Update on Multiple Myeloma Treatment Update on Multiple Myeloma Treatment. Professor Chng Wee Joo....
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Transcript of Update on Multiple Myeloma Treatment Update on Multiple Myeloma Treatment. Professor Chng Wee Joo....
Update on Multiple Myeloma Treatment
Professor Chng Wee JooDirectorNational University Cancer Institute of Singapore (NCIS)National University Health System (NUHS)Deputy DirectorCancer Science Institute, Singapore (CSI)National University of Singapore (NUS)
20 Jun 2018
• Neoplastic clonal proliferation of plasma cells• Production of paraprotein (monoclonal Ig)• Normal production of Ig impaired (immuneparesis)
Multiple Myeloma
Marrow infiltration
Bone Resorption
Hypercalcemia
Osteolytic lesions, fractures
Deposition of Ig in kidney
Renal impairment
Anaemia
Anaemia
Hyperviscosity syndr
Recurrent infection
Courtesy of Dr Sathish Kumar
Treatment Goals
• Young Patients (<65 years)– Best OS outcome with possibility of cure– MRD negative and maintained– Is this needed for all patients?
• Old Patients (>70 years)– Maximize OS with good quality of life
[Caveat: Cost to achieve these aims]
Treatment of Transplant Eligible NDMM
Phases of Treatment
Induction Stem cell Transplant Consolidation Maintenance
Phases of Treatment
Induction Stem cell Transplant Consolidation Maintenance
Objective Rapid and Deep
Response Able to harvest Minimal toxicity
Significant improvement in post-induction CR/nCR and VGPR rates induction regimens
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Pavia et al. Blood 2015
Response and Survival
Phases of Treatment
Induction Stem cell Transplant Consolidation Maintenance
Objective Increase CR
rates
Is ASCT still needed in Era of Novel Agents
Significant improvement in post-induction and post-transplant CR/nCR and VGPR rates with bortezomib-based induction regimens
Phases of Treatment
Induction Stem cell Transplant Consolidation Maintenance
Objective Increase MRD
negative rates
Phases of Treatment
Induction Stem cell Transplant Consolidation Maintenance
Objective Maintain deepest
response Increase OS Tolerable with good
QoL
TreatmentPFS/OS Increase Survival
post-relapseThal Induction ASCT
MaintenanceThal
Thal/PAM vs PAM vs None1 – 2X + + / + Similar
Thal/Pred vs Pred2 – 1X + + / + Similar
Thal vs No Thal3-5 + 2X + + / + post-Thal
Thal vs IFN6 + 1X/2X + + / – post-Thal
Thal vs None7 + 1X + + / – post-Thal
Thal/Pred vs None8 + 1X + + / – post-Thal
1. Attal M, et al. Blood. 2006;108:3289-3294; 2. Spencer A, et al. J Clin Oncol. 2009;27:1788-1793; 3. Barlogie B, et al. N Engl J Med. 2006;354:1021-1030; 4. Barlogie B, et al. Blood. 2008;112:3115-3121; 5. Barlogie B, et al, J Clin Oncol. 2010;28:1209-1214; 6. Lokhorst HM, et al. Blood. 2010;115:1113-1120; 7. Morgan GJ, et al. Blood. 2010;116. Abstract 623; 8. Stewart AK, et al. Blood. 2010;116. Abstract 39.
Phase 3 Studies of Thalidomide Maintenance
PAM = pamidronate; PD = progressive disease.; Pred = prednisone; Thal = thalidomide.
• Thal maintenance improve OS• Toxicity leads to poor QoL• Median duration of maintenance on 6-9 months• Median dose 50mg• Especially not useful for patients with high-risk cytogenetic
Morgan GJ et al. Blood 2012
LEN Maintenance After ASCT in MM: OS AnalysisStudies Included in the Meta-Analysis
aStarting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD. bPatients received 10 mg/day on days 1-21/28 until PD. ASCT, autologous stem cell transplant; DEX, dexamethasone; LEN, lenalidomide; MM, multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival;; PD, progressive disease; Tx, treatment. Attal M, et al. Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta-Analysis of Overall Survival. ASCO 2016, abstract 8001.
LEN Maintenance After ASCT in MM: OS AnalysisOS
aMedian for LEN treatment arm was extrapolated to be 116 months based on median of the CTL arm and HR (median, 86 months; HR = 0.74). ASCT, autologous stem cell transplant; CTL, control; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; NE, not estimable; OS, overall survival; pt, patient.Attal M, et al. Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta-Analysis of Overall Survival. ASCO 2016, abstract 8001.
• 26% reduction in risk of death, with an estimated 2.5-year increase in median survivala
LEN Maintenance After ASCT in MM: OS AnalysisSubgroup Analysis
aNumber of patients. bCytogenetic data were only available for the IFM and GIMEMA studies. c CrCl post-ASCT data were only available for the CALGB and IFM studies.ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; CTL, control; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.Attal M, et al. Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta-Analysis of Overall Survival. ASCO 2016, abstract 8001.
