tezomib, od partial espect to induction ntenance figure 1). PAd was asone 20 2, days 1, -9, 11-12 venously on of 314

NDMM N=662

Percent (%)

Randomized (n = 504)

0.44

Conclusions Both induction regimens in the current GMMG-MM5 trial show relevant efficacy after three cycles and a non-inferiority of VCD compared to PAd was found. PAd and VCD are well tolerated with more than 90% of the patients receiving all planned induction cycles. In conclusion, VCD was found to be a valid alternative to PAd with comparable efficacy and a favourable toxicity profile.

First primary endpoint, end of induction MRD -5), was met in ITT analysis negativity by NGF (10 nosed Multiple Myeloma to evaluate PAd vs VCD induction prior to HDT followed by HD7

consolidation and maintenance – final analysis on induction therapy Patients with MRD negativity at the end of induction therapy Kunz , Thomas Hielscher , Elias K. Loos , Mathias Haenel , Igor W. Blau , Dirk Hose , Anna Jauch , Baerbel Schurich , Kai Neben , Anja Seckinger , Barbara 3

nder2, Hans-Walter Lindemann2, Matthias Zeis2, Christian Gerecke2, Ingo G. H. Schmidt-Wolf2, Katja Weisel2, Christof Scheid2, Hans Salwender2 MG) and University Hospital Heidelberg, Germany, 2GMMG, Germany, 3Division of Biostatistics, German Cancer Research Center Heidelberg, Germany Randomized (n = 504)

Patients not receiving allocated intervention due to: - myocardial infarction prior to therapy (n = 1) - death (n = 1)

VCD (n = 251)

Received allocated intervention (n = 248)

Received allocated intervention (n = 249)

Patients not receiving allocated intervention due to: - non-compliance (n = 1) - withdrawal of consent (n = 2) One patient excluded from ITT (due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy) received VCD therapy and was included in safety analysis

3 cycles 2 cycles 1 cycle

n = 234 n = 10 n=5

3 cycles 2 cycles 1 cycle

n = 244 n=4 n=1

ITT Per-Protocol Safety

n = 251 n = 233 n = 249

ITT Per-Protocol Safety

n = 251 n = 240 n = 249

Excluded from PP analysis - incomplete induction therapy (n = 5) - missing response assessment (n = 3) - one patient not ITT not PP but Safety (see above)

50% 40%

20%

10%

0 CR

Table 1: Patient baseline characteristics Characteristic

ysis were ses were

ene, Chugai ch Funding; chmidt-Wolf: , Honoraria, ssen Cilag:

missing

PAd

VCD

P value

No of patients

% in PAd arm

no of patients

% in VCD arm

147 / 104

58.6 / 41.4

153 / 98

61.0 / 39.0

59.4 (37 - 70)

The proportion of patients with any adverse event was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.04). VCD led to a significantly higher proportion of leukocytopenia and neutropenia CTCAE grade 3 and 4 (PAd 11.3% vs. VCD 35.2%, p=<0.001). The number of infections (≥ CTCAE grade 2) and infection-related SAE was similar (PAd 24.6% vs. VCD 22.4% for AE, p=0.60 and PAd 12.9% vs. VCD 10.8% for SAE, p=0.49). Compared to the infection rate (AE ≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg on days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4trial, a reduction in MM5 during induction was observed. Preliminary data (412 patients) of numbers of collected CD34+ stem cells were comparable (PAd median 9.8x106 vs. VCD median 9.4x106 kg bodyweight, p=0.15). In the PAd arm more deaths were observed compared to the VCD arm (5 vs 1).

Isa-RVd is the first regimen to demonstrate a rapid and statistically significant benefit from treatment by reaching a MRD negativity of 50.1% at the end of induction and to show superiority vs. RVd in a Phase 3 trial 58.7 (33 - 70)

0.65 0.04

27 / 224

10.8 / 88.2

30 / 221

12.0 / 88.0

0.78

ISS stage (I / II / III)

99 / 80 / 72

39.4 / 31.9 / 28.7

94 / 82 / 75

37.5 / 32.7 / 29.9

0.91

WHO performance status (0-1 / 2-3 / unknown)

215 / 30 / 6

85.7 / 11.9 / 2.4

230 / 21 / 0

91.6 / 8.4 / 0.0

0.01

LDH above ULN

18.4

17.5

0.82

Calcium elevation

15.9

12.3

Characteristic

PAd

VCD

P value

No of patients % in PAd arm No of patients % in VCD arm

AE ≥ 3º (or ≥ 2º for infections, cardiac disorders, PNP and thromboembolic events)

152

61.3

160derived from 64.0 stratified 0.58 conditional logistic regression analysis *P value † Missing NGF-MRD values were due to either patients’ loss to follow-up during induction therapy or to missing bone marrow samples or technical failures60in measurement counted as non-responders, i.e. NGF-MRD positive 24.0 0.04 CI, confidence interval; d, dexamethasone; Isa, isatuximab; ITT, intent-to-treat; MRD, minimal residual disease; NGF, next-generation flow; 88 ratio; R,35.2 <0.01 V, bortezomib OR, odds lenalidomide;

Any SAE

32.7

11.3

AE Infections and Infestations ≥ 2º

24.6

22.4

0.60

0.31

SAE Infections and Infestations ≥ 2º

12.9

10.8

0.49

15.1

15.5

1.00

Anemia

124

49.4

138

55.0

0.25

Bone disease

229

91.2

223

88.8

0.46

61 28.5 53 25.0 (26 / 25 / 25) (12.0 / 11.6 / 11.7) (23 / 22 / 19) (10.4 / 10.1 / 8.9)

Table 2: Toxicity during induction

Leukocyto-/Neutropenia ≥ 3º

Renal insufficiency

High-risk cytogenetics (del 17p / t (4;14) / gain 1q21)

Low number of not assessable/missing † MRD status: Isa-RVd (10.6%) and RVd (15.2%)

(IMWG).

ponse to

Response rates (ITT)

Baseline characteristics

Age in years (median, range) Salmon and Durie stage (IA-IIB / IIIA-IIIB)

0%VGPR

nCR

Figure 3: Response rates after induction PAd or VCD induction therapy.

Patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, kidney function and the high-risk cytogenetic abnormalities deletion (17p), translocation t(4;14) and gain 1q21 (>3 copies). There were significant differences in patient age and distribution of WHO performance status (table 1).

