MULTIPLE MYELOMA TREATMENT in 2017 MC. VEKEMANS
NATURAL HISTORY of MM
WHO SHOULD BE TREATED?
DEFINITION MGUS Smouldering Multiple Myeloma Symptomatic Multiple Myeloma Monoclonal component (blood and/or urine) Monoclonal component (blood and/or urine) Monoclonal component (blood and/or urine) BM PC < 10 % BM PC 10 % BM PC 10 % No CRAB No CRAB At least 1 CRAB Kyle, NEJM 2007
NEW DEFINITIONS, 2014 2y incidence of end-organ damage > 80% Rajkumar, Lancert Oncol 2014
WHO SHOULD BE TREATED? Rajkumar, Blood 2015
GOAL OF THERAPY
BEST RESPONSE, SUSTAINED RESPONSE Achievement of CR after initial treatment is associated with improved PFS and OS
The true value of CR relies on the MRD status Lahuerta, in press
FRONT LINE THERAPY
FRONTLINE THERAPY Moreau, 2015
META-ANALYSIS INDUCTION, ROLE of BORTEZOMIB PFS VAD, TD Sonneveld, JCO 2013
INDUCTION, 2 or 3 DRUGS Phase 2-3 RCT incorporating new agents Improving response rates with combination therapies adapted from Stewart, 2009
INDUCTION, VTD or VCD IFM 2013-04 Moreau, Blood 2016
INDUCTION, VTD or VCD IFM 2013-04 VGPR and PR rates significantly superior in the VTD arm synergistic activity of IMiDs and PI First prospective trial VTD vs. VCD Median number of CD34+ stem cells higher in the VTD arm Data support the preferential use of VTD over VCD prior to ASCT Moreau, ASH 2015, #393
FRONT LINE THERAPY TRANSPLANTATION STILL OF VALUE?
ASCT, UPFRONT or AT RELAPSE IFM 2009-DFCI ASCT remains a standard of care Attal, NEJM 2017
IFM 2015-01 TREATMENT for YOUNG MM : FUTURE
FRONT LINE THERAPY NON TRANSPLANT ELIGIBLE PATIENTS
FRONTLINE THERAPY Co-morbidities Frailty (geriatric assessment) Moreau, 2015
VISTA, MPV or MP VISTA San Miguel, NEJM 2008
VISTA, MPV or MP VISTA Persistant significant reduction in risk of death with VMP versus MP that is maintained after 5y follow up, despite the use of novel agentsbased salvage therapy OS benefit of 13 months No emerging signal of SPM San Miguel, ASH 2011
FIRST, Rd or Rd18 or MPT FIRST Benboubker, NEJM 2014; Facon, ASH 2016, #241
FIRST, Rd or Rd18 or MPT FIRST Rd continuous significantly prolonged PFS, OS and TTNT. Rd continuous showed also a PFS benefit compared to Rd18 in delaying TTNT. PFS2 outcomes also suggest that Rd does not induce resistant relapses. Incidence of solid SPM is similar in Rd continuous and Rd18. Benboubker, NEJM 2014; Facon, ASH 2016, #241
TREATMENT for ELDERLY MM : FUTURE ALKYLATOR-BASED REGIMENS MP ALKYLATOR-FREE REGIMENS IMiDs MPT VMP Rd MPT (6 RCT) benefit in PFS and OS, 6 months VMP (1 RCT) benefit in PFS and OS KMP CLARION = VMP D-VMP vs. VMP CVD-SAR Rd (1 RCT) benefit in PFS and OS, compared to MPT SWOG VRd S0777 KRd IRd ERd DRd
FRONT LINE THERAPY OPTIONS after ASCT CONSOLIDATION MAINTENANCE
CONSOLIDATION Short term, to improve disease control by deepening response Limited period of time VTD Upgrade to CR post-consolidation by 30% (molecular and PFS) MAINTENANCE Less intensive treatment to suppress any MRD and prolong response duration, PFS, OS, while minimizing toxicity Long term administration Cavo, Blood 2012 Sonnevelt, ASH 2016, #242; Rosinoll, ;Atal, NEJM 2012; McCarthy, NEJM 2012; Palumbo, NEJM 2012
CONSOLIDATION EMN02 Sonneveld, ASH 2016, #242
CONSOLIDATION EMN02 Consolidation with RVd improves scr/cr rates and PFS (vs. no consolidation) no impact on OS (86% in both arms) Benefit in low risk cytogenetics (HR 0.68, p=0.03), not in high-risk disease (25% pts) Sonneveld, ASH 2016, #242
