IMF Virtual Regional Community Workshop (RCW) - California Greater Bay and Surrounding Area by International Myeloma Foundation

Welcome and Announcements Kelly Cox

Director Support Groups & Senior Director Regional Community Workshops 2

Thank you to our sponsors!

Workshop Video Replay & Slides As follow up to today's workshop, we will have the speaker slides and a video replay available. These will be provided to you shortly after the workshop concludes.

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Pacific Northwest REGIONAL COMMUNITY WORKSHOP Saturday October 9, 2021~ 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 Edward Stadtmauer, MD, University of Pennsylvania, Philadelphia, PA 10:40 AM - Q & A with Panel 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials Luciano Costa, MD, University of Alabama at Birmingham, Birmingham, AL 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Daniel Verina, DNP, ACNP-BC, Mount Sinai Hospital, New York, NY IMF Nurse Leadership Board 12:05 PM - Q&A with Panel

Myeloma 101 and Frontline Therapy Edward Stadtmauer, MD, University of Pennsylvania, Philadelphia, PA

Myeloma 101 and Frontline Therapy

Edward A. Stadtmauer, MD Chief, Hematologic Malignancies Section Professor of Medicine Abramson Cancer Center University of Pennsylvania Philadelphia, Pa IMF Regional Community Myeloma Workshop San Francisco and Surrounding Region Saturday, November 6, 2021

The Treatment Team

Oncologist Primary care physician

Nurse practitioner/ physician assistant Patient & Caregiver

Technicians

Clinical nurses Social worker

What is multiple myeloma?

Multiple myeloma Normal plasma cells

Antibodies M proteins

Light chain

Light chain Heavy chains

Multiple myeloma cells

Bone Bone marrow

How common is multiple myeloma?

SEER Cancer Stat Facts: Myeloma. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/mulmy.html

Effects of Myeloma and Common Symptoms

Low blood counts

• Weakness • Fatigue • Infection

Decreased kidney function

Weakness

Bone damage

Bone pain

Bone turnover

• Loss of appetite • Weight loss

About 10% to 20% of patients with newly diagnosed myeloma do not have any symptoms. Multiple Myeloma Complications. http://www.themmrf.org/multiplemyeloma/multiple-myeloma-complications. Campbell K. Nurs Times. 2014;110:12. Kyle R et al. Mayo Clin Proc. 2003;78:21.

Diagnosis and Monitoring of MM Initial work-up • General – H&P – Comorbidities – Fitness – Lifestyle and personal wishes – Financial considerations – Availability of a caregiver • Peripheral blood tests • BM biopsy and aspirate tests • Diagnostic radiology • Additional testing

Treatment planning • Establish a diagnosis – MGUS – SMM – Active MM – Solitary plasmacytoma • Determine “signature” – Heavy chain/light chain  IgG, IgA, IgM, IgD – Light chain only  Kappa  Lambda – Non-secretory • Determine stage • Estimate prognosis

Monitoring for response and surveillance

Treatment and supportive care • Determine need for immediate intervention – Hypercalcemia – Renal failure – Cord compression – Pain – Impending fracture • Risk-adapted treatment selection • Prevention/palliative and supportive care/survivorship—may require additional diagnostic testing

• Evaluation of treatment response until best response • Surveillance • Suspected relapse or progression

H&P, history and physical; BM, bone marrow; MGUS, monoclonal gammopathy of undetermined significance; SMM, smoldering multiple myeloma Kurtin S et al. J Adv Pract Oncol. 2016;7:59.

Diagnosing Myeloma: Learn Your Labs! Common Laboratory Tests Conducted Blood tests

Urine tests

Imaging tests

• CBC • CMP • B2M • SPEP with IFE • SFLC

• UPEP with IFE • 24-hour urine

• X-ray • MRI • CT scan • PET scan Assess changes in the bone structure and determine the number and size of tumors in the bone

CBC, complete blood count; CMP, complete metabolic panel; B2M; beta-2 microglobulin; SPEP, serum protein electrophoresis; IFE, immunofixation electrophoresis; SFLC, serum free light chain assay; UPEP, urine protein electrophoresis

Diagnosing Myeloma: The Bone Marrow Biopsy Bone marrow aspiration and biopsy Jamshidi needle

Bone marrow Hip bone

Conventional cytogenetic analysis Karyotyping

Skin

Chromosome FISH (fluorescence in situ hybridization)

Myeloma cell

Putting the Results Together

Imaging results

Blood and urine test results

Bone marrow analysis

Staging, Prognosis and Treatment

Evolution of Myeloma Staging Systems R-ISS Stage I II III

Criteria ISS stage I and standard-risk CA by iFISH and normal LDH Not R-ISS stage I or III ISS stage III and either high-risk CA by iFISH or high LDH

International Staging System Durie-Salmon Staging System

1975

Revised International Staging System

2005

2015

• B2M and albumin • Stages I, II, or III

• Myeloma cell mass, hemoglobin, calcium, bone health, M protein, and Bence-Jones protein • Stages I, II, or III • Subclassification A or B (based on renal function)

B2M; beta-2 microglobulin; ISS, International Staging System; LDH, lactate dehydrogenase; CA. chromosomal abnormality; iFISH, interphase fluorescent in situ hybridization. Durie BGM, Salmon SE. Cancer. 1975;36:842. Greipp PR et al. J Clin Oncol. 2005;23:3412. Palumbo A et al. J Clin Oncol. 2015;33:2863.

• ISS and LDH, and detection of CA by FISH • High-risk CA by FISH: − del(17p) − t(4;14) − t(14;16) • Stages I, II, or III

How aggressive is my myeloma?

