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
Download The PPT/PDF document "Hematology Mastery in Multiple Myeloma" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Hematology Mastery in
Multiple Myeloma
Slide2Part 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
Slide3International 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.
Slide4Lenalidomide 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.
Slide5International 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.
Slide6CRAB CriteriaC:
hyperCalcemia
R: Renal failureA: AnemiaB: Bone lesions
Rajkumar
SV, et al.
Lancet Oncol
.
2014;15:e538-548.
Slide7Treatment 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.
Slide8Induction 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.
Slide9SWOG 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.
Slide10Intergroupe 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.
Slide11Induction 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.
Slide12Induction 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.
Slide13Part II: Transplantation, Consolidation, and Maintenance Therapy for
Multiple
Myeloma
Moderator:
Sagar
Lonial, MD
Panelists:
Jonathan Kaufman, MD and Ajay
Nooka
, MD
Slide14Consolidation 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.
Slide15Candidates 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.
Slide16Lenalidomide, 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.
Slide17The 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.
Slide18Results 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%
Slide19Panelist’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
.
Slide20Approach 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.
Slide21Part III: Management of
Relapsed Multiple Myeloma
Moderator:
Sagar
Lonial
, MDPanelists: Jonathan Kaufman, MD and Ajay
Nooka
, MD
Slide22Meta-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.
Slide23Algorithm 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.
Slide24Emerging 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]