Update on Multiple Myeloma Treatment

Transcription

1 Update on Multiple Myeloma Treatment Professor Chng Wee Joo Director National University Cancer Institute of Singapore (NCIS) National University Health System (NUHS) Deputy Director Cancer Science Institute, Singapore (CSI) National University of Singapore (NUS) 20 Jun 2018

2 Multiple Myeloma Neoplastic clonal proliferation of plasma cells Production of paraprotein (monoclonal Ig) Normal production of Ig impaired (immuneparesis)

3 Hypercalcemia Osteolytic lesions, fractures Bone Resorption Deposition of Ig in kidney Renal impairment Anaemia Marrow infiltration Hyperviscosity syndr Recurrent infection Anaemia

4 Courtesy of Dr Sathish Kumar

5 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]

6 Treatment of Transplant Eligible NDMM

7 Phases of Treatment Induction Stem cell Transplant Consolidation Maintenance

8 Phases of Treatment Induction Stem cell Transplant Consolidation Maintenance Objective Rapid and Deep Response Able to harvest Minimal toxicity

9 Significant improvement in post-induction CR/nCR and VGPR rates induction regimens

10 Response and Survival Pavia et al. Blood

11 Phases of Treatment Induction Stem cell Transplant Consolidation Maintenance Objective Increase CR rates

12 Is ASCT still needed in Era of Novel Agents

13 Significant improvement in post-induction and posttransplant CR/nCR and VGPR rates with bortezomibbased induction regimens

14 Phases of Treatment Induction Stem cell Transplant Consolidation Maintenance Objective Increase MRD negative rates

15 Phases of Treatment Induction Stem cell Transplant Consolidation Maintenance Objective Maintain deepest response Increase OS Tolerable with good QoL

16 1. Attal M, et al. Blood. 2006;108: ; 2. Spencer A, et al. J Clin Oncol. 2009;27: ; 3. Barlogie B, et al. N Engl J Med. 2006;354: ; 4. Barlogie B, et al. Blood. 2008;112: ; 5. Barlogie B, et al, J Clin Oncol. 2010;28: ; 6. Lokhorst HM, et al. Blood. 2010;115: ; 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 Thal Induction Treatment ASCT Maintenance Thal PFS/OS Increase Survival post-relapse Thal/PAM vs PAM vs None 1 2X + + / + Similar Thal/Pred vs Pred 2 1X + + / + Similar Thal vs No Thal X + + / + post-thal Thal vs IFN 6 + 1X/2X + + / post-thal Thal vs None 7 + 1X + + / post-thal Thal/Pred vs None 8 + 1X + + / post-thal PAM = pamidronate; PD = progressive disease.; Pred = prednisone; Thal = thalidomide.

17 Morgan GJ et al. Blood 2012 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

18 LEN Maintenance After ASCT in MM: OS Analysis Studies Included in the Meta-Analysis a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients 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.

19 LEN Maintenance After ASCT in MM: OS Analysis OS 26% reduction in risk of death, with an estimated 2.5-year increase in median survival a a Median 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.

20 LEN Maintenance After ASCT in MM: OS Analysis Subgroup Analysis a Number of patients. b Cytogenetic 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.

21 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

22 Treatment of NDMM in transplant Ineligible Patients

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25 FIRST (MM-020): Final Survival Analysis Study Design 1,2 Screening Active Tx + PFS Follow-Up Phase LT Follow-Up RANDOMIZATION 1:1:1 (N = 1623) Arm A Rd Continuous (n = 535) Arm B Rd18 (n = 541) Arm C MPT (n = 547) LEN + LoDEX: Continuously LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15, 22/28 LEN + LoDEX: 18 Cycles (72 weeks) LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15, 22/28 MEL + PRED + THAL 12 Cycles (72 weeks) MELPHALAN 0.25 mg/kg days 1-4/42 PREDNISONE 2 mg/kg days 1-4/42 THALIDOMIDE 200 mg days 1-42/42 PD or Unacceptable Toxicity PD, OS, and Subsequent anti-mm Tx 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 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 Benboubker L, et al. N Engl J Med. 2014;371:

26 FIRST (MM-020): Final Survival Analysis Progression-Free Survival Updated PFS was prolonged with Rd continuous a 1.0 Results remain consistent nearly 3 years after the original PFS analysis Survival Probability year PFS 32.6% Median PFS, mos 4-year PFS, % Rd continuous Rd MPT HR (95% CI) Rd continuous vs MPT: 0.69 ( ), P < % 14.3% Progression-Free Survival (Months) a PFS is based on investigator assessment of IMWG criteria; Data cutoff: January 21, 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.