High Risk

• High-risk genetic abnormalitiesa,b − t(4;14) − t(14;16) − t(14;20) − Del 17p − p53 mutation − Gain 1q • RISS Stage 3 • High plasma cell S-phasec • GEP: high-risk signature

Standard Riska

• All others including: − Trisomies − t(11;14)d − t(6;14)

• Double-hit myeloma: any two high-risk genetic abnormalities • Triple-hit myeloma: three or more highrisk genetic abnormalities

Currently cannot predict with great certainty all high-risk patients. Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013 aTrisomies may ameliorate; bBy FISH or equivalent method; cCut-offs vary; dt(11;14) may be associated with plasma cell leukemia Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

After Establishing a MM Diagnosis, Find Out From Your Doctor...

Myeloma 101: Summary

Multiple myeloma can have numerous effects on the body. Genomics is growing but does not yet lead to personalized treatments. Survival improving because of new drugs and new combinations of drugs. Treatment paradigm will continue to change with the approval of additional novel agents. Be an informed and empowered part of your health care team!

Multiple Myeloma Disease Trajectory

Diminished depth and duration of response NDMM MGUS SMM

AMM MRD

Disease plateau of variable length

RRMM

Disease plateau of variable length

MGUS, monoclonal gammopathy of undetermined significance; SMM, smoldering multiple myeloma; AMM, active multiple myeloma; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/refractory multiple myeloma Kurtin S. J Adv Pract Oncol. 2016;7:9.

Know the Diagnosis

Key Items That Define the Diagnosis MGUS

• M protein <3 g/dL • Clonal plasma cells in BM <10% • No myeloma-defining events

Smoldering myeloma

• M protein ≥3 g/dL (serum) or ≥500 mg/ 24 hrs (urine) • Clonal plasma cells in BM ≥10%–60% • No myeloma-defining events

1% risk of progression/year to multiple myeloma or related conditions

10% risk of progression/year to active myeloma

High-risk smoldering myeloma • M protein ≥3 g/dL (serum) • IgA • Immunoparesis of immunoglobulins • Cytogenetics: t(4;14) or del17p or 1q gain • “Evolving type” ≥10% increase in M protein within 6 months 50% chance of progression/year to get active myeloma

*C: Calcium elevation (>11 mg/dL or >1 mg/dL higher than ULN) R: Renal insufficiency (creatinine clearance <40 mL/min or serum creatinine >2 mg/dL) A: Anemia (Hb <10 g/dL or 2 g/dL < normal) B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)

Rajkumar SV et al. Lancet Oncol. 2014;15:e538.

Multiple myeloma

• Underlying plasma cell proliferative disorder • AND ≥1 myelomadefining events • ≥1 CRAB* feature • Clonal plasma cells in BM ≥60% • Serum free light chain ratio ≥100 • >1 MRI focal lesion

Overview of Treatment Approach

MGUS

Close monitoring (observation)

SMM

Close monitoring (observation) If high risk: possible myeloma drugs?*

If bone loss: bisphosphonates

Clinical trial participation should be considered *Promising but limited studies to date.

Your Personal Treatment Plan: Partnering With Your Health Care Team Induce remission (a reduction in plasma cells/M protein to a very low level) High response rate; rapid response Improve performance status Minimal side effects Prolong overall survival and preserve function and quality of life

Testing for Minimal Residual Disease (MRD): Even in CR You Still Have 100 Million Myeloma Cells in Your Bone Marrow

Poon ML, Chng WJ. Cancer Ther. 2008;6:275. Mailankody S et al. Nat Rev Clin Oncol. 2015;12:286.

Current Treatment Approaches: Active Myeloma The criteria for transplant eligibility: • Good organ function: • Heart, Lung and Kidney • Good performance status. • Able to walk and conduct activities of daily life. • We often talk about age, but it is not absolute. • The key is risk adapted dosing of the high dose Melphalan (decreased dose based on age and kidney function). • United States centers generally use full dose up to around 70 years old. • The decision should not be made at the initial diagnosis. See how patients respond and tolerate therapy.

IFM 2009: RVD ± ASCT for Transplant-Eligible NDMM Transplant-eligible NDMM

RVD x 3 cycles, ASCT collection, Cy 3 g/m2 • RVD cycles 4-8

RVD x 3 cycles, ASCT collection, Cy 3 g/m2 • ASCT with MEL 200 • RVD cycles 4, 5

Lenalidomide 10-15 mg daily x 12 months 36 mo

mPFS (44 mo fu)1

50 mo

35 mo

mPFS (90 mo fu)2

47.3 mo

60.2%

8-y OS (90 mo fu)2

62.2%

44-mo followup1 1. Attal M, et al. N Engl J Med 2017;376;1311-20. 2. Perrot A, et al. ASH 2020 Attal M, et al. N Engl J Med 2017;376;1311-20. 2. Perrot A, et al. ASH 2020.

IFM 2009 Study of RVD± ASCT: PFS by MRD Status MRD at Start of Maintenance mPFS: NR vs 29 mo

MRD After 1-Year Maintenance mPFS: NR vs 20 mo

PFS by MRD + Treatment

PFS by MRD + Risk

Perrot A, et al. Blood. 2018;132(23):2456-2464..

FORTE Trial of KCd Vs KRd: Design

Gay F, et al. ASCO 2019. Abstract 8002. Gay F, et al. ASH 2020. Abstract 141.

FORTE Trial of KRd-ASCT-KRd vs KRd vs KCd KCD-ASCT—PFS From Randomization 1  mPFS: KRd_ASCT, NR; KRd12, 57 m; KCd_ASCT, 53 m

Median follow-up from R1 of 45 m Gay F, et al. ASH 2020. Abstract 141.

FORTE Trial of KR vs R Maintenance (Randomization 2): PFS  356 patients randomized to maintenance (pre-maintenance response (KR vs R): ≥ CR: 62% vs 59%; sCR: 50% vs 48%; MRD negativity: 65% vs 66%

• 3-year PFS from R2 (ITT, KR vs R): 75%, KR vs 66%, R (HR 0.63; P=0.026). Median follow-up from R2, 31 m; median duration of maintenance, 27 m.

Gay F, et al. ASH 2020. Abstract 141..