CONSOLIDATION, ROLE of ASCT StaMINA BMT CTN 0702 n = 758 Stratification upon ISS, cytogenetics risk and center Stadtmauer, ASH 2016, LBA1
CONSOLIDATION ROLE of ASCT StaMINA BMT CTN 0702 At 38 months PFS OS PD ASCT + 4 VRD 57% 86% 42% No differences in PFS, OS, PD Double ASCT 56% 82% 42% Single ASCT 52% 83% 47% Consolidation therapy (or a second ASCT) does not seem to provide an incremental outcome benefit in the era of lenalidomide maintenance (EMN02-HOVON95) Results are not uniform between studies Stadtmauer, ASH 2016, #LBA1
FRONT LINE THERAPY OPTIONS after ASCT CONSOLIDATION MAINTENANCE
CONSOLIDATION Short term, to improve disease control by deepening response Limited period of time MAINTENANCE Less intensive treatment, to suppress any MRD and prolong response duration, PFS, OS, while minimizing toxicity Long term administration Cavo, Blood 2012 Thalidomide (6 trials) PFS: + 6/6, OS: +3/6 Bortezomib (2 Trials). PFS: + 2/2, OS: +1/2 Lenalidomide (3 trials) PFS: +3/3, OS: + 1/3 Sonnevelt, ASH 2016, #242; Rosinoll, ;Atal, NEJM 2012; McCarthy, NEJM 2012; Palumbo, NEJM 2012
MAINTENANCE, ROLE of LENALIDOMIDE IFM 2005-02 Attal, NEJM 2012
Survival probability MAINTENANCE, ROLE OF LENALIDOMIDE META ANALYSIS IFM 2005-02 CALGB GIMEMA 1.0 7-year OS median FU 80 months OS 0.8 0.6 0.4 N = 1,209 N = 1209 LEN CONTROL Median OS (95% CI), months NE (NE NE) 86.0 (79.8 96.0) 50% 62% 0.2 HR (95% CI) p value 0.74 (0.62 0.89) 0.001 0 Patients at risk 0 10 20 30 40 50 60 70 80 90 100 110 120 Overall survival (months) 605 578 555 509 474 431 385 282 200 95 20 1 0 604 569 542 505 458 425 350 271 174 71 10 0 Attal, McCarthy, EHA 2016
LENALIDOMIDE MAINTENANCE Lenalidomide maintenance is associated with a 26% reduction in risk of death an estimated 2.5 year increase in median OS Benefit seen in all subgroups except HR cytogenetics and ISS 3 Overall survival benefit outweights the risk of developing a SPM Len maintenance after ASCT is a new standard of care
MAINTENANCE after ASCT : FUTURE Sponsor/cooperative group IFM/DFCI 2009 Myeloma XI GEM14MAIN GMMHD6 GIMEMA SWOG US Cooperative group trials (pick the winner) AFT-40 C16019 Takeda Millennium HOVON-IFM CCT-PNK-004-mmy001 Treatment Lenalidomide-based Len 1y vs. Len until DP Len vs. Len + vorinostat vs. no maintenance Len vs. Len + ixazomib for up to 2 years Patients with MRD will continue 3 additional years Len-dex vs. Len-dex + elotuzumab Len vs. Len + carfilzomib Len vs. Len + ixazomib until DP Len vs. Len + vaccination/len 2y vs. Len until DP Len vs. Len + ixazomib Len vs. Len + durvalumab vs. Len + daratumumab vs. Len + ACY241 Ixazomib 2 y vs. placebo Daratumumab vs. placebo Human cord blood derived, cultured and expanded NK cells Developing early endpoints as surrogate markers for long-term outcomes and OS is critically important... Otherwise, trials may continue for 10 years or longer!
SECOND TRANSPLANTATION Front-line therapy, tandem-asct Patients in CR/VGPR after one ASCT do not benefit from a second ASCT Patients with HR cytogenetics, t(4;14) or del(17p). Allogeneic transplantation or tandem auto-allo-sct May improve PFS in patients with t(4;14) or del(17p). Results are better in an early stage of the disease. Novel treatments may challenge the role of allo-sct and its use should be restricted to clinical trials.
