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Hematology Mastery in Multiple Myeloma Hematology Mastery in Multiple Myeloma

Hematology Mastery in Multiple Myeloma - PowerPoint Presentation

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Hematology Mastery in Multiple Myeloma - PPT Presentation

Part I Smoldering Multiple Myeloma and Induction Therapy for Patients with Newly Diagnosed Multiple Myeloma Moderator Sagar Lonial MD Panelists Jonathan Kaufman MD and Ajay Nooka ID: 793316

myeloma lenalidomide multiple dexamethasone lenalidomide myeloma dexamethasone multiple bortezomib response vrd 2017 survival age induction progression transplant free serum

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Slide1

Hematology Mastery in

Multiple Myeloma

Slide2

Part I: Smoldering Multiple Myeloma

and

Induction Therapy for Patients with Newly Diagnosed Multiple Myeloma

Moderator:

Sagar

Lonial

, MD

Panelists:

Jonathan Kaufman, MD and Ajay

Nooka

, MD

Slide3

International Myeloma Working Group Definition of Smoldering Multiple Myeloma

Serum monoclonal protein (

IgG

or IgA ≥30 g/dL)OR

Bence

-Jones protein ≥500 mg/24 h

AND/ORClonal bone marrow plasma cells 10%-60%ANDAbsence of myeloma-defining events or amyloidosisIf skeletal survey is negative, assess for bone disease with whole-body MRI or PET/CT

Rajkumar

SV, et al.

Lancet

Oncol

.

2014;15:e538-548.

Slide4

Lenalidomide Plus Dexamethasone for High-Risk Smoldering Multiple Myeloma

Number enrolled: 119 patients with high-risk smoldering multiple myeloma

Median time to progression

Not reached (treatment group) vs 21 months (observation group)Hazard ratio for progression to symptomatic myeloma 0.18 (95% CI, 0.09-0.32; P

<.001)

5-year overall survival

94% (treatment group) vs 78% (observation group)Hazard ratio for death 0.28 (95% CI, 0.09-0.91; P = .02)

Mateos

MV, et al.

N Engl J Med.

2013;369:438-447.

Slide5

International Myeloma Working Group Definition of Multiple Myeloma

Clonal bone marrow plasma cells ≥10%

OR

Biopsy-proven bony or extramedullary

plasmacytoma

AND any 1 or more of the following:Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specificallyHypercalcemia

Serum calcium >0.25

mmol

/L (>1 mg/

dL

) higher than the upper limit of normal OR

Serum calcium >2.75 mmol/L (>11 mg/dL)Renal insufficiencyCreatinine clearance <40 mL/min ORSerum creatinine >177 μmol/L (>2 mg/dL)AnemiaHemoglobin >20 g/L below the lower limit of normal ORHemoglobin <100 g/LBone lesions≥1 osteolytic lesion on skeletal radiography, CT, or PET-CTAny 1 or more of the following biomarkers of malignancyClonal bone marrow plasma cell percentage ≥60%Involved:uninvolved serum free light chain ratio ≥100>1 focal lesion on MRI studies

Rajkumar

SV, et al.

Lancet

Oncol

.

2014;15:e538-548.

Slide6

CRAB CriteriaC:

hyperCalcemia

R: Renal failureA: AnemiaB: Bone lesions

Rajkumar

SV, et al.

Lancet Oncol

.

2014;15:e538-548.

Slide7

Treatment of Smoldering Multiple Myeloma

Primary therapy: observation or enrollment in a clinical trial

Surveillance

3- to 6-month intervalsLaboratory tests: CBC; serum chemistry for creatinine, albumin, LDH, calcium, and beta-2 microglobulin

; serum quantitative

immunoglobulins

, SPEP, and SIFE; serum FLC assay; 24-hour urine assay for total protein, UPEP, and UIFEAnnual skeletal survey or whole-body low-dose CT (or as clinically indicated)Bone marrow aspiration and biopsy and imaging studies with MRI and/or CT and/or PET/CT as clinically indicated

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 3.2017.

Abbreviations: CBC, complete blood count

; CT,

computed

tomography

; FLC, free light chains; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET, positron emission tomography; SIFE, serum immunofixation electrophoresis; SPEP, serum protein electrophoresis; UIFE, urine immunofixation electrophoresis; UPEP, urine protein electrophoresis.