Phase III CASSIOPEIA: VTd ± Dara in Transplant-Eligible NDMM—Study Design & Baseline Characteristics • Adults ≥ 65, ECOG PS 0-2; Primary endpoint: sCR

(cyclophosphamide)

Clinical Trial NCT02541383; Moreau P, et al. Lancet. 2019;394:29-38..

Phase III CASSIOPEIA: VTD ± Daratumumab— Efficacy sCR rate 29% vs 20% (P=0.001)

MRD-negative rates after ASCT:

NGF (P<.0001)

NGS (P<.0001)

D-VTd

64%

57%

VTD

44%

37%

Arm

Subgroup analysis of PFS favored DVTd in all subgroups, except stage III and high-risk cytogenetics

Moreau P, et al. Lancet. 2019;394:29-38.

Phase III CASSIOPEIA: DAR Maintenance or Observation (OBS) After VTd ± DARA and ASCT in NDMM—Part 2

• PFS benefit with DARA was consistent across most prespecified subgroups • Notable exception, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons ± DARA maintenance achieved similar PFS

Median follow-up of 35.4 mo from second randomization. Moreau P, et al. ASCO 2021. Abstract 8004..

Randomized Phase 2 GRIFFIN Trial of D-RVd vs RVd in Transplant Eligible NDMM: Design

Induction: Cycles 1-4 D-RVd

1:1 Randomization

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

90%

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

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

Stem cell mobilization with G-CSF ± plerixaforb

T R A N S P L A N T

76%

Consolidation: Cycles 5-6c

Maintenance: Cycles 7-32d

D-RVd

D-R

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

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

D: 16 mg/kg IV Day 1 Q4W or Q8W e R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycle 10+

R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycle 10+ 28-day cycles

Endpoints & statistical assumptions Primary endpoint:

sCR (by end of consolidation); 1-sided alpha of 0.1 80% power to detect 15% improvement (50% vs 35%), N = 200

Secondary endpoints:

MRD (NGS 10–5), CR, ORR, ≥VGPR

• Median age ~60; ISS3 14%, High risk 15% • Lower ASCT rate in RVd arm due to early discontinuations

Voorhees P, et al. IMW 2019.

Phase 2 GRIFFIN: Responses Deepened Over Time

• Results for end of induction, ASCT, and consolidation are based on a median follow up of 13.5 months at the primary analysis • Median follow up at 12-months-of-maintenance therapy cutoff was 27.4 months

aData

are shown for the response-evaluable population. bP values (2-sided) were calculated using the Cochran–Mantel–Haenszel chi-square test.

Kaufman JL, et al. ASH 2020..

Phase 2 GRIFFIN Trial: Subgroup Analyses by 12-Months-of-Maintenance Therapy Cutoff sCR

MRDneg

D-RVd improved sCR and MRD-negativity rates across most subgroups MRD-Negativity Rates: 62.5% DRVd (n = 104) versus 27.2% VRd (n = 103) aThe

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. Median follow-up was 27.4 months.

Kaufman JL, et al. ASH 2020.

Phase 2 GRIFFIN: PFS and OS (ITT)

Median PFS and OS were not reached for D-RVd and RVd Durability of PFS and OS benefits are suggested by the GRIFFIN safety run-in cohort (>40 months median follow-up; ASH 2020 poster 3243) OS, overall survival. aKaplan‒Meier estimate.

Kaufman JL, et al. ASH 2020.

Most Common Hematologic AEs Reported During Treatment (Safety Population)

AE, n (%)

D-RVd, n = 99

RVd, n = 102

Any grade

Grade 3/4

Any grade

Grade 3/4

Neutropenia

57 (57.6)

41 (41.4)

36 (35.3)

22 (21.6)

Thrombocytopenia

43 (43.4)

16 (16.2)

36 (35.3)

9 (8.8)

Leukopenia

36 (36.4)

16 (16.2)

29 (28.4)

7 (6.9)

Anemia

35 (35.4)

9 (9.1)

33 (32.4)

6 (5.9)

Lymphopenia

30 (30.3)

23 (23.2)

28 (27.5)

22 (21.6)

Any-grade infections DRVd vs RVd: 81 (90.9%) vs 56 (61.89) – largely due to grade 1/2 URTI in DRVd group; grade 3/4 infections were similar (23.2% vs 21.6%).

Voorhees P, et al. Blood. 2020;136(8):936-945. Kaufman JL, et al. ASH 2020..

Summary: NDMM With SCT Study N

IFM 20091,2 RVd-SCT vs RVd

FORTE3,4 KRd-SCT vs KRd

350

158

350 89.92

Median F/u, mos No days (28-d cycles) chemo induction to post induction

105 (3.75)

543

168 (6)

224 (8)

104

103

27.4

168 (6)

126 (4.5)

Cy 3 gm/m2

Plerixafor

336 (12)

Cy 2 gm/m2

GRIFFIN6,7 SCT DaraVRd vs VRd

542

Cy 3 gm/m2

SCH mobilization

157

CASSIOPEIA5 SCT Dara VTd vs VTd

Postconsolidation ORR

N/A

93%

81%

99%

91.8%

Postconsolidation > VGPR

78%

69%

89%

87%

83.4%

78%

90.9%

73.2%

Postconsolidation sCR

N/A

50%

48%

28.9%

20.3%

42.4%

32%

Median PFS, mos

47.32

352

PFS, HR (95% CI)

0.70 (0.59-0.83)2 --

MRD Negativity (10-5), %

Ongoing studies:

0.64, P = .023 65

0.47 (0.33–0.67) 64

•

Perseus: Daratumumab(SQ)-RVd vs RVd

•

GMMG HD7: Isatuximab-RVd vs RVd

NR 62.5

27.2

Slide courtesy A Chari.

1. Attal, et al. N Engl J Med. 2017; 376:1311-1320. 2. Perrot A, et al. ASH 2020. 3. Gay F, et al. ASCO 2019. Abstract 8002. 4. Gay F, et al. ASH 2020. Abstract 141. 5. Moreau P, et al. Lancet. 2019;394:29-39. 6. Voorhees P, et al. Blood. 2020;136(8):936-945. 7. Kaufman JL, et al. ASH 2020.