CURRENT OPTIONS at RELAPSE
IMPROVING SURVIVAL in MM
2015, A GREAT YEAR FOR MM POMALIDOMIDE CARFILZOMIB Third generation IMiD Second generation PI, epoxyketone PANOBINOSTAT IXAZOMIB DARATUMUMAB ELOTUZUMAB Pan HDAC inhibitor (with VD) Oral proteasome inhibitor (with Rd) Monoclonal antibody anti-cd38 (monotherapy) Monoclonal antibody anti-cs1 (with Rd)
FIRST RELAPSE IMiDs based studies PFS HR (95% CI) POLLUX DRd vs Rd 0.37 (0.27-0.52) ASPIRE KRd vs Rd 0.69 (0.57-0.83) ELOQUENT-2 ERd vs Rd 0.73 (0.60-0.89) TOURMALINE IRd vs Rd 0.74 (0.59-0.94) ORR 93% 87% 79% 78% VGPR 76% 70% 33% 48% CR 43% 32% 5% 14% DOR (months) OS HR (95% CI) NE 38.6 20.7 20.5 0.64 (0.40-1.01) 0.79 (0.63-0.99) 0.77 (0.61-0.97) NE HR PFS of 0.37, the lowest hazard ratio ever seen in a myeloma trial to date Usmani, ASH 2016; Stewart, NEJM 2015; Dimopoulos, Blood 2015; Moreau, NEJM 2016
FIRST RELAPSE Bortezomib based studies PFS HR (95% CI) PFS, median (months) CASTOR DVd vs Vd 0.39 (0.28-0.53) ENDEAVOR Kd vs Vd 0.53 (0.44-0.55) PANORAMA Pan-Vd vs Vd 0.63 (0.52-0.76) EVd vs Vd 0.72 (0.59-0.88) NE 18.7 12 9.7 ORR 84% 77% 61% 66% VGPR 59% 54% 28% 36% CR 19% 13% 11% 4% DOR (months) OS HR (95% CI) NE 21.3 13.1 11.4 0.77 (0.47-1.26) 0.79 (0.58-1.08) 0.94 (0.78-1.14) 0.61 (0.32-1.15) Mateos, ASH 2016; Dimopoulos, Lancet Oncol 2016; San Miguel, Lancet Oncol 2014; Jakubowiak, Blood 2016
DARATUMUMAB CASTOR POLLUX Game changer?
DARATUMUMAB, PFS CASTOR POLLUX Moreau, ASH 2016; Mateos, ASH 2016
CASTOR DARATUMUMAB, MRD negativity POLLUX Combination of Daratumumab with SOC induced MRD-negativity in over 4 times as many CR patients as SOC regimens Moreau, ASH 2016; Avet-Loiseau, Blood 2016
MRD-negative rate, % % surviving without progression DARATUMUMAB, DRd vs. Rd POLLUX P <0.0001 MRD negative rate (10-5 ) by prior treatment status 30 25 25 100 80 Rd MRD negative DRd MRD negative 20 60 DRd MRD positive 15 10 5 6 40 20 Rd MRD positive 0 DRd Rd (n = 272) (n = 264) 1-3 prior 1-3 pl lines population No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive 0 0 3 6 9 12 15 18 21 24 27 16 68 248 204 16 68 215 185 16 68 177 170 15 67 154 160 15 63 134 154 Months 12 55 110 132 10 27 35 52 0 6 5 9 0 0 0 1 0 0 0 0 MRD-negativity is associated with a lower rate of progression PFS benefit in MRD-positive patients who received Dara-containing regimens vs. standard of care Moreau, ASH 2016
STRATEGIES at RELAPSE Age? Comorbidities? Cytogenetics? Type of relapse? Ease of administration Costs/reimbursement Efficacy of previous treatments Toxicity of previous treatments Further options ACHIEVE MAXIMAL RESPONSE
How to proceed in clinical practice? Time of relapse? Early? (<1y post-asct) Intermediate? (1-3y) Late? (>3y post-asct) Overcome drug resistance VTD-PACE VRD-Dox-C RIC-allo Prolong survival until curative treatments are developed Retreatment Reinduction ASCT 2 5-10% 80% 10%
How to proceed in clinical practice? Type of relapse? Aggressive? Rapid disease control KRd, DRd
How to proceed in clinical practice? Age? All combos work better in young patients IMiD based combos PI based combos DRd, ERd, IRd DVd, Kd