27 FIRST (MM-020): Final Survival Analysis Overall Survival The pre-specified final OS analysis for the primary comparison showed that Rd continuous significantly extended OS vs MPT 1.0 Median OS, mos 4-yr OS, % Survival Probability % 4-year OS 59.0% 58.0% Rd continuous Rd MPT HR (95% CI) Rd continuous vs MPT: 0.78 ( ), P = Overall Survival (Months) 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.

28 SWOG S0777: RVd vs Rd With Rd Maintenance Phase 3 Study Design 1,2 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:

29 SWOG S0777: RVd vs Rd With Rd Maintenance Survival Analyses RVd (n = 242) Rd (n = 232) Median PFS (95% CI), mos 43 (39-51) 31 (26-40) HR (96% Wald CI) ( ) 1-sided stratified log-rank P value.0066 a Median OS (95% CI), mos NR 63 (55-69) HR 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.

30 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

31 Management of Relapse Disease

32 Emerging Therapies 1.New Generation Proteasome Inhibitor a) Carfilzomib (Onyx) Aspire, Endeavour b) Ixazomib (Millenium) - Tourmaline 2.New Generation Imids a) Pomalidomide (Celgene) MM003 3.Histone Deacetylase Inhibitor a) Panobinostat (Novartis) - Panorama 4.Monoclonal Antibodies a) Daratumumab (Anti-CD38) Sirius, Pollux, Castor b) Elotuzumab (Anti-CS1) - Eloquent 5.CDK4/6 Inhibitor 6.Venetoclax (BCL2) 7.Selinexor 8.Immunotherapies

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35 TOURMALINE-MM1: Phase 3 study of weekly oral ixazomib plus lenalidomide-dexamethasone Global, double-blind, randomized, placebo-controlled study design N=722 Randomization 1:1 Ixazomib + Lenalidomide + Dexamethasone Ixazomib: 4 mg on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Repeat every 28 days until progression, or unacceptable toxicity Placebo + Lenalidomide + Dexamethasone Placebo: on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Stratification: Prior therapy: 1 vs 2 or 3 ISS: I or II vs III PI exposure: yes vs no Primary endpoint: PFS Key secondary endpoints: OS OS in patients with del(17p) Response and progression (IMWG 2011 criteria 1 ) assessed by an independent review committee (IRC) blinded to both treatment and investigator assessment *10 mg for patients with creatinine clearance 60 or 50 ml/min, depending on local label/practice 1. Rajkumar S, et al. Blood 2011;117:

36 Outcomes by cytogenetic risk group IRd ORR, % VGPR, % CR, % Median PFS, months Placebo -Rd IRd Placebo -Rd Median OS was not reached in either arm IRd Placebo -Rd IRd Placebo -Rd All patients 78.3* * * * Standard-risk patients All high-risk patients * 79* 60 45* 21 12* Patients with * del(17p) Patients with t(4;14) alone *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). HR 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

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38 Infusion-related Reactions (IRRs) Safety Analysis Set (n = 243) All grades Grade 3 Patients with IRRs, % 45 9 Most common (>5%) IRRs Dyspnea 11 2 Bronchospasm 9 3 Cough 7 0 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 Preinfusion: dexamethasone 20 mg, paracetamol mg, diphenhydramine mg Stop infusion immediately for mild symptoms; once resolved, resume at half the infusion rate 15

39 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(%) CR (%) 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 NR NR HR

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41 Thank you for your attention