Summary for Approach to Transplant Eligible patients
• Triplet induction• Velcade based [VRD/KRD for HR patients]• Transplant still needed [Double transplant
for HR patients]• Consider further consolidation for patient
with suboptimal response• Maintenance may prolong OS
Treatment of NDMM in transplant Ineligible Patients
FIRST (MM-020): Final Survival AnalysisStudy Design1,2
• Stratification: Age (≤ 75 vs > 75 yrs), country, and ISS stage (I/II vs III)• Thromboprophylaxis was mandatory• Data cutoff: January 21, 2016
FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; LoDex, low-dose dexamethasone; LT, long-term; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; Tx, treatment.1. Facon T, et al. Final Analysis of Overall Survival From the FIRST Trial. ASH 2016, abstract 241. 2. Benboubker L, et al. N Engl J Med. 2014;371:906-917.
RAN
DO
MIZ
ATI
ON
1:1
:1(N
= 1
623)
Arm CMPT(n = 547)
Arm BRd18(n = 541)
LEN + LoDEX: 18 Cycles (72 weeks) LENALIDOMIDE 25 mg days 1-21/28LoDEX 40 mg days 1, 8, 15, 22/28
MEL + PRED + THAL 12 Cycles (72 weeks)MELPHALAN 0.25 mg/kg days 1-4/42PREDNISONE 2 mg/kg days 1-4/42THALIDOMIDE 200 mg days 1-42/42
PD, O
S, a
nd
Subs
eque
nt a
nti-M
M T
x
PD o
r Una
ccep
tabl
e To
xici
ty
Active Tx + PFS Follow-Up PhaseScreening LT Follow-Up
Pts aged > 75 yrs: LoDEX 20 mg days 1, 8, 15, 22/28; THAL 100 mg days 1-42/42; MEL 0.2 mg/kg days 1-4
LEN + LoDEX: ContinuouslyLENALIDOMIDE 25 mg days 1-21/28LoDEX 40 mg days 1, 8, 15, 22/28
Arm ARd Continuous(n = 535)
FIRST (MM-020): Final Survival AnalysisProgression-Free Survival
• Updated PFS was prolonged with Rd continuousa
– Results remain consistent nearly 3 years after the original PFS analysis
a PFS is based on investigator assessment of IMWG criteria; Data cutoff: January 21, 2016. FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; HR, hazard ratio; IMWG, International Myeloma Working Group; MPT, melphalan, prednisone, thalidomide; PFS, progression-free survival; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.Facon T, et al. Final Analysis of Overall Survival From the FIRST Trial. ASH 2016, abstract 241.
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 6660 7872 9084
Progression-Free Survival (Months)
Sur
viva
l Pro
babi
lity
4-year PFS
32.6%
14.3%13.6%
Median PFS,mos
4-year PFS,%
Rd continuous 26.0 32.6Rd18 21.0 14.3MPT 21.9 13.6
HR (95% CI)Rd continuous vs MPT: 0.69 (0.59-0.79), P < .00001
FIRST (MM-020): Final Survival AnalysisOverall Survival
• The pre-specified final OS analysis for the primary comparison showed that Rd continuous significantly extended OS vs MPT
FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; HR, hazard ratio; MPT, melphalan, prednisone, thalidomide; OS, overall survival; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.Facon T, et al. Final Analysis of Overall Survival From the FIRST Trial. ASH 2016, abstract 241.
Median OS, mos
4-yr OS, %
Rd continuous 59.1 59.0
Rd18 62.3 58.0
MPT 49.1 51.7
HR (95% CI)Rd continuous vs MPT: 0.78 (0.67-0.92), P = .0023
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 6660 7872 9084
Overall Survival (Months)
Sur
viva
l Pro
babi
lity
4-year OS
59.0%58.0%
51.7%
SWOG S0777: RVd vs Rd With Rd MaintenancePhase 3 Study Design1,2
BORT, bortezomib; D, day; DEX, dexamethasone; HSV, herpes simplex virus; ISS, International Staging System; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, oral administration; pt, patient; Rd, lenalidomide and low-dose dexamethasone; RVd, bortezomib, lenalidomide, and low-dose dexamethasone; SCT, stem cell transplant.1. Durie B et al. Blood. 2015;126:25. 2. https://clinicaltrials.gov/ct2/show/NCT00644228.
SWOG S0777: RVd vs Rd With Rd MaintenanceSurvival Analyses
RVd(n = 242)
Rd(n = 232)
Median PFS (95% CI), mos 43 (39-51) 31 (26-40)HR (96% Wald CI) 0.742 (0.579-0.951)1-sided stratified log-rank P value .0066a
Median OS (95% CI), mos NR 63 (55-69)HR 0.6662-sided log-rank P value .0114
a This analysis reached the prespecified significance level of .02.HR, hazard ratio; Rd, lenalidomide and low-dose dexamethasone; NR, not reached; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide and low-dose dexamethasone; RVd, bortezomib, lenalidomide, and low-dose dexamethasone.Durie B et al. Blood. 2015;126:25.