RVd vs Rd – Both Arms With Rd Maintenance: SWOG S0777 Trial— Study Design INDUCTION RVd LEN 25 mg PO D1-14 DEX 20 mg PO

ENDPOINTS Primary: PFS Key Secondary: ORR, OS, safety

D1, 2, 4, 5, 8, 9, 11, 12

BORT 1.3 mg/m² IV D1, 4, 8, 11

NDMM without intention for immediate ASCT N = 525

Study start date: February 2008

8 × 21-day cycles 1:1

MAINTENANCE Rd LEN 25 mg PO D1-21 DEX 40 mg PO

Stratified by ISS stage and intention to ASCT

D1, 8, 15, 22

28-day cycles

Rd LEN 25 mg PO D1-21

FOLLOW-UP Every 6 months for up to 6 years for disease status

Treatment until PD, unacceptable toxicity, or patient withdrawal

DEX 40 mg PO D1, 8, 15, 22 6 × 28-day cycles

•

Median overall follow-up was 55 months

•

43% patients age ≥65 years

Durie BG, et al. Lancet. 2017;389(10068):519-527..

RVd vs Rd – Both Arms With Rd Maintenance: SWOG S0777—PFS (Median follow up, 84 mo)

 RVd significantly improved PFS compared with Rd Median PFS, 41 mo vs 29 mo HR, 0.742; 96% CI, 0.594-0.928; P = .003 HR for PFS in patients ≥ 65 years (n = 197), 1.27; 95% CI, 1.00-1.61; P = .048

Durie BG, et al. Blood Ca J. 2020;10:53.

RVd vs Rd – Both Arms With Rd Maintenance: SWOG S0777—OS (Median follow up, 84 mo)

Median OS, NR vs 69 mo HR, 0.709; 96% CI, 0.543-0.926; P = 0.0114

Durie BG, et al. Blood Ca J. 2020;10:53..

RVD vs RD Adverse Events ≥ Grade 3 Neurologic ≥ Grade 3 Pain ≥ Grade 3 Sensory ≥ Grade 3 Gastrointestinal

33%

VRd Rd VRd Rd VRd Rd VRd Rd

P <.0001

11% 12%

P =.0002

4% 23% 3%

P =.004

22% 8%

• Rates of second cancers at long-term follow up: 8%, VRd vs 7%, Rd • Median duration maintenance Rd, 17.1 mo Note: Bortezomib administered I.V. twice/week *Includes only those toxicities at least possibly attributable to protocol treatment

Durie BG, et al. 2015 ASH. Abstract 25..

Triplet Therapy Adapted for Transplant-ineligible Patients: RVD-Lite

Patients with NDMM ≥ 65 years and/or ineligible for ASCT ECOG PS ≤ 2

Induction: RVD Lite LEN: 15 mg PO D1–21 BORT: 1.3 mg/m2 SCa D1, 8, 15, 22 DEX: 20 mg PO D1, 2, 8, 9, 15, 16, 22, 23 (patients ≤ 75 years); D1, 8, 15, 22 (patients > 75 years)

N = 50

9 x 35-day cycles

• ORR 86% • ≥VGPR 66% • ≥CR 44% aThe

Consolidation: LEN + BORT LEN: 15 mgb PO D1–21 BORT: 1.3 mg/m2b SC D1, 15 6 x 28-day cycles

Optional Maintenance: LENc Until PD or unacceptable side effects

Median PFS 41.9 months

first 10 patients received bortezomib IV for cycle 1 only followed by SC administration. Subsequent patients received bortezomib SC. bOr last tolerated dose as of Cycle 9. cMaintenance with LEN was optional and at the discretion of the investigator; 66% of patients in the study received maintenance

O’Donnell E, et al. Br J Haematol. 2018;182(2):222-230..

Phase III ENDURANCE (E1A11) Study of VRd vs KRd Followed by Limited or Indefinite Len Maintenance for NDMM: Study Schema

Primary endpoints: OS with 2 different len maintenance strategies; PFS between induction combinations followed by len maintenance ASCO 2020: Primary endpoint not met (no PFS improvement with KRd vs VRd). Safety: KRd, increased cardio-pulmonary and renal toxicity; VRd, increased neuropathy

Kumar S, et al. ASCO 2020. Abstract LBA3.

Phase 3 ENDURANCE Trial of KRD vs VRd: PFS and OS Co-Primary Endpoints (ITT) PFS

• •

PFS was similar between treatment groups among all subgroups examined ≥VGPR: 65% VRd vs 74% KRd

Estimated median follow-up: 9 mo from randomization for induction comparison; median follow-up for OS: 26 mo.

Phase 3 ENDURANCE Trial of KRD vs VRd: TRAEs of Interest Cardiac, pulmonary and renal

Peripheral neuropathy

P <.001 16.1

53.4 45.4

12.6

24.4 4.8

23.6

4.6 2.5 0

Total

VRd (n = 527) KRd (n = 526)

P <.001

Grade 3

Grade 4

0.2

Grade 5

0.8

Total

1-2

Grades 1-2 not required reporting. Kumar SK, et al. ASCO 2020. Abstract LBA3.

Phase III MAIA Study Design: ASCT-Ineligible Newly-Diagnosed Myeloma

Transplant-ineligible NDMM ECOG PS 0-2 CrCl ≥30 mL/min (N = 737)

1:1

Stratification: • ISS (I, II, III) • Region (N America vs other) • Age (<75 y vs ≥75 y)

Daratumumab 16 mg/kg IVa + Lenalidomide 25 mg/d PO, d 1-21 + Dexamethasone 40 mg/w PO or IV (n = 368)

Lenalidomide 25 mg/d PO, d 1-21 + Dexamethasone 40 mg/w PO or IV (n = 369)

Primary endpoint: PFS Secondary endpoints: CR, VGPR, MRD negativity, ORR, OS, safety

28-day cycles until PD

Median age: 73 years (45-90) 99% of patients age ≥ 65 years aQW

cycles 1-2, Q2W cycles 3-6, Q4W cycle ≥7.