Sex (male / female)

35.6%

VCD

30%

Figure 2: Consort diagram

dard ication ding to rotocol MG dard)

Isa-RVd RVd

50.1%

PAd (n = 251)

randomized PAd and treated VCD (n = 1)

Excluded from PP analysis - incomplete induction therapy for reasons other than PD (n = 9) - missing response assessment (n = 6) - randomized PAd and treated VCD (n = 1)

Results

60%

Two patients were excluded from ITT due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy

Percent (%)

designed of VCD tezomib, od partial espect to induction ntenance figure 1). PAd was asone 20 2, days 1, -9, 11-12 venously on of 314

OR 1.83 (95% CI 1.34–2.51) P<0.001*

0.44

Response rates after induction therapy HD7

nosed Multiple Myeloma to evaluate PAd vs VCD induction prior to HDT followed by consolidation and maintenance – final analysis on induction therapy Isa-RVd†

100%

Randomized (n = 504) Two patients were excluded from ITT due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy

Patients not receiving allocated intervention due to: - myocardial infarction prior to therapy (n = 1) - death (n = 1)

PAd (n = 251)

VCD (n = 251)

Received allocated intervention (n = 248)

Received allocated intervention (n = 249)

randomized PAd and treated VCD (n = 1)

Excluded from PP analysis - incomplete induction therapy for reasons other than PD (n = 9) - missing response assessment (n = 6) - randomized PAd and treated VCD (n = 1)

3 cycles 2 cycles 1 cycle

n = 234 n = 10 n=5

3 cycles 2 cycles 1 cycle

n = 244 n=4 n=1

ITT Per-Protocol Safety

n = 251 n = 233 n = 249

ITT Per-Protocol Safety

n = 251 n = 240 n = 249

Baseline characteristics

ysis were ses were

PAd

VCD

P value

% in PAd arm

no of patients

% in VCD arm

147 / 104

58.6 / 41.4

153 / 98

61.0 / 39.0

59.4 (37 - 70)

ene, Chugai ch Funding; chmidt-Wolf: , Honoraria, ssen Cilag:

58.7 (33 - 70)

0.65 0.04

27 / 224

10.8 / 88.2

30 / 221

12.0 / 88.0

0.78

ISS stage (I / II / III)

99 / 80 / 72

39.4 / 31.9 / 28.7

94 / 82 / 75

37.5 / 32.7 / 29.9

0.91

WHO performance status (0-1 / 2-3 / unknown)

215 / 30 / 6

85.7 / 11.9 / 2.4

230 / 21 / 0

91.6 / 8.4 / 0.0

0.01

LDH above ULN

18.4

17.5

0.82

Calcium elevation

15.9

12.3

30 40%

83.6%

60.5%

VCD

36.2%

24.2% 21.6%

20% 10

10% 0 CR

nCR

VGPR

missing

Response rates (ITT)

>nCR ≥

>VGPR ≥

>PR ≥

Characteristic

PAd

VCD

P value

No of patients % in PAd arm No of patients % in VCD arm

AE ≥ 3º (or ≥ 2º for infections, cardiac disorders, PNP and thromboembolic events)

152

61.3

160 derived 64.0 0.58 exact test *P values from Fisher’s † Data adjusted per M-protein interference 60 24.0 CR, complete response; d, 0.04 dexamethasone; Isa, isatuximab; nCR; near-complete response; ORR, overall response rate; PR, partial response; R, lenalidomide; V, bortezomib; 88 35.2 <0.01 VGPR, very good partial response

Any SAE

32.7

11.3

AE Infections and Infestations ≥ 2º

24.6

22.4

0.60

0.31

SAE Infections and Infestations ≥ 2º

12.9

10.8

0.49

15.1

15.5

1.00

Anemia

124

49.4

138

55.0

0.25

Bone disease

229

91.2

223

88.8

0.46

61 28.5 53 25.0 (26 / 25 / 25) (12.0 / 11.6 / 11.7) (23 / 22 / 19) (10.4 / 10.1 / 8.9)

Table 2: Toxicity during induction

Leukocyto-/Neutropenia ≥ 3º

Renal insufficiency

High-risk cytogenetics (del 17p / t (4;14) / gain 1q21)

41.7%

P=0.46*

77.3%

90.0%

RVd

Although the rates of CR after induction therapy did not differ between the Isa-RVd and RVd arms, there was a significant increase in ≥VGPR rates and ORR with Isa-RVd

No of patients

(IMWG).

ponse to

50%

Table 1: Patient baseline characteristics

Age in years (median, range) Salmon and Durie stage (IA-IIB / IIIA-IIIB)

P=0.15*

60%

Figure 3: Response rates after induction PAd or VCD induction therapy.

Sex (male / female)

70%

Characteristic

P<0.001*

80%

20 30%

Excluded from PP analysis - incomplete induction therapy (n = 5) - missing response assessment (n = 3) - one patient not ITT not PP but Safety (see above)

Figure 2: Consort diagram

dard ication ding to rotocol MG dard)

Results

90%

Percent (%)

designed of VCD tezomib, od partial espect to induction ntenance figure 1). PAd was asone 20 2, days 1, -9, 11-12 venously on of 314

P=0.02*

0.44

Addition of Isa to RVd had limited impact on safety profile

HD7

nosed Multiple Myeloma to evaluate PAd vs VCD induction prior to HDT followed by Isa-RVd consolidation and maintenance – final analysis induction therapy AEs CTCAE grade ≥3, on n (%)

RVd (n=330) (n=328) Kunz3, Thomas Hielscher3, Elias K. Loos1, Mathias Haenel2, Igor W. Blau2, Dirk Hose1, Anna Jauch1, Baerbel Schurich1, Kai Neben2, Anja Seckinger1, Barbara

Isa-RVd (n=330)

RVd (n=328)

Leukocytopenia/Neutropenia†

87 (26.4)

30 (9.1)

Lymphopenia

48 (14.5)

65 (19.8)

77 (23.5)

Anemia

13 (3.9)

20 (6.1)

85 (25.8)

55 (16.8)

Thrombocytopenia

21 (6.4)

15 (4.6)

43 (13.0)

34 (10.4)

Specific non-hematologic AE (PT) 25 (7.6)

22 (6.7)

Thromboembolic events

5 (1.5)

9 (2.7)

Infusion-related reactions ‡

4 (1.2)

nder2, Hans-Walter Lindemann2, Matthias Zeis2, Christian Gerecke2, Ingo G. H. Schmidt-Wolf2, Katja Weisel2, Christof Scheid2, Hans Salwender2 2GMMG, Germany, 3Division of Biostatistics, German Cancer Research Center Heidelberg, Germany MG) and University Hospital Heidelberg, Germany, Any AE 210 (63.6) Randomized (n = 504)

Any serious AE (any grade)

Two patients were excluded from ITT due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy

Patients not receiving allocated intervention due to: - myocardial infarction prior to therapy (n = 1) - death (n = 1)

VCD Deaths (n = 251)

PAd (n = 251) Received allocated intervention (n = 248)

Received allocated intervention (n = 249)

Investigations* (SOC)

randomized PAd and treated VCD (n = 1)

Excluded from PP analysis - incomplete induction therapy for reasons other than PD (n = 9) - missing response assessment (n = 6) - randomized PAd and treated VCD (n = 1)

Patients not receiving allocated intervention due to: - non-compliance (n = 1) - withdrawal of consent (n = 2)

3 cycles 2 cycles 1 cycle

n = 234 n = 10 n=5

ITT Per-Protocol Safety

n = 251 n = 233 n = 249

One patient excluded from ITT (due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy) received VCD therapy and was included in safety analysis

Results

1 cycle

n=1

Safety

Excluded from PP analysis - incomplete induction therapy (n = 5) - missing response assessment (n = 3) - one patient not ITT not PP but Safety (see above)

n = 249

nCR

VGPR

PD 28SD(8.5)

missing

33 (10.1)

Peripheral neuropathy

Response rates (ITT) Figure 3: Response rates after induction PAd or VCD induction therapy.