Summary of Approach to Transplant Ineligible Patients
• MP is no longer good enough• MPR is not a good regimen• MPT, Rd, VMP are all active• VRd better than Rd• Continuous treatment prolongs PFS
Management of Relapse Disease
Emerging Therapies
1.New Generation Proteasome Inhibitora) Carfilzomib (Onyx) – Aspire, Endeavourb) Ixazomib (Millenium) - Tourmaline
2.New Generation Imidsa) Pomalidomide (Celgene) – MM003
3.Histone Deacetylase Inhibitora) Panobinostat (Novartis) - Panorama
4.Monoclonal Antibodiesa) Daratumumab (Anti-CD38) – Sirius, Pollux, Castorb) Elotuzumab (Anti-CS1) - Eloquent
5.CDK4/6 Inhibitor6.Venetoclax (BCL2)7.Selinexor8.Immunotherapies
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TOURMALINE-MM1: Phase 3 study of weekly oral ixazomib plus lenalidomide-dexamethasone
Ran
dom
izat
ion
Ixazomib + Lenalidomide + DexamethasoneIxazomib: 4 mg on days 1, 8, and 15Lenalidomide: 25 mg* on days 1-21
Dexamethasone: 40 mg on days 1, 8, 15, 22
N=722
1:1
Placebo + Lenalidomide + DexamethasonePlacebo: on days 1, 8, and 15
Lenalidomide: 25 mg* on days 1-21Dexamethasone: 40 mg on days 1, 8, 15, 22
Repeat every 28 days until progression, or unacceptable toxicity
Stratification:• Prior therapy: 1 vs 2 or 3• ISS: I or II vs III• PI exposure: yes vs no
Global, double-blind, randomized, placebo-controlled study design
*10 mg for patients with creatinine clearance ≤60 or ≤50 mL/min, depending on local label/practice1. Rajkumar S, et al. Blood 2011;117:4691–5.
Response and progression (IMWG 2011 criteria1) assessed by an independent review committee (IRC) blinded to both treatment and investigator assessment
Primary endpoint: • PFSKey secondary endpoints: • OS • OS in patients with del(17p)
Outcomes by cytogenetic risk group
Median OS was not reached in either arm
In the IRd arm, median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics
ORR, % ≥VGPR, % ≥CR, % Median PFS, months
IRd Placebo-Rd
IRd Placebo-Rd
IRd Placebo-Rd
IRd Placebo-Rd HR
All patients 78.3* 71.5 48.1* 39 11.7* 6.6 20.6 14.7 0.742*
Standard-riskpatients
80 73 51 44 12 7 20.6 15.6 0.640*
All high-risk patients
79* 60 45* 21 12* 2 21.4 9.7 0.543
Patients with del(17p)†
72 48 39 15 11* 0 21.4 9.7 0.596
Patients with t(4;14) alone
89 76 53 28 14 4 18.5 12.0 0.645
*p<0.05 for comparison between regimens. †Alone or in combination with t(4;14 or t(14;16). Data not included on patients with t(14:16) alone due to small numbers (n=7).
Infusion-related Reactions (IRRs)
No grade 4 or 5 IRRs observed 98% of patients with IRRs experienced the event on the first infusion 2 patients discontinued due to IRRs
– Bronchospasm in the first patient– Bronchospasm, laryngeal edema, and skin rash in the second patient
Safety Analysis Set (n = 243)All grades Grade 3
Patients with IRRs, % 45 9Most common (>5%) IRRs
Dyspnea 11 2Bronchospasm 9 3Cough 7 0
Preinfusion: dexamethasone 20 mg, paracetamol 650-1000 mg, diphenhydramine 25-50 mgStop infusion immediately for mild symptoms; once resolved, resume at half the infusion rate
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Trials in Relapse MM (1-3 prior lines)
Panorama Endeavour Castor Aspire Eloquant-2 Tourmaline-1 Pollux
VD PVD VD KD VD DVD RD KRD RD Elo-RD RD IRD RD DRD
ORR(%) 55 61 63 77 63 83 67 87 66 79 72 78 76 93
≥CR (%) 6 11 6 13 9 19 9 32 4 7 7 12 19 43
sCR (%) NR NR 2 2 NR NR 4 14 NR NR NR NR 7 18
MRD NR NR NR NR NR NR NR NR NR NR NR NR 2 10
PFS/mths 7.7 10.0 9.4 18.7 7.2 NR 17.6 26.3 14.9 19.4 14.7 20.6 18.4 NR
HR 0.63 0.53 0.39 0.69 0.7 0.74 0.37
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