Facon T, et al. 2018 ASH. Abstract LBA2..

Phase III MAIA: Efficacy Daratumumab + Rd (n = 368)

Rd (n = 369)

HR (95% CI)

5-year PFS Median PFS

53 NR

29 34.4

0.53 (0.43-0.66)

<.0001

5-year OS, % Median OS, mo

66 NR

53 NR

0.68 (0.53-0.86)

.0013

ORR, % Stringent CR CR VGPR PR

93 35 16 30 12

82 15 15 27 25

MRD negativitya, %

Outcome

   

P Value

< .0001

Median follow-up: 56.2 months Daratumumab favored in most subgroups, including for both PFS and OS endpoints Reduced risk of progression or death with MRD negativity in both arms Responses deepened over time Data from 47.9 months of follow up Facon T, et al. 2018 ASH. Abstract LBA2; Facon T, et al. N Engl J Med. 2019;380:2104-2115. Kumar. ASH 2020. Abstract 2276. Facon T, et al. EHA 2021. Abstract LB1901. a

Phase III MAIA: PFS (Primary Endpoint) and OS at 5 Years of Follow Up PFS

5-Years

5-Years 66%

53% HR, 0.53; 95 CI, 0.43-0.66 P <.0001

NR 34 mo

29%

47% reduction in risk of disease progression or death in DRd vs Rd

NR HR, 0.68; 95 CI, 0.53-0.86 P = .0013

53%

32% reduction in risk of death in DRd vs Rd DRd

Median follow-up: 56.2 months. Facon T, et al. EHA 2021. Abstract LB1901..

Phase III MAIA: Safety TEAE, %

Daratumumab + Rd (n = 364)

Rd (n = 365)

Any Grade

Grade 3/4

Any Grade

Grade 3/4

57 35 19 18

50 12 7 15

42 38 19 12

35 20 9 11

57 41 40 38 34 32 32 23 12

7 2 8 2 3 4 1 14 6

46 36 28 29 26 25 23 13 13

4 <1 4 <1 3 4 <1 8 6

Hematologic Neutropenia Anemia Thrombocytopenia Lymphopenia Nonhematologic Diarrhea Constipation Fatigue Peripheral edema Back pain Asthenia Nausea Pneumonia DVT and/or pulmonary embolism Infusion-related reaction Invasive second primary malignancy

TEAE resulting in death



No new safety concerns were identified at 5-year follow up Facon T, et al. 2018 ASH. Abstract LBA2; Facon T, et al. N Engl J Med. 2019;380:2104-2115. Facon T, et al. EHA 2021. Abstract LB1901.

Summary: NDMM Without SCT SWOG 777 VRd vs Rd

Study N

229

242

RVd-lite 50

ALCYONE Dara VMP vs VMP 356

MAIA DaraRd vs Rd

350

368

Median age

Median F/u, mos

ORR

90.2%

78.8%

86%

91%

74%

93%

82%

24.2%

12.1%

44%

46%

25%

51%

30%

Median PFS, mos

35.1

34.4 mo

PFS HR (95% CI)

0.74 (0.59-0.93)a

N/A

0.42 (0.34 - 0.51)

OS HR (95% CI)

69 mos

OS 0.71 (0.54–0.93)

*V for 6 mos (biw q21 d * 8 cycles)

N/A

*V for 17 mos (qwk:35d *9, q2wk:28d *6)

78% @ 3y

68% @ 3y

0.53 (0.43- 0.66) NR 66% @ 5 y

0.60 (0.46-0.80)

*V for 12 mos (6 wk cycles, biw *1, qwk * 8)

NR 53% @ 5 y

HR 0.68 (0.53-0.86) a

96% Wald Confidence Interval Slide courtesy A Chari.

Duriet et al. Blood Ca J. 2020;10(53). O’Donnell. Br J Haematol. 2018;182:222. Mateos MV, et al. NEJM. 2018;378:518-528. Mateos MV, et al Lancet 2020:395:132-141. Kumar. ASH 2020. Abstr 2276. Facon T, et al. EHA 2021. Abstract LB1901..

What’s Happening 2021 for Early Myeloma?  Optimal Induction, ASCT, Maintenance • Dara-VRD vs VRD • PENN Clinical Trial (BLAST) (Balantamab immunoconjugate maintenance) • SWOG 1803 lenalidomide with or without daratumumab maintenance therapy

 BCMA CAR trials for less-heavily treated patients • 1-3 prior lines of therapies • Post-induction in biologically high risk MM • Post-auto SCT to improve response – BMT CTN ASCT + CAR T in High Risk or Poor Response

 Venetoclax for 11;14 translocated relapsed MM  Once triple class exposed if relapse requires novel therapies, immunotherapies and CAR T

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.

We will begin with a 5-minute mindful meditation and then go into a 5-minute break For more guided audio and video meditations, and guided yoga, please visit our website: https://wellness.myeloma.org/mind-body/ Meditation is led by Kelley Sidorowicz, IMF Regional Director, Support Groups

Welcome Back!