The proportion of patients with any adverse event was comparable in PAd vs. VCD (61.3% vs. 64.0%, Gastrointestinal disorders (SOC) 27 (8.2) 31 (9.5) p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.04). VCD led to a significantly higher proportion of leukocytopenia and neutropenia CTCAE grade 3 and 4 (PAd 11.3% vs. VCD 35.2%, p=<0.001). The number of infections (≥ CTCAE grade 2) and infection-related SAE was similar (PAd 24.6% vs. VCD 22.4% for AE, p=0.60 and PAd 12.9% vs. VCD 10.8% for SAE, p=0.49). Compared to the infection rate (AE ≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg on days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4trial, a reduction in MM5 during induction was observed. Preliminary data (412 patients) of numbers of collected CD34+ stem cells were comparable (PAd median 9.8x106 vs. VCD median 9.4x106 kg bodyweight, p=0.15). In the PAd arm more deaths were observed compared to the VCD arm (5 vs 1).

Metabolism and nutrition disorders (SOC)

Table 1: Patient baseline characteristics PAd

VCD

P value

12 (3.6)

26 (7.9)

A comparable number of patients discontinued induction therapy due to AEs in the Isa-RVd arm vs. RVd arm

No of patients

% in PAd arm

no of patients

% in VCD arm

147 / 104

58.6 / 41.4

153 / 98

61.0 / 39.0

59.4 (37 - 70)

58.7 (33 - 70)

0.65 0.04

27 / 224

10.8 / 88.2

30 / 221

12.0 / 88.0

0.78

ISS stage (I / II / III)

99 / 80 / 72

39.4 / 31.9 / 28.7

94 / 82 / 75

37.5 / 32.7 / 29.9

0.91

WHO performance status (0-1 / 2-3 / unknown)

215 / 30 / 6

85.7 / 11.9 / 2.4

230 / 21 / 0

91.6 / 8.4 / 0.0

0.01

LDH above ULN

18.4

17.5

0.82

Calcium elevation

15.9

12.3

Characteristic

PAd

VCD

P value

No of patients % in PAd arm No of patients % in VCD arm

AE ≥ 3º (or ≥ 2º for infections, cardiac disorders, PNP and thromboembolic events)

152

61.3

160 64.0 0.58 *SOC considered as “Investigations” as defined by the CTCAE † Includes five episodes of febrile neutropenia during induction: Isa-VRd (n=3) vs. VRd (n=2) ‡ Infusion-related reactions of CTCAE grade 2 or higher in the Isa-RVd arm were n=42 (12.7%) 60 24.0 0.04 AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; d, dexamethasone; Isa, isatuximab; NA, not applicable; PT, preferred 35.2 SOC, <0.01 term; R,88lenalidomide; system organ class; V, bortezomib

Any SAE

32.7

11.3

AE Infections and Infestations ≥ 2º

24.6

22.4

0.60

0.31

SAE Infections and Infestations ≥ 2º

12.9

10.8

0.49

Renal insufficiency

15.1

15.5

1.00

Anemia

124

49.4

138

55.0

0.25

Bone disease

229

91.2

223

88.8

0.46

61 28.5 53 25.0 (26 / 25 / 25) (12.0 / 11.6 / 11.7) (23 / 22 / 19) (10.4 / 10.1 / 8.9)

Table 2: Toxicity during induction

Leukocyto-/Neutropenia ≥ 3º

(IMWG).

High-risk cytogenetics (del 17p / t (4;14) / gain 1q21)

Specific hematologic AE (PT)

VCD

ITT n = 251 Infections and infestations (SOC) Per-Protocol n = 240 10

Baseline characteristics

Age in years (median, range) Salmon and Durie stage (IA-IIB / IIIA-IIIB)

ene, Chugai ch Funding; chmidt-Wolf: , Honoraria, ssen Cilag:

8 (2.4)

30 3 cycles n = 244lymphatic system disorders Blood and (SOC) 2 cycles n=4

Sex (male / female)

ponse to

4 (1.2)

79 (23.9)

Nervous system disorders (SOC)

Characteristic

ysis were ses were

119 (36.3)

Figure 2: Consort diagram

dard ication ding to rotocol MG dard)

115 (34.8)

Percent (%)

designed of VCD tezomib, od partial espect to induction ntenance figure 1). PAd was asone 20 2, days 1, -9, 11-12 venously on of 314

201 (61.3)

AEs CTCAE grade ≥3, n (%)

0.44

Summary of Frontline

• • • • • •

Adding a CD38 antibody to VRD or KRD is feasible with limited incremental toxicity Depth of response is improved, including MRD negativity MRD will be an even more important measure going forward There is a trend to improved PFS This may overcome the high risk feature of some patients Ultra high risk disease remains challenging to treat with current strategies

Upfront Therapy Status..Evovlving • Adding a CD38 antibody to VRD or KRD is feasible with limited incremental toxicity • Depth of response is improved, including MRD negativity • MRD will be an even more important measure going forward • There is a trend to improved PFS • This may overcome the high risk feature of some patients • Ultra high risk disease remains challenging to treat with current strategies • What about transplant??

Audience Q&A with Panel

• Open the Q&A window, allowing you to ask questions to the host and panelists. They can either reply to you via text in the Q&A window or answer your question live. • If the host answers live, you may see a notification in the Q&A window. • If the host replies via the Q&A box – you will see a reply in the Q&A window.

