Advances in the Management of Myeloma Parameswaran Hari, MD

Transcription

1 Advances in the Management of Myeloma Parameswaran Hari, MD Medical College of Wisconsin Milwaukee, WI

2 What is the standard? Induction/Transplant/Maintenance UPDATED OS DATA from CALGB & IFM REF:

3 Current Trials Exploring Interventions For Smoldering Multiple Myeloma Study Sponsor/Study Director Intervention Status ECOG-E3A06 NCT NCI/ S. Lonial Lenalidomide vs observation Currently recruiting NCT MSKC/ C.O. Landgren Ixazomib/dex x12 cycles followed by 24 cycles of maintenance for patients PR Currently recruiting NCT PETHEMA/ San Miguel & Mateos KRd x6 cycles stem cell collection KRd 2cycles Rd maintenance 24 cycles Currently recruiting NCT Janssen Research & Development 3 schedules of Daratumumab (Long intense, intermediate, short intense) Currently recruiting NCT MD Anderson/ Manasanch Pembrolizumab 200mg IV Q21d 24 cycles Not yet open NCT DFCI/ I. Ghobrial Elotuzumab/Lenalidomide +/- Dex Currently recruiting Eligibility criteria and definition of high risk SMM varies among trials

4 Questions in Induction / Transplant Does induction matter if transplant is planned? 3 drugs or 2 drugs for Induction Which 3 drugs steroids + PI + IMID vs others Can we do better with Induction? Role of autotransplant Early ; Delayed or Never? Maintenance / Consolidation After transplant Can we improve the current standard of transplant + Lenalidomide maintenance Special Groups Some thoughts on relapse

5 SWOG S0777 RVD vs. VD Newly diagnosed MM (transplant eligible and non-eligible patients) VRd Q21d x 8 cycles vs Rd Q28d x 6 cycles Rd maintenance Survival VRd (n = 242) Rd (n = 229) HR P Value Median PFS, months ( ).0018* Median OS, months ( ).025 Durie B, et al. ASH Abstract 25.

6 IFM Phase III Trial of VTD vs VCD induction VTD Arm (n = 169) Bortezomib 1.3 mg/m 2 /day SC Days 1, 4, 8, 11 + Thalidomide 100 mg/day PO Days Dexamethasone 40 mg/day PO Days 1-4, Days 9-12 VCD Arm (n = 169) Bortezomib 1.3 mg/m 2 /day SC Days 1, 4, 8, 11 + Cyclophosphamide 500 g/m 2 /day PO Days 1, 8, 15 + Dexamethasone 40 mg/day PO Days 1-4, Days 9-12 x4 cycles ASCT Response,* % VTD (n = 169) VCD (n = 169) P Value CR VGPR PR In per-protocol analysis, trend toward significantly higher numbers of CD34+ cells harvested for stem cell transplantation with VTD vs VCD x 10 6 vs 9.17 x 10 6 CD34+ cells/kg, respectively (P =.05