Agenda After the Break Relapsed Therapy and Clinical Trials Luciano Costa, MD, University of Alabama at Birmingham, Birmingham, AL How to Manage Myeloma Symptoms and Side Effects Daniel Verina, DNP, ACNP-BC, Mount Sinai Hospital, New York, NY IMF Nurse Leadership Board Q&A with Panel

Relapsed Therapy and Clinical Trials

Luciano Costa, MD, University of Alabama at Birmingham, Birmingham, AL 60

Relapsed Myeloma and Clinical Trials

Luciano J. Costa, MD, PhD Professor of Medicine University of Alabama at Birmingham

When to change therapy? • Development of new signs and symptoms of disease • Increase in “M” spike • Unmanageable toxicity from current regimen • Goals:  Regain control of myeloma, for the longest possible time  Alleviate current symptoms  Prevent myeloma serious events (severe anemia, renal failure, fracture, etc)  Prolong survival

How to chose a regimen • NOT one size fits all. • Pillars are IMIDs and Proteasome inhibitors • Consider Clinical Trial • Factors:  Disease characteristics  Prior therapies  Unresolved toxicities from prior regimens  Coexisting diseases (heart disease, neuropathy)  Frailty  Convenience (oral vs. injectable agents)

Available MM treatments Alkylators  Melphalan (High doses)

Proteasome Inhibitors

Others  Corticosteroids

 Bortezomib

 Doxil

 Cyclophosphamide

 Ixazomib

 Panobinostat

 Bendamustine

 Carfilzomib

 Selinexor

IMiDs

Monoclonal antibiodies

New Immunotherapies

 Thalidomide

 Elotuzumab

 Belantamab

 Lenalidomide

 Daratumumab

 Ide-cel

 Pomalidomide

 Isatuximab

Monoclonal Antibodies

Elotuzumab, First MoAb Available for Treatment of Multiple Myeloma

PFS- Eloquent 2

Lonial S. N Engl J Med 373:621, 2015

Daratumumab • A human mAb that targets CD38-expressing tumor cells • DARA+LEN enhanced killing of MM cells in vitro and lead to synergistically higher efficacy in clinical setting  Antibody-dependent cellmediated cytotoxicity (ADCC)  Antibody-dependent cellular phagocytosis (ADCP)  Complement-dependent cytotoxicity (CDC)  Apoptosis

DARA: daratumumab; LEN: lenalidomide; mAB: monoclonal antibody; MM: multiple myeloma

Pollux - Efficacy 18-month PFSa

100

76%

≥CR: 46%b 23

50 40

Median: 17.5 months

HR: 0.37 (95% CI, 0.28-0.50; P <0.0001) 0

48 82

5 15

0 1

0 0

Months

No. at risk 283 286

249 266

206 249

181 237

159 227

132 194

≥CR: 20% ≥VGPR: 78%b

8 12

CR 32

VGPR PR

15 DRd (n = 281)

≥VGPR: 45% sCR

20 10

ORR = 76%

80 70

49%

ORR = 93%

DRd

Rd DRd

P <0.0001

Median: not reached

ORR, %

% surviving without progression

100

Rd (n = 276)

Castor- Efficacy 12-month

P <0.0001

PFSa

100 90

60%

DVd

22% 20

No. at risk Vd 247 DVd 251

 

Median: 7.1 months

129 198

73 160

23 91

9 33

0 5

≥CR 26%b

ORR = 63% 2% ≥CR 8% 10%

19%

≥VGPR 62%b

35%

20 21

Months 182 215

HR: 0.33 (95% CI, 0.26-0.43; P <0.0001) 0

ORR = 84%

ORR, %

% surviving without progression

100

0 1

0 0

sCR 34%

10 0

19%

22% DVd (n = 240)

≥VGPR 29%

CR VGPR PR

Vd (n = 234)

Median (range) follow-up: 13.0 (0-21.3) months An additional 7% of patients receiving DVd achieved ≥CR with longer follow up

New Proteasome Inhibitors

PFS- Aspire

PFS- Endeavor

PFS- Tourmaline MM1

Rd and Vd are inferior regimens in RRMM Randomized phase 3 trials in RRMM (1-3 lines) Rd < KRd (ORR, PFS, QOL, OS) Rd < Elo-Rd (ORR, PFS) Rd < Ixa-Rd (ORR,PFS) Rd < Dara-Rd (ORR, PFS)

Lonial S et al N Engl J Med 373:621, 2015 Stewart AK et al. N Engl J Med 372:142, 2015 Moreau P et al. N Engl J Med 374:1621, 2016 Dimopoulos MA et al. N Engl J Med 375:1319, 2016

Vd < Pano-Vd (ORR, PFS) Vd < Kd (ORR, PFS, QOL, OS) Vd < Dara-Vd (ORR, PFS) Vd < Selinexor-Vd (ORR, PFS)

San-Miguel JF et al. Lancet Oncol 15:1195, 2014 Dimopoulos MA et al. Lancet Oncol 18:1327, 2017 Palumbo A et al. N Engl J Med 375:754, 2016

More Advanced Disease

Lenalidomide refractory MM - Eloquent 3 (Elo-Pd vs. Pd) -

87%% Len refractory, 70% refractory to PI

ORR: 53% vs. 26% ≥VGPR: 20% vs. 9%

Dimopoulos et al. N Engl J Med 379:1811, 2018

Apollo trial (Dara-Pd vs. Pd) -

Dimopoulos et al. ASH 2020

Lenalidomide refractory MM -ICARIA (Isa-Pd vs. Pd) -

>90% Len refractory 72% PI refractory

ORR: 60.4% vs. 35.3% ≥VGPR: 31.8% vs. 8.5%

Attal M, Lancet 394:2096, 2019

CANDOR Trial – Improved PFS

Dimopoulos M, Lancet 396:186, 2020 Dimopoulos M, ASH, 2020

CANDOR Trial – Responses

Responses, %

100

P=0.0040 84.3 74.7

69.2 48.7

28.5

20 0

Kd (n=154)

Responses, %

100

KdD (n=312)

10.4

60 40 20

P<0.0001 17.6 3.9

ORR

VGPR or better

CR or better

Median time to first response was 1 month in both treatment arms Dimopoulos M, Lancet 396:186, 2020

13.8

12.5 1.3

3.2

IKEMMA Trial

Moreau P et al. EHA 2020

IKEMMA Trial

Moreau P et al. EHA 2020

More Advanced Disease

Venetoclax N 30

t(1 1 ;1 4 ) M M R e fr a c t o r y t o : L a st lin e o f th e ra p y

B o rte z o m ib (B O R T )