IMF REGIONAL COMMUNITY WORKSHOP – Tri-State Agenda After Break

11:05 AM - Relapsed Therapy and Clinical Trials Raymond Comenzo, MD, Tufts Medical Center, Boston, MA 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Kimberly Noonan, DNP, ANP-BC, AOCN, Dana-Farber Cancer Center, Boston, MA , IMF Nurse Leadership Board 12:05 PM - Q&A with Panel

Relapsed Therapy and Clinical Trials Raymond Comenzo, MD Tufts Medical Center, Boston, MA 54

Having and Treating Relapsed Refractory Multiple Myeloma Raymond L. Comenzo, M.D. June 18, 2022

VirtualRegionalCommunityWorkshop

Disclosures • Research Funding • Janssen • Karyopharm • Lymphoma Foundation • Lloyd Foundation • Sidewater Family Fund • MacKenzie’s Mission • NIA/NIH

• Consultant/Advisor • Takeda • Caelum • Janssen • Karyopharm • Sanofi

Definitions IMWG criteria for Progressive Disease1 • ≥25% increase from nadir in ≥1 of the following: • Serum/urine M-protein (absolute increase ≥0.5 g/dL* and ≥200 mg/24 hr, respectively) • Difference between involved and uninvolved FLC levels† (absolute increase >100 mg/L) • BM plasma cells‡ (absolute increase ≥10%) • New lesions (≥50% increase in SPD of >1 lesion or longest diameter of previous lesion >1 cm in short axis) • Circulating plasma cells (≥50% increase [minimum 200 cells/μL] if only measure of disease) *If lowest M component ≥5 g/dL, increase must be ≥1 g/dL. †In patients without measurable serum/urineM-protein. ‡In patients without measurable serum/urine M-protein or involved FLC.

1. Kumar. Lancet Oncol. 2016;17:e328. 2. Nooka. Blood. 2015;125:3085. 3. Rajkumar. Blood. 2011;117:4691. 4. Richardson. NEJM. 2003;348:2609. 5. Richardson. Cancer. 2006;106:1316.

• Primary refractory • Not achieving at least MR on a given treatment

• Relapsed • Meets IMWG criteria for PD but not R/R MM or primary refractory MM

• Relapsed Refractory • Meets IMWG criteria for PD1 • PD on treatment after at least MR or • PD ≤60 days on most recent treatment

Burden of Disease • Social circumstances • Effectiveness with a supportive partner • Support within the medical practice • Navigators • Nurse practitioners • Social workers • Accessibility of your myeloma doctor • Having your second opinion doctor available too • Support within the IMF

Trying to stay as well as you are • Myeloma disease has many faces • Blood and urine numbers • Images of myeloma tumors • Images of bones • Bone marrow genetics • The better you follow up, the better you will be • Mental health, fitness, bone health • Complexity of decision making

The Basics: A monoclonal protein SERUM OR URINE ELECTROPHERESIS

SERUM OR URINE IMMUNOFIXATION

FREE LIGHT CHAINS

DIAGNOSTIC SENSITIVITY FOR MONOCLONAL GAMMOPATHIES Laboratory test

Dis penzieri et al. Leukemia volume 23, pages 215 –224 (2009) 8

% abnormal

Serum immunofixation electrophoresis

93.5

Serum protein electrophoresis

80.8

Serum FLC κ/λ ratio

85.7

Serum immunofixation electrophoresis or FLC ratio

99.5

Katzmann et al. Clin Chem. 2005;51:878.

Presence of clonal plasma cells Bone marrow

2022 American Society of Hematology 10

PLASMACYTOMA

Blum et al. Sci Rep 9, 2922 (2019)

PERIPHERAL BLOOD

Assessment of end-organ damage: Bone disease Skeletal Survey

+ Low cost, widespread availability - Limited sensitivity

WB LOW-DOSE CT +/- PET

+ Increased sensitivity, EMD detection, FL viability, convenient - Expensive, less sensitive for very early bone involvement

Ede l styn e t al . Cl i n Radi ol . 1967 ; 18 : 158 -162 Rubi ni et1a1l. Cri t Re v Oncol Hematol , 101 (2016 ), pp. 169 -183

WB-MRI

+ Infiltrative disease, cystic changes - Expensive, cumbersome

Se be s e t al . Ske l e tal Radi ol ogy vol ume 15, page s354 – 359 (1986 ) Tre i tl e t al . Ske l e tal Radi ol ogy vol ume 51, page s43 –58 (2022 )

Burden of Therapy: Continuous treatment • Many newer and tried and true options • Three and four medicines combined

• • • • • •

Peripheral neuropathy Fatigue Low blood counts GI side effects Insomnia Fluid retention

Burden of disease: Need for re-staging Discussion of Options Including Clinical Trials

Burden of Therapy: Critical Factors • • • • •

Age, fitness and frailty Compliance First relapse? Progression on treatment? Resistance

• Progression on lenalidomide maintenance? • Prior therapies?

• Co-morbidities (i.e., other problems) • • • • •

Peripheral neuropathy Thromboembolic complications Heart or lung disease Kidney and liver function Infection history

• Resistance to 2, 3, 4, 5 prior drugs • Number of lines of prior therapy

This is where the definitions come into play

Burden of Decision Making: Options and Clinical Trials • Is another stem cell transplant an option? • Is a transplant from my twin brother an option? • Phases of clinical research • • • •

Why is this a phase III trial? What happened on the phase II trial? What were the side effects? Am I eligible?

• Options

• Is there a standard therapy for me? • Why do you think the clinical trial is better for me?

• What makes my myeloma possibly susceptible to the new drug? • Can we go back to XXXX?

So many options: why? • Pharmaceutical companies • Scientific efforts • Discoveries • Innovation • Expert guidance • Ethical challenges • Global challenges • IMF • Patients and health care

BELANTAMAB MAFODOTIN Belantamab mafodotin: BCMA-directed mAb conjugated with microtubule inhibitor via linker A phase II, open-label, randomized 2-dose study in RR MM after an anti-CD38 therapy. Primary analysis of DREAMM-2 completed at median follow-up of 6.3 and 6.9 months for the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Additional analysis was completed at 13 months of follow-up. *Patients stratified based on number of previous lines of therapy(≤4 vs >4) and high-risk cytogenetic features; **According to IMWG 2016 criteria.

Treatment until disease progression or unacceptable toxicity

• Measurable disease • ECOG PS 0-2 • 3 or more prior lines of antimyeloma therapy • Refractory to a PI and an IMiD and progression on an anti-CD38 antibody • Prior anti-BCMA therapy excluded • Prior auto-SCT allowed; allo-SCT excluded

Key baseline characteristics=>

RANDOMIZE 1:1*

POPULATION

Primary Outcome

Belantamab mafodotin 2.5 mg/kg IV, every 3 weeks (n=97)

▪ DOR (time from ≥PR

ORR: % of patients with ≥PR**

Belantamab mafodotin 3.4 mg/kg IV, every 3 weeks (n=99)

Characteristic

2.5 mg/kg

3.4 mg/kg

Medi an prior Lines

7 (3-21)

6 (3-21)

Tri pl e class exposed

~100%

Lonial. Lancet Oncol. 2020;21:207‐221. Lonial. Canc2e0r 2021;127:4198.