Slide8

Induction Therapy Regimens for Transplant Candidates

Preferred

Bortezomib/cyclophosphamide/dexamethasone

Bortezomib/doxorubicin/dexamethasoneBortezomib/lenalidomide/dexamethasoneOtherBortezomib/dexamethasoneBortezomib/thalidomide/dexamethasoneCarfilzomib/lenalidomide/dexamethasoneIxazomib/lenalidomide/dexamethasone

Lenalidomide/dexamethasone

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 3.2017.

Slide9

SWOG S0777—Results

Number enrolled: 473 patients with newly diagnosed multiple myeloma

Median progression-free survival

43 mo with bortezomib, lenalidomide, and dexamethasone (VRD) vs 30

mo

with

lenalidomide and dexamethasone alone (RD)HR 0.712, 96% CI 0.56-0.906, one-sided P = .0018Median overall survival75 mo

with VRD

vs

64

mo

with RD

HR 0.709, 95% CI 0.524-0.959, two-sided P = .025Overall response rates (partial response or better)82% with VRD vs 72% with RDComplete response or better16% with VRD vs 8% with RDDurie BG, et al. Lancet. 2017;389:519-527.

Slide10

Intergroupe Francophone

du

Myelome

Study of VTD vs VCD Induction—Results

Number enrolled: 340 patients with newly diagnosed multiple myeloma

Response rates (very good partial response or better)

66.3% with VTD vs 56.2% with VCDP

= .05

Overall response rates

92.3% with VTD

vs

83.4% with VCD

P = .01Moreau P, et al. Blood. 2016;127:2569-2574.Abbreviations: VCD, bortezomib, cyclophosphamide, dexamethasone; VTD, bortezomib, thalidomide, dexamethasone.

Slide11

Induction With VRD vs VCD—Results

Number enrolled: 176 patients with transplant-eligible multiple myeloma

Overall response rate

100% with VRD (38.6% CR, 69.3% VGPR or better)90.9% with VCD (6.8% CR, 56.8% with VGPR or better)

Progression-free survival

46

mo for VRD43 mo with VCD

Nooka A, et al.

Clin Lymphoma Myeloma

Leuk

.

2017;17(1):e137.

Abbreviations: CR, complete response; VCD, bortezomib, cyclophosphamide, dexamethasone; VGPR, very good partial response; VRD, bortezomib, lenalidomide, dexamethasone.

Slide12

Induction Therapy Regimens forTransplant Candidates

Immunomodulatory

+ protease inhibitor triplets

Bortezomib/lenalidomide/dexamethasone

Bortezomib

/thalidomide/dexamethasone

Carfilzomib/lenalidomide/dexamethasoneIxazomib/

lenalidomide

/dexamethasone

Chemotherapy + protease inhibitor triplets

Bortezomib

/cyclophosphamide/dexamethasone

Bortezomib/doxorubicin/dexamethasoneDoubletsBortezomib/dexamethasoneLenalidomide/dexamethasoneNCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 3.2017.

Slide13

Part II: Transplantation, Consolidation, and Maintenance Therapy for

Multiple

Myeloma

Moderator:

Sagar

Lonial, MD

Panelists:

Jonathan Kaufman, MD and Ajay

Nooka

, MD

Slide14

Consolidation and Maintenance Treatment

Consolidation:

treatment after induction therapy to deepen the initial remission from induction

Maintenance: treatment to maintain the response achieved with induction and consolidation at the lowest level of disease burden

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 3.2017.

Slide15

Candidates for Stem Cell Transplant—Panelist’s Views

2 most important considerations

Performance status

ComorbiditiesLess important consideration: age

Courtesy of

Sagar

Lonial

, MD; Jonathan Kaufman, MD; and Ajay Nooka, MD, MPH. 2017.

Slide16

Lenalidomide, Bortezomib

, and Dexamethasone With or Without Transplantation

Number enrolled: 700 patients with multiple myeloma

Median progression-free survival

50

mo

with VRD + transplant vs 36 mo with VRD aloneAdjusted HR, 0.65; P

<.001

Complete response rates

59% with VRD + transplant

vs

48% with VRD alone

P = .03Patients in whom minimal residual disease not detected79% with VRD + transplant vs 65% with VRD aloneP <.001Overall survival at 4 y81% with VRD + transplant vs 82% with VRD aloneAttal M, et al. N Engl J Med. 2017;376:1311-1320.Abbreviation: VRD, bortezomib, lenalidomide, dexamethasone.