L e n a lid o m id e (L E N )

C a rfilz o m ib (C A R F )

P o m a lid o m id e (P O M )

B O R T /L E N

B O R T /C A R F

B O R T /P O M

L E N /C A R F

L E N /P O M

C A R F /P O M

B O R T /L E N /C A R F

B O R T /L E N /P O M

O v e ra ll re s p o n s e ra te (% )

1. Touzeau C et al. Leukemia 2014 2. Punnoose E et al. Mol Cancer Ther 2016

6 80

B O R T /L E N /C A R F /P O M 60

L E N /C A R F /P O M

B O R T /C A R F /P O M

Selinexor

New Immunotherapies

Immunotherapy Targets in MM Naked antibody - Elotuzumab ADC- Belantamab Mafodotin TCE- Teclistamab, CC-93269 CAR-T – Ide-Cel, Cilta-Cel

Naked antibody – Daratumumab, Isatuximab

TCE– Talquetamab CAR-T - ?

CD38 TCE– Cevostamab

CAR-T– ?

figure

CAR-T– ?

ANTIBODY-DRUG CONJUGATE • • • • • • • • •

Lonial S. et al. Lancet Oncology 2020 21:207

Prior PI, IMiD and CD38+ monoclonal antibody 3+ prior lines of therapy 2.5 mg/kg or 3.4 mg/kg q3weeks ORR 31% (2.5 mg) and 34% (3.4 mg) 24% grades 3 and 4 keratopathy Median PFS 2.9 and 4.9 months Frequent dose omissions and interruptions Unknown duration of keratopathy Complex co-management with ophthalmology

CAR-T Cells

IDE-CEL

Munshi et al. ASCO 2020

KARMMA STUDY

Munshi et al. N Engl J Med 384 ;705, 2021

KARMMA STUDY • 3% grade 3 neurotoxicity • Cytopenias were common, median 2 months for improvement

Munshi et al. N Engl J Med 384 ;705, 2021

KARMMA STUDY

Munshi et al. N Engl J Med 384 ;705, 2021

CILTA-CEL, CARTITUDE-1

Usmani et al. ASCO 2021

CILTA-CEL, CARTITUDE-1

Usmani et al. ASCO 2021

CILTA-CEL, CARTITUDE-1

Usmani et al. ASCO 2021

CILTA-CEL, CARTITUDE-1

Usmani et al. ASCO 2021

BCMA TCE IN MM

Seckinger A, et al. Cancer Cell. 2017;31:396-410.

TECLISTAMAB

Krishnan et al. ASCO 2021 Annual Meeting.

TECLISTAMAB

Krishnan et al. ASCO 2021 Annual Meeting.

Clinical trials • Are an important option for everyone • Can be for people newly diagnosed, with limited disease or advanced disease • Are appropriate for people of different age, gender, and race, depending on the purpose and phase of the study • Take into account all the above factors as well as stage of disease, other treatments used and presence of any other illness Remember…communication with your healthcare team is important in making treatment decisions about standard treatment or clinical trial treatment

How do clinical trials work? Phase I investigates for safety and side effects, dosage and best way to give treatment–includes 20 or more people Phase II determines effectiveness and safety–typically includes fewer than 100 (may include up to 300) people Phase III looks at effectiveness, side effects and safety in comparison with other treatments–includes 100s to 1000s of people Phase IV gathers more information after FDA approval & drug is on market

Placebos are rarely used in cancer clinical trials and only in the context of another active drug

Why Do So Few Cancer Patients Participate in Clinical Trials?

Patients may: • Be unaware of clinical trials • Lack access to trials • Fear, distrust, or be suspicious of research • Have practical or personal obstacles • Face insurance or cost problems • Be unwilling to go against their physicians’ wishes 105

Common Misconceptions about Clinical Trials •Something to consider when there are no more options. •You don’t know what you are getting. •They are too dangerous, too many side effects. •Sponsor/investigators hide information from you. •Something one does to help others. 106

INFORMATION IS KEY – AND FREE!

107

Thank you!

ljcosta@uabmc.edu

109

How to Manage Myeloma Symptoms and Side Effects

Daniel Verina,

DNP, ACNP-BC, Mount Sinai Hospital, New York, NY IMF Nurse Leadership Board 110

Be the Commander of Your Galactic Journey: Navigating the Journey Daniel Verina DNP, RN, MSN, ACNP-BC Mount Sinai Medical Center New York City, NY November 6, 2021

You are in the Commander’s Chair Patient Education Slides 2021

All Crew Members are Needed for a Successful Journey

Navigating the Journey

• You and your Subspecialists

Primary Care Provider (PCP)

caregiver are the center

General Hem/Onc

• Understand the

different roles of your health care team

You and Your Caregiver(s)

Family/Support Network

Allied Health Staff

Myeloma Specialist

• Understand how they can help you

Explore Treatment Options & Plan Your Course Drug class Proteosome inhibitor Immuno-modulatory agent Monoclonal antibody Antibody-drug conjugate Nuclear export inhibitor

Anthracycline

Alkylating agents

HDACi CAR T Many

Navigating the Journey

Myeloma therapies Common combinations Bortezomib (SQ) VRD, Vd Carfilzomib KRd, Kd, K Ixazomib IxRd Pomalidomide Pd, DPd, EPd Lenalidomide VRD, Rd HCP Data Clinical From Thalidomide Dara + VTd Research Daratumumab DRd, DVd, DPd, D-VMP Experience Elotuzumab ERd, EPd TREATMENT Isatuximab-irfc IsaPd DECISION Belantamab mafodotin Bela montherapy Selinexor Sel + d, Sel + Vd Liposomal doxorubicin BRd, BVd Cyclophosphamide PCd, VTD-PACE Your Melphalan MVP, MPT Preference Panobinostat Panobinostat + Vd Abecma Philippe Moreau. ASH 2015. Clinical trials are always an option

Bela = belantamab C = cyclophosphamide; D = daratumumab; d = dexamethasone; E = elotuzumab; HDACi = histone deacytlase inhibitor; Isa = Isatuximab; Ix = ixazomib; K = carfilzomib; P = pomalidomide; R = lenalidomide; Sel = Selinexor; SQ = subcutaneous; V = bortezomib Faiman B, et al. J Adv Pract Oncol. 2016;2016:7(suppl 1):17-29. Philippe Moreau. ASH 2015; Prescribing information.