Key Secondary Outcomes

until PD or death due to PD ▪ Other efficacy: CBR, PFS, OS, TTBR, TTR ▪ Safety, including keratopathy (MECs)

Lonial. Pos ter pres ented at ASCO 2020. Abs tr 436. Clinicaloptions .com

VENETOCLAX PFS

Kumar2S1, et al. Lancet Oncology. 2020 Oct 29;S1470-2045

CAR T-Cell Therapy 1 In the Clinic WBCs (including T-cells) are separated out and the rest of the blood is returned to the patient

TCR

CD3 T-cell

3 In the Body T-cells are sent to the lab

CAR T-cells are infused back into the patient after lymphodepleting chemotherapy

2 In the Lab/Manufacturing T-cells are engineered to target and kill cancer cells using viral vector to express chimeric antigen receptors

CAR T-Cells Viral vector scFv Signaling Dom ain

CAR T-cell Leukemia and Lymphoma Society.

Causes Tumor Cell Death CAR T-cells remain in the body for some time to help prevent new cancer cells from growing

▪ In myeloma, CAR T-cells target myeloma-specific antigens, eg, BCMA

CARTITUDE-1: Responses With Ciltacabtagene Autoleucel For R/R MM ORR* by IRC: 97.9

100

High-risk cytogenetics, n (%)

23 (23.7)

Median prior lines of therapy, n (range)

6 (3-18)

Characteristic, n (%)

Triple-class refractory

85 (87.6)

Penta-drug refractory†

41 (42.3)

*≥1

PI, ≥IMiD, and 1 anti-CD38 antibody. †≥2 PIs, ≥IMiDs, and 1 anti-CD38 antibody.

Patients (%)

All Patients (N = 97)

sCR: 82.5

82.5

≥VGPR: 94.9

40 20

▪

Median of 2 yr follow-up: 97 patients

▪

Median time to ≥CR: 2.9 mo (range: 0.9-17.8)

▪

Median DoR: NE (range: 21.8-NE)

Best response:

▪

Percentage of patients remaining progression free at 2 yr: 60.5%

*ORR assessed by independent review committee.

▪

Of 61 patients evaluable for MRD, 92% were MRDnegative (at 10-5)

Martin. ASH 2021. Abstr 549.

3.1

12.4 sCR

VGPR

Slide credit: clinicaloptions.com

Cytokine Release Syndrome and Neurotoxicity With Ciltacabtagene Autoleucel and Idecabtagene Vicleuce l CARTITUDE-1: Cytokine Release Syndrome

CARTITUDE-1: Cytokine Neurotoxicity

Cilta-cel (N = 97)

Ide-cel (bb2121) (n = 54)

94.8%

96%

≥Grade 3

5.2%

Tocilizumab

69.1%

67%

Other (not ICANS)†

Corticosteroids

21.6%

22%

Anakinra

18.6%

≥Grade 3 9.3% Not reported †Other includes movement, neurocognitive changes, nerve palsy, peripheral motor neuropathy

CRS

*Target dose of 450 x 106 cells

Neurotoxicity

≥Grade 3

Cilta-cel (N = 97)

Ide-cel (bb2121) (n = 54)

20.6%

20%

10.3%

12.4%

Not reported

Promising responses and PFS, but await further follow up of “late” neurotoxicities with cilta-cel Madduri. ASH 2020. Abstr 177. Munshi. ASCO 2020. Abstr 8503.

Slide credit: clinicaloptions.com

Types of Antibodies Naked

Antibody Drug Conjugates (ADC)

Bispecific Antibodies (BsAbs) T cell

MM Cell Nothing is attached Barila. Pharmaceuticals (Basel). 2021;14:40.

A toxin or radioactive isotope is attached

Target antigen (CD33, CD19, etc)

Engineered so that one end binds to MM cell, the other end binds to T cell Slide credit: clinicaloptions.com

Targeting BCMA May Be Is a New Standard Antibody–drug conjugate

Bispecific antibody

CAR T-cell

Approved product

Belantamab mafodotin (August 2020)

Several in phase II

Ide-cel (March 2021) Cilta-cel (February 2022)

Efficacy

++ (as single agent; higher in combinations)

+++

++++

How given

IV, Q3 weeks, until progression

IV or SC, weekly or Q2W until PD

One-and-done

Where given

Community

Academic medical centers

Notable adverse events

Ocular (corneal)

CRS and neurotoxicity

CRS

Not seen

+++

Neurotoxicity

Not seen

Availability

Off-the-shelf; after ophthalmology evaluation

Off-the-shelf

Wait time for manufacturing

Ciltacabtagene autoleucel PI. Idecabtagene ciltaleucel PI. Belantamab mafodotin PI.

Slide credit: clinicaloptions.com

BCMA x CD3 Bispecific Antibodies: Summary Therapy Teclistamab1,2

Characteristics ▪ Bispecific ▪ IV/SC (RP2D: 1500μg/kg SC) ▪ Weekly and every other week in f/u

AMG7013

▪ BiTE modified ▪ IV ▪ Weekly

REGN54584

▪ Bispecific ▪ IV ▪ Weekly and every other week C4->

ABBV-383 (TNB-383B)5,6

▪ Triple chain anti-BCMA bispecific ▪ IV fixed doses ▪ Every 3 weeks

Elranatamab (PF-3135)7

▪ Bispecific ▪ SC and weekly ▪ RP2D: 1000 μg/kg

N ▪ 157 ▪ ▪ ▪ 85

Population At SC cohorts: Median of 5 prior lines of tx 79% triple refractory 38% penta refractory

▪ Median of 6 prior lines of tx ▪ 62% triple refractory

▪ Median of 5 prior lines of tx ▪ 100% triple refractory ▪ 57% penta refractory

▪ Median of 5 prior lines of tx 118 ▪ 61% triple refractory

▪ Median of 8 prior lines of tx ▪ 87% triple refractory ▪ 23% prior BCMA-based tx

▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Safety At RP2D: CRS 70% G1-2 Neurotox 1% (G1) Infections 51% CRS 55% G1-2, G3-4: 9% No ICANS 21% cytopenias CRS 39%, no G3-4 ICANS 12% Neutropenia 16%, thrombocytopenia 18% Infection 47%, G3-4 18%

Response At RP2D, ORR: 65% with 40% sCR/CR

DO3R/PFS No mature data

83% ORR at the No mature top dose level and data 50% VGPR 62.5% at 96 mg and 95% of Preliminary responders were mDOR: VGPR; some CR in 6 mo lower dose levels

▪ CRS 54%, G3-4: 3% ▪ ICANS 2% ▪ 27% neutropenia; 22% thrombocytopenia

81% (39% CR) at the ≥40 mg dose No mature escalation; 60% at data ≥40 mg dose ESC + EXP

▪ CRS 73%, no G3-4 ▪ ICANS 20% ▪ ISR 50%

83% ORR at RP2D

1. Usmani. Lancet. 2021;398:655. 2. Krishnan. ASCO 2021. Abstr 8007. 3. Harrison. ASH 2020. Abstr 181. 4. Madduri. ASH 2020. Abstr 291. 5. Rodriguez. ASH 2020. Abstr 293. 6. Kumar. ASH 2021. Abstr 900. 7. Bahlis. ASCO 2021. Abstr8006.