Slide17

The Effect of Age on Transplant Outcomes

Comparison of 3 age cohorts: 18-59 y (n = 5818), 60-69 y

(n = 4666), and >70 y (n = 946)

1Median overall survival not reached for any age cohort1-y nonrelapse mortality: 0% for >70 y and 2% for all other ages (

P

not significant)

3-y relapse rate: 56% ages 18-59, 61% ages 60-69, and 63% age >70 (P not significant)3-y progression-free survival: 42% ages 18-59, 38% ages 60-69, 33% age >70 (

P

not significant)

Comparison of 2 age cohorts: ≤50 y (n = 86)

vs

>70 y (n = 105)

21-y progression-free survival: 60% age ≤50 vs 58% age >70Overall survival at 1 y: 92% age ≤50 vs 85% age >701. Sharma M, et al. Biol Blood Marrow Transplant. 2014;20:1796-1803. 2. Dhakal B, et al. Clin Lymphoma Myeloma Leuk. 2017;17:165-172.

Slide18

Results of the StaMINA Trial(38-Month Estimated Probabilities)

Stadtmauer

EA, et al. Presented at: ASH 58th Annual Meeting, 2016. Abstract LBA-1.

Treatment

Progression-Free Survival

Overall Survival

Cumulative Incidences of Disease Progression

AutoHCT

followed by

bortezomib

,

lenalidomide

, and dexamethasone consolidation and lenalidomide maintenance57%86%42%Tandem autoHCT followed by lenalidomide maintenance56%

82%

42%

AutoHCT

followed by

lenalidomide

maintenance

52%

83%

47%

Slide19

Panelist’s Approach to High-Risk Maintenance Therapy

Induction:

Bortezomib

, Lenalidomide

, Dexamethasone

Transplant

Maintenance:

Bortezomib

,

Lenalidomide

, Dexamethasone

Maintenance:

Carfilzomib, Thalidomide, Dexamethasone

Good Response to Induction

Lesser/Partial Response

to Induction

Courtesy

of

Sagar

Lonial

, MD; Jonathan Kaufman, MD; and Ajay Nooka, MD, MPH. 2017

.

Slide20

Approach to Standard-Risk Patients—Panelist’s Approach

Induction:

Bortezomib

,

Lenalidomide

, Dexamethasone

Single Autologous Transplant

Maintenance:

Lenalidomide

Courtesy

of

Sagar

Lonial, MD; Jonathan Kaufman, MD; and Ajay Nooka, MD, MPH. 2017.

Slide21

Part III: Management of

Relapsed Multiple Myeloma

Moderator:

Sagar

Lonial

, MDPanelists: Jonathan Kaufman, MD and Ajay

Nooka

, MD

Slide22

Meta-Analysis—2 vs 3 Drug Regimens for Relapsed MM

Pooled odds ratios for triplets

vs

doubletsOverall response rate: 1.811

≥Very good partial response: 1.962

≥Complete response: 2.325

Pooled hazards ratios for triplets vs doubletsProgression-free survival: 0.674

Relative risk of ≥grade 3 serious adverse events for triplets

vs

doublets

Diarrhea: 2.232

Fatigue: 1.654

Thrombocytopenia: 2.161Overall: 1.438Nooka AK, et al. J Clin Oncol. 2016;34(suppl):abstract 8020.

Slide23

Algorithm for the Treatment of Relapsed Multiple Myeloma Used by Panelists

Patients not refractory to lenalidomide, with slower progression of disease

Elotuzumab, lenalidomide, dexamethasone

Ixazomib, lenalidomide, dexamethasonePatients with aggressive diseaseCarfilzomib, lenalidomide, dexamethasoneDaratumumab, lenalidomide, dexamethasone

Daratumumab, bortezomib, dexamethasone

Memo courtesy of

Sagar

Lonial

, MD; Jonathan Kaufman, MD; and Ajay Nooka, MD, MPH. 2017.

Slide24

Emerging Immune Therapies for Relapsed Multiple Myeloma

Venetoclax

:

BCL-2 inhibitorSelinexor: XPO1 inhibitor, used in combination with lenalidomide and dexamethasone

Pembrolizumab

:

PD-1 inhibitor, used in combination with pomalidomide and dexamethasone OR lenalidomide and low-dose dexamethasoneCAR (chimeric antigen receptor) T cells:

targeting CD19 and B-cell maturation antigen

Terpos

E, et al.

Clin Lymphoma Myeloma

Leuk

. 2017 Mar 18. [Epub ahead of print]