How to proceed in clinical practice? Prior lines of therapy? KRd IRd DRd ERd Kd DVd after PIs, PIs sensitive, after 1 and 2 lines after PIs, PIs sensitive, after 2 or 3 prior lines; primary refractory patients after PIs, regardless PIs sensitive, after 1 and 2 linesv after PIs, regardless PIs sensitive, time from Dx > 3.5y, regardless 1 and 2 lines after Pis/IMiDs, after 1 and 2 lines after Pis/IMiDs, after 1 line
% surviving without progression % surviving without progression POLLUX, DRd vs. Rd Lenalidomide-naïve Lenalidomide-exposed 100 18-month PFS b 100 18-month PFS b 79% 80 76% 80 DRd DRd 60 49% 60 59% Rd 40 Rd 40 20 Median: 17.1 months 20 No. at risk Rd DRd 0 HR: 0.37 (95% CI, 0.26-0.51; P <0.0001) 0 3 6 9 12 15 18 21 24 27 Months 219 226 193 212 158 200 140 190 123 180 100 157 41 71 4 14 0 1 0 0 0 No. at risk Rd DRd HR: 0.45 (95% CI, 0.20-0.99; P = 0.042) 0 3 6 9 12 15 18 21 24 45 46 38 41 35 38 29 37 Months 26 37 22 30 4 8 1 1 0 0 DRd treatment benefit maintained in lenalidomide-naïve and exposed patients Moreau, ASH 2016
% surviving without progression % surviving without progression POLLUX, DRd vs. Rd Refractory to last line of therapy 100 Bortezomib-refractory 18-month PFS b 100 18-month PFS b 80 80 60 40 20 65% 37% Median: 8.8 months DRd Rd 60 40 20 65% 40% Rd Median: 10.3 months DRd 0 HR: 0.45 (95% CI, 0.27-0.74; P = 0.0014) 0 3 6 9 12 15 18 21 24 No. at risk Months Rd DRd 67 73 52 62 38 58 29 52 25 49 21 37 14 22 1 2 0 0 0 No. at risk Rd DRd HR: 0.51 (95% CI, 0.28-0.91; P = 0.021) 0 3 6 9 12 15 18 21 24 Months 49 54 39 46 29 43 23 37 20 36 16 27 8 15 0 2 0 0 DRd treatment benefit in patients refractory to last line of therapy, including bortezomibrefractory patients Moreau, ASH 2016
How to proceed in clinical practice? KRd IRd Best option in t(4;14) and del17p (> 60% PC) DRd Improve but not overcome Cytogenetics? ERd Improve t(4;14) and overcome del17p Kd Not good for HR cytogenetics DVd Improve and almost overcome HR cytogenetics
CYTOGENETICS, DRd vs. Rd POLLUX RESPONSE by CYTOGENETICS
Kd vs. Vd ENDEAVOR Chng, Leukemia 2017
Proportion Surviving Without Progression KRd vs. Rd ASPIRE High-risk Standard-risk 1.0 1.0 0.8 0.8 0.6 0.4 Proportion Surviving Without Progression 0.6 0.4 0.2 0 0 KRd Rd 6 12 18 24 30 36 42 Months Since Randomization 0.2 0 0 KRd Rd 6 12 18 24 30 36 42 48 Months Since Randomization PFS, median months Hazard ratio (95% CI) KRd (n=48) Rd (n=52) KRd (n=147) Rd (n=170) 23.1 13.9 PFS, median months 29.6 19.5 0.703 (0.426 1.160) Hazard ratio (95% CI) 0.656 (0.480 0.897) P-value 0.0829 P-value 0.0039 KRd effective in patients with t(4;14) and del (17/17p) Avet-Loiseau, Blood 2016
ERd vs. Rd ELOQUENT-2 Elotuzumab combined to Rd improves outcome in t(4;14) and overcomes del17p Lonial, ASCO 2015
How to proceed in clinical practice? Moderate/severe cardiac avoid K Comorbidities? PN Severe COPD/asthma avoid V, I avoid D Severe thrombotic events avoid IMiDs