No mature data

Slide credit: clinicaloptions.com

Future of CAR T Cells and/or Bispecifics in Multiple Myeloma

Wudhikarn. Hematology Am Soc Hematol Educ Program. 2020;2020:272.

Slide credit: clinicaloptions.com

Phase I First-in-Human Study of Teclistamab in Patients With RRMM: Study Design and Patient Characteristics ▪ ▪

Teclistamab is a B-cell Maturation Antigen (BCMA) x CD3 bispecific antibody

Median age (range), yrs

Key eligibility criteria

Extramedullary plasmacytomas 1

‒ RR or intolerant to established MM therapies ‒ No prior BCMA-targeted therapy Dosing Overview ▪ Premedications (glucocorticoid, antihistamine, antipyretic) limited to step-up dosing and first full dose ⎼ No steroid requirement after first full dose ⎼ Step-up dose*: Wk -1 ⎼ Initial Q2W IV dosing switched to weekly IV or SC ± step-up dosing IV Teclistamab (n = 84) 0.3-720 µg/kg (+ step-up dosing†)

SC Teclistamab (n = 73) 80-3000 µg/kg RP2D: 1500 µg/kgc

Key objectives: RP2D (Part 1), RP2D safety/tolerability (Part 2) Antitumor activity, PK, PD

Patient Characteristics, n (%)

SC Total (n = 73)

RP2D (n = 40)

64 (39–84)

62.5 (39–84)

11 (15)

8 (20)

5.9 (0.8–23.5)

5.7 (0.8–17.4)

High-risk cytogenetics ‡

16 (30)

10 (37)

Prior transplantation

63 (86)

34 (85)

Median prior lines of tx (range), n

5 (2–14)

5 (2–11)

Triple-class exposed‡

71 (97)

40 (100)

Penta-drug exposed§

50 (68)

26 (65)

Refractorystatus, n (%) ▪ Carfilzomib ▪ Pomalidomide ▪ Anti-CD38 antibody ▪ Triple-class ▪ Penta-drug ▪ Refractory to last line of tx, n (%)

49 (67) 55 (75) 68 (93) 58 (79) 28 (38) 64 (88)

27 (68) 28 (70) 39 (98) 33 (83) 15 (38) 33 (83)

Median time since diagnosis (range), yrs

*1-3 step-up doses given within 1 week before a full dose. †With 60 and 300 µg/kg step-up doses given within 1 week before a full dose. ‡Defined as del(17p), t(4;14), t(14;16), t(14;20).ePI, IMiD, and anti-CD38, §2 PIs, 2 IMiDs, and anti-CD38., Usmani. Lancet. 2021;398:655. Krishnan. ASCO 2021. Abstr 8007.

Slide credit: clinicaloptions.com

MajesTEC-1 Update: Efficacy Outcomes ▪ Teclistamab single agent update in the safety analysis cohort combining patients in phase I and phase II expansion

ORR

Patients (%)

93 of 150 pts 62.0% (95% CI: 53.7-69.8)

≥CR: 28.7%

21.3%

– ~78% triple class refractory

sCR: 21.3%

7.3%

29.3%

– 26% high-risk cytogenetics ≥VGPR: 58.0% sCR CR VGPR

4.0%

– 17% extramedullary disease Event MRD negativity, n (%, 95% CI) ▪ At 10-5 ▪ At 10-6 Median TTR, mo (range)

All Patients (N = 165) (n = 150) 37 (24.7; 18.0-32.4) 25 (16.7; 11.1-23.6) 1.2 (0.2-5.5)

Efficacy Analysis Subset

Median follow-up: 7.8 mos (range: 0.5+ to 18) Moreau. ASH 2021. Abstr 896.

Slide credit: clinicaloptions.com

MagnetisMM-1: Elranatamab in R/R MM • Phase I trial of elranatamab, a BCMA-targeted CD3engaging bispecific molecule

Prior Treatment

Elranatamab (N = 55)

Median no. of prior tx (range)

6 (2-15)

Triple-class exposed, n (%)

54 (98.2)

Triple-class refractory, n (%)

50 (90.9)

Prior BCMA-targeted tx, n (%) ▪ Anti-BCMA ADC ▪ CAR T-cell

12 (21.8) 7 (12.7) 9 (16.4)

*Refractory to ≥1 PI, 1 IMiD, and 1 anti-CD38 mAb

Efficacy Summary ▪

Elranatamab 1000 μg/kg Q2W achieved exposure associated with anti-myeloma efficacy

▪

Confirmed ORR: 69% (9/13) at recommended dose (1000 μg/kg Q1W) 70% (7/10) of patients with prior BCMA-targeted tx achieved response

▪

Sebag. ASH 2021. Abstr 895.

Part I, Dose escalation (n = 30)

Elranatamab 1000 g/kg QW (n = 6)

Elranatamab600 g/kg QW (n = 6) Elranatamab 360 g/kg QW (n = 4)

Elranatamab 215 g/kg QW (n = 4) Subcutaneous dosing

Elranatamab 130 g/kg QW (n = 4)

Elranatamab80 g/kg QW (n = 6)

Data cut-off: July 26, 2021

Priming cohorts ( Part 1.1, n = 20) 600 g/kg → 1000 g/kg (Q1W or Q2W) Expansion (Part 2A, n = 15) 44 g/kg → 76 g/kg (Q1W) premedication†

▪ Heavily pretreated population ▪ Good efficacy rates ▪ Small study population

†acetaminophen, diphenhydramine, dexamethasone Slide credit: clinicaloptions.com

Phase I/II First in Human Trial of anti-BCMA Bispecific REGN5458 in R/R MM: Response Clinical Response (ITT*)

ORR 75% ORR 48% ORR 29%

4 24

13 4

8 8 42

Data cut-off: September 30, 2021

*Full analysis set: all patients who had the opportunity for response assessment at 4 wks †per modified IMWG Zonder. ASH 2021. Abstr 160.

Slide credit: clinicaloptions.com

Phase I First in Human Trial of ABBV-383 (TNB383B ) in R/R MM: Response by IMWG Criteria CR

100

Patients (%)

80 60

ORR: 81% ≥VGPR: 69% 12 31

VGPR

Duration of Response ORR: 60% ≥VGPR: 40% 20

40 20 20 0

39 ≥40 mg ESC (n = 26)

ORR: 53% ≥VGPR: 35%

NR 81.7 (66.2-90.6) 72.1 (52.1-84.8)

18 23

≥40 mg ESC + EXP (n = 60)

Triple Class Refractory* ≥40 mg ESC + EXP (n = 40)

*Refractory to PI, IMiD, and anti-CD38 mAb.

Median DoR, mo ▪ 6-mo DoR, % (95% CI) ▪ 12-mo DoR, % (95% CI)

≥40 mg ESC + EXP (n = 52)

Data cut-off: Aug 9, 2021

▪ Updated analysis of this BCMA × CD3 bispecific TCE ▪ IV administration (Q3W) ▪ N = 118 patients – 61% triple-class refractory

• Median f/u for ≥40 mg ESC: 8.0 mo (range: 0.8-12.8) • Median f/u for ≥40 mg ESC + EXP: 4.3 mo (range: 0.6-12.8) Kumar. ASH 2021. Abstr 900.

Slide credit: clinicaloptions.com

The Future: Trispecific Antibodies Myeloma antigen

T-cell costimulatory antigen

• Still in pre-clinical stages of development

T-cell antigen

• Wu, et al. recently demonstrated a trispecific T cell engager targeting CD38, CD3, and CD28 (co-stimulatory protein on T-cells) very potent killing of CD38+ MM cell lines, 3- to 4-log higher than daratumumab

Fc Myeloma antigen

NK-cell antigen

Myeloma antigen Fc

• With bispecifics, in absence of T cell co-stimulation likelihood of anergy is higher, leading to a suboptimal anti-tumor response

• Also suppressed MM growth in mice and promoted proliferation of memory and effector T-cells and downregulation of regulatory T-cells in non-human primates • Trispecific NK cell engagers also being developed, targeting CD16A on NK cell as well as the MM antigens BCMA and CD200

Slide Courtesy of Dr. Ajai Chari, MD Lancman. Hematology Am Soc Hematol Educ Program . 2020;2020:264. Wu. Nature Cancer. 2019;1:86.

Slide credit: clinicaloptions.com

UNIVERSAL: Allogeneic CAR T-Cell Therapy With Anti-BCMA ALLO-715 in Patients With R/R MM

• Multicenter, open-label, dose-escalation phase I study Day 56

Day 0* Adults with R/R MM; ≥ 3 previous therapies (including IMiD, PI, anti-CD38); refractory to last therapy; ECOG PS 0/1; no donor specific Abs; no bridging therapy permitted (N = 35)

Treatment Single ALLO-715 Infusion on Day 0 40, 160, 320, 480 x 106 CAR+ T-cells

*Following lymphodepletion with FCA, CA regimen (fludarabine 30 mg/m2/day x 3 days, cyclophosphamide 300 mg/m2/day x 3 days ALLO-647 13-30 mg x 3 days).

• Primary endpoint: safety and tolerability • Secondary endpoints: lymphodepletion regimen and recommended ALLO-715 phase II dose, ORR, DoR, PFS, MRD, ALLO-715 cellular kinetics, ALLO-647 PK data Mailankody. ASH 2020. Abstr 129. Mailankody. ASH 2021. Abstr 651.

Slide credit: clinicaloptions.com

Future of CAR T Cells and/or Bispecifics in Multiple Myeloma

Wudhikarn. Hematology Am Soc Hematol Educ Program. 2020;2020:272.

Slide credit: clinicaloptions.com

Conclusions • • • • • • • • • • • •

The pipeline of new therapies for RRMM is brimming Age, fitness and frailty? Other medical conditions? Standard or high risk myeloma? What drugs and combinations have you received and when? What persisting or significant side effects have you had? Do you have stem cells available to you? Has your doctor discussed clinical trials? Allogeneic transplant? Where are trials available? Will the sponsors pay for travel and lodging? Call the IMF for guidance if your questions do not get answered

How to Manage Myeloma Symptoms and Side Effects Kimberly Noonan, DNP, ANP-BC, AOCN Dana-Farber Cancer Center, Boston, MA, IMF Nurse Leadership Board 96

June 18, 2022

LIFE IS A CANVAS, YOU ARE THE ARTIST Kimberly Noonan, DNP, RN, ANP, AOCN Nurse Practitioner

Dana-Farber Cancer Institute Boston, MA

Patient Education Slides 2022

FRAMING YOUR CARE Know your care team, Shared Decision Making & Reliable Resources

You are central to the care team

Pharmacist

CARE TEAM COLLAGE General Hem/Onc Myeloma Specialist

Communicate with your team • Myeloma is a chronic disease • Understand the roles of each

team member and who to contact for your needs • Participate in support network

Be empowered • Ask questions, learn more • Participate in decisions • Know your history –

Myeloma ManagerTM Personal Care AssistantTM

Primary Care Provider (PCP)

You and Your Caregiver(s) Support Network

Subspecialists Allied Health Staff

SHARED DECISION-MAKING Be empowered to be part of the treatment decision-making • Ask for time to consider options (if needed/appropriate) • Understand options; consider priorities • Use reliable sources of information • Use caution considering stories of personal

experiences • Consider your goals/values/preferences • Get a 2nd opinion, Meet with a Myeloma expert

Data From Research

HCP Clinical Experience TREATMENT DECISION

• Express your goals/values/preferences; create a

dialog

• My top priority is [goal/value]; additional [preferences] are also important. • I think [treatment] may be a good choice given my priorities… What do you think?

• Arrive at a treatment decision together

Your Preference Philippe Moreau. ASH 2015.

100

COLOR WHEEL OF TREATMENT Treatment options, side effects, symptom management, & supportive care

GALLERY OF GOALS MYELOMA TREATMENT • Rapid and effective disease control

• Durable disease control • Minimize side effects • Allow for good quality of life

SUPPORTIVE THERAPIES • Prevent disease- and treatmentrelated side effects • Optimize symptom management • Allow for good quality of life

• Improved overall survival

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 102

MANAGING MYELOMA: THE BIG PICTURE Transplant Eligible Patients

Transplant Ineligible patients

Everyone

Transplant Consolidation

Maintenance

Initial Therapy

Treatment of Relapsed disease Consolidation/ Maintenance/ Continued therapy

Supportive Care

103

SHADES OF “AUTO” STEM CELL TRANSPLANT (ASCT) • There are no black and white answers to deciding to undergo a transplant

• Undergoing transplant is a commitment for both you and your care partner • Understanding the process will help bring to focus elements needed to decide if/when to undergo transplant

Clinical Experience

Data from Research DECISION

Patient Preference

Adapted from Philippe Moreau, ASH 2015

(WHEN) IS TRANSPLANT RIGHT FOR ME?  Current studies continue to support early autologous transplant  Commitment: Quality of life must be considered when deciding timing  Allogeneic transplant not recommended as initial therapy

Phase 1: Eligibility

Phase 2: Transplantation

Phase 3: Post-Transplantation

Miceli T, et al. Clin J Oncol Nurs. 2013;17(6)suppl:13-24. Kaufman GP, et al. Leukemia (2016) 30, 633-639.

TRANSPLANT BY NUMBER

• Duration: Approximately 2 weeks • Location: Transplant Center

• High Dose Chemotherapy, stem cell infusion • Supportive Care • Engraftment

• Duration: Approximately 3-4 weeks • Location: Transplant Center

POST-TRANSPLANT

PHASE 3

•Measuring treatment response •Determining Transplant Eligibility •Insurance authorization •Collecting stem cells

TRANSPLANT

PHASE 2

PHASE 1

ELIGIBILITY

• Restrengthening • Appetite recovery • “Day 100” assessment • Begin maintenance therapy • Duration: Approximately 10-12 weeks • Location: HOME!

CARE PARTNER SUPPORT Care partner support is essential for the entire transplant process. Phase 1: Sedated procedures; Education sessions; Phase 2: Some transplant centers allow for outpatient transplant management Phase 3: Continued support and assistance is often Care partner can be one person or a rotation of many people.

PATIENT-REPORTED SYMPTOMS Symptoms resulted from both myeloma disease and treatment and can impact quality of life at all stages of disease. They fall into 3 categories:

Physical

Psychological

• Fatigue

• Depression

• Constipation

• Anxiety

• Pain

• Sleep Disturbance

• Neuropathy

• Decreased Cognitive Function

• Impaired Physical Functioning • Sexual Dysfunction

Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790.

Financial • Financial burden (80%) • Financial toxicity (43%)

• Decreased Role & Social Function

108

GI SYMPTOMS: PREVENTION & MANAGEMENT Diarrhea may be caused by medications and supplements • • • •

Laxatives, antacids with magnesium Antibiotics, antidepressants, others Milk thistle, aloe, cayenne, saw palmetto, ginseng Sugar substitutes in sugar free gum

Avoid caffeinated, carbonated, or heavily sugared beverages Take anti-diarrheal medication • Imodium ®, Lomotil ®, or Colestid if recommended • Fiber binding agents – Metamucil®, Citrucel®, Benefiber® • Welchol ® if recommended

Physical

Constipation may be caused by • Opioid pain relievers, antidepressants, heart or blood pressure medications, others • Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency

Increase fiber • Fruits, vegetables, high fiber whole grain foods • Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

Fluid intake can help with both diarrhea and constipation, and good for kidneys. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.

Smith LC, et al. CJON.2008;12(3)suppl:37-52. Faiman B. CJON. 2016;20(4):E100-E105. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

109

PAIN: PREVENTION AND MANAGEMENT

Physical

Pain can significantly compromise quality of life Sources of pain include bone disease, neuropathy and medical procedures Management • Prevent pain when possible • Bone strengtheners to decrease fracture risk; anti v iral to prev ent shingles; sedation before procedures

• Interventions depends on source of pain • May include medications, physical therapy, surgical intervention, radiation therapy, etc

• Complementary therapies • Mind-body, meditation, yoga, supplements, acupuncture, activity, etc

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

Tell your health care provider about any new bone pain or chronic pain that is not adequately controlled

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PERIPHERAL NEUROPATHY MANAGEMENT Peripheral neuropathy: damage to nerves in extremities (hands, feet, or limbs) • • • • • •

Numbness Tingling Prickling sensations Sensitivity to touch Burning and/or cold sensation Muscle weakness

Physical

Prevention / Management: • Bortezomib once-weekly or subcutaneous administration • Massage area with cocoa butter regularly • Supplements:

• B-complex v itamins (B1, B6, B12) • Folic acid, and/or amino acids but do not take on day of Velcade® (bortezomib) infusion

• Safe environment: rugs, furnishings, shoes

If PN worsens, your HCP may: Report symptoms of peripheral neuropathy early to your health care provider; nerve damage from PN can be permanent if unaddressed

• Change your treatment • Prescribe oral or topical pain medication • Suggest physical therapy

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

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FATIGUE, ANXIETY & DEPRESSION

Physical Psychological

Physical symptoms impact mental well being. All can affect quality of life and relationships.

• Fatigue is the most common reported symptom (98.8%) Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

• Anxiety reported in >35% • Depression nearly 25% Financial concerns, disease progression, end-of-life, and change in social and sexual function were highlighted sources

Often, people do not share these symptoms with their provider. Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available. Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790. Catamero D et al. CJON. 2017; 21(5)suppl:7-18.

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REST AND RELAXATION CONTRIBUTE TO GOOD HEALTH 🐑 Adequate rest and sleep are

essential to a healthful lifestyle

Short and disturbed sleep increase risk of • Heart related death • Increase anxiety • Weaken immune system • Worsened pain • Falls and personal injury

🐑 Things that can interfere with sleep • Medications : steroids, stimulants, herbal

supplements, alcohol • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, nocturia, pain, inactivity, heart issues Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227. National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene

Psychological

🐑 Sleep hygiene is necessary for

quality nighttime sleep, daytime alertness

• Engage in exercise but not too near • • • • • •

bedtime Increase daytime natural light exposure Avoid Daytime napping Establish a bedtime routine - warm bath, cup of warm milk or tea Associate your bed ONLY with sleep Sleep aid may be needed Avoid before bedtime: • Caffeine, nicotine , alcohol and sugar • Large meals and especially spicy, greasy foods • Computer screen time

Mustian et al. Journal of clinical Oncology. Sep 10 2013;31(26):3233 -3241. Stan DL, et al. Clin J Oncol Nurs. Apr 2012;16(2):131-141. Zeng Y et al., Complementary therapies in medicine. Feb 2014;22(1):173-186.

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HEALTHFUL LIVING STRATEGIES: PREVENTION Manage stress • Rest, relaxation, sleep hygiene

• Myeloma management

• Complementary therapy

• Hydration

• Nutrition • Activity / exercise

Preventative health care • Health screenings, vaccinations • Prevent falls, injury, infection • Stop smoking

Psychological

Maintain renal health

• Mental health / social engagement

Maintain a healthy weight

Physical

• Avoid renally-toxic medications – Dose adjust to renal function • Diabetes management

Protect your bones • Nutrition, Calcium + D supplement • Weight-bearing activity / walking • Bone strengthening agents

• Dental care

“An ounce of prevention is worth a pound of cure.”

Benjamin Franklin

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476. Brigle K, et al. CJON. 2017;21(5)suppl:60-76. Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Faiman B, et al. CJON. 2011;15suppl:66-76. Miceli TS, et al. CJON. 2011;15(4)suppl:9-23.

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Financial

FINANCIAL BURDEN Financial burden comes from • Medical costs • • • •

Premiums Co-payments Travel expenses Medical supplies

• Prescription costs • Loss of income • Time off work or loss of employment • Caregiver time off work

Contact the Social Services department at your hospital or clinic to talk to a social worker for assistance.

Funding and assistance may be available • • • •

Federal programs Pharmaceutical support Non-profit organizations Websites: • • • • • • •

Medicare.gov SSA.gov LLS.org Rxassist.org NeedyMeds.com HealthWellFoundation.org Company-specific website

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YOU ARE NOT ALONE

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Audience Q&A with Panel

• Open the Q&A window, allowing you to ask questions to the host and panelists. It will be sent to our moderator and panelists for discussion. • If you have a question that does not get answered today, you can contact our Infoline at 800-452-CURE (2873) US & Canada, 1-818-4877455, or email infoline@myeloma.org.

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