Be an Empowered Patient “Scotty, We Need More Power!”

Navigating the Journey

• Participate in decisions • Ask for time to consider options (if needed/appropriate)

• Understand options - Use reliable sources of information - Use caution considering stories of personal experiences

• Create a dialogue • Express your goals/values/preferences • Arrive at a treatment decision together This Photo by Unknown Author is licensed under CC BY-SA

Major Tom to Ground Control… Communicating Effectively with Your Crew Prepare for Your Away Mission

Achieve Your Appointment

• Write down your questions and concerns • Bring current medications and supplements or a list • Any medical or life changes since your last visit? • Current symptoms - how have they changed?

• Speak up! • Ask your most important questions first • Understand your treatment plan and next steps • Have a list of who to contact and when • Bring a Caregiver for another “set of ears”

Navigating the Journey

Navigate Home • Communicate with other members of your health care crew (pharmacist, others) • Take your medications as directed • Follow up with members of your heath care crew

A Tool to Help You Discuss Your Treatment With Your Healthcare Team

Navigating the Journey

Take Time to Consider Your Preferences Before an Appointment Ask Important Questions at Your Appointments • What Can I Expect Now? • What Can I Expect In the Future? Have these conversations… • Whenever your treatment stops working • Whenever you start a new treatment • Whenever there is a change in your life priorities • Whenever you have a question or concern Available at myeloma.org or by calling the InfoLine

Myeloma and Treatments Both Contribute to How You Feel

Constellation of Symptoms

Myeloma cells in excess can cause symptoms

Treatments for myeloma kill myeloma cells but can cause symptoms

• • • •

Calcium elevation Renal dysfunction Anemia Bone pain

• Fatigue • Infection • Other symptoms

Myelosuppression Peripheral neuropathy Diarrhea Fatigue

• Deep vein thrombosis • Infection (eg, shingles) • Other symptoms

How You Feel 11

What Happens if Symptoms Are Not Managed Effectively? Poorly managed symptoms can lead to... • Anxiety • Depression • Social isolation • Missed doses • Reduced treatment efficacy • Reduced quality of life

Constellation of Symptoms

Discuss how you feel with your team... • Keep a symptom diary; discuss with team • Many options but your team cannot help if they don’t know • Express your priorities – Fatigue is common concern but making the right treatment decision is higher priority for most

Faiman, B. CJON. 2017, 21(5)suppl 3-6. Faiman, B. et al 2017. Patient Reported Symptoms, Concerns and Provider Intervention in Patients with Multiple Myeloma

Steroid Side Effects and Management Steroid Side Effects • Irritability,

mood swings, depression

• Blurred vision, cataracts • Flushing/sweating

• Difficulty sleeping

• Stomach bloating,

• Increased risk of

• Weight gain, hair

(insomnia), fatigue

infections, heart disease • Muscle weakness, cramping

hiccups, heartburn, ulcers, or gas thinning/loss, skin rashes

• Increase in blood

sugar levels, diabetes

Constellation of Symptoms

Managing Steroid Side Effects • Consistent schedule (AM vs. PM) • Take with food • Stomach discomfort: Over-the-counter or prescription medications • Medications to prevent shingles, thrush, or other infections

Steroids help kill myeloma cells. Do not stop or adjust steroid doses without discussing it with your health care provider.

• Increase in blood pressure,

water retention

King T, Faiman B. CJON. 2017; 21(5)suppl:240-249. Faiman B, et al. CJON. 2008;12(3)suppl:53-63.

Fatigue, Depression, and Anxiety

Constellation of Symptoms

• All can effect quality of life and relationships • Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

Management

• Exercise (walking, yoga, etc) • Proper rest • Support (social network, support group, professional counseling, etc) • Prayer, meditation, spiritual support • Mindfulness-based stress reduction

• • • • •

Medications Massage, aroma therapy Supplements: ginseng Transfusion, if indicated Effective management of other symptoms

At least 70% of patients experience fatigue, but only 20% tell their provider. Let your provider know about symptoms that are not well controlled or thoughts of self harm. Catamero D et al. CJON. 2017; 21(5)suppl:7-18. Faiman, B. et al 2017. Patient Reported Symptoms, Concerns and Provider Intervention in Patients with Multiple Myeloma.

Infection Prevention & Treatment • Compromised immune function comes from multiple myeloma and from treatment • Good personal hygiene (skin, oral) • Environmental control (wash hands, avoid crowds and sick people, etc) • Growth factor (Neupogen [filgrastim]) • Immunizations (NO live vaccines) • Medications (antibacterial, antiviral)

Constellation of Symptoms

Report fever of more than 100.4°F, shaking chills even without fever, dizziness, shortness of breath, low blood pressure to HCP as directed. Infection is serious for myeloma patients!

– New research: for patients receiving active myeloma therapy, levofloxacin 500 mg once daily for 12 weeks reduced infection (fevers, death) (ASH 2017 #903)

Brigle K, et al. CJON. 2017; 21(5)suppl:60-76.

Pain Prevention and Management

Constellation of Symptoms

• 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; antiviral to prevent shingles; sedation before procedures – Intervention depends on source of pain – May include medications, activity, surgical intervention, radiation therapy, etc – Complementary and alternative medicine (supplements, acupuncture, etc)

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

Faiman B, et al. CJON. 2017;21(5)suppl:19-36.

Knowledge is Power

IMF has many resources to help you learn more

Website: http://myeloma.org

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Download or order at myeloma.org

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