SUBSEQUENT RELAPSES PIs based combinations IMiDs based combinations 1 Kd, DVd, Pan-Vd, Elo-Vd KRd, DRd, Elo-Rd, Ird 2 Pd +/- something else Daratumumab Other Monoclonal antibodies
POMALIDOMIDE MM-003 STRATUS (MM-010) Pd vs. Cyclo-Pd Treatment Pd Pd Pd Cyclo-Pd PVd n 302 682 36 34 47 population Failed V and Len, refractory to last line At least 2 prior lines, Len-refractory 1-4 prior lines, Lenrefractory ORR 31% 33% 39% 65% 85% VGPR 14% 12% 45% PFS, m 4 4.6 4.4 9.5 10.7 OS, m 12.7 11.9 16.8 NR 94% EFS at 12m PVd SanMiguel, Lancet Oncol 2013; Dimopoulos, Blood 2016; Baz, Blood 2016; Lacy, ASH 2014
DARATUMUMAB monotherapy GEN-501 and SIRIUS Rapid, deep, durable responses in heavily pretreated / highly refractory MM pts Remarkable depth of response in pts refractory to newer agents including POM and Carfilzomib OS benefit even in pts who achieved a SD or MR Usmani, Blood 2016
NEW AGENTS Venetoclax Check-point inhibitors Selinexor Adoptive cell therapy
SUPPORTIVE CARE
SUPPORTIVE CARE Prevent osteonecrosis of the jaw, alert patient and dentist Consider thromboprophylaxis with IMiDs and Carfilzomib Monitor polyneuropathy Preserve renal function Avoid NSAID, IV iodine contrast media Monitor serum creatinine during Biphosphonates therapy, lenalidomide Provide adequate hydration Prevent infection Antiviral therapy Vaccination Infusion reactions with Elotumumab, Daratumumab RBC compatibility interferences with Daratumumab Cardiac monitoring (blood pressure) with Carfilzomib
CONCLUSIONS
ESMO guidelines, FRONTLINE THERAPY Yes Eligibility for ASCT No Induction: 3-drug regimens VTD VCD VRD PAD First option: VMP, Rd, VRD Second option: VCD, MPT 200 mg/m 2 melphalan followed by ASCT Other options: BP, CTD, MP Maintenance lenalidomide ASCT, autologous stem cell transplantation; BP, bendamustine-prednisone; CTD, cyclophosphamide-thalidomide-dexamethasone; E SMO, European Society of Medical Oncology; MP, melphalan-prednisone; MPT, melphalan-prednisone-thalidomide; PAD, bortezomib-doxorubicindexamethasone; Rd, lenalidomide-dexamethasone; VCD, bortezomib-cyclophosphamide-dexamethasone; VMP, bortezomib-melphalan-prednisone; VRD, bortezomib-lenalidomide-dexamethasone;vtd, bortezomib-thalidomide-dexamethasone. Moreau P, et al. Ann Oncol. 2017; in press.
ESMO Guidelines 2017, RRMM IMiD-based induction First relapse after Bortezomib-based induction Doublets Kd/Vd Bortezomib-based triplets DaraVD PanoVD EloVD VCD Rd Rd-based triplets DRd KRd IRd ERd At second or subsequent relapse Pomalidomide-dexamethasone + Cyclo or Ixa or Bort or Dara or Elo Dara (single agent or combination) Clinical trial Bort, bortezomib; Cyclo, cyclophosphamide; Dara, daratumumab; DRd, daratumumab-lenalidomide-dexamethasone; Elo, elotuzumab; ERd, elotuzumab-lenalidomide-dexamethasone; IRd, ixazomib-lenalidomide-dexamethasone; Ixa, ixazomib; Kd, carfilzomib-dexamethasone; KRd, carfilzomib-lenalidomide-dexamethasone; Pano, panobinostat; Rd, lenalidomide-dexamethasone; VCD, bortezomib-cyclophosphamide-dexamethasone; VD, bortezomib-dexamethasone. Moreau P, et al. Ann Oncol. 2017; in press.
SURVIVAL in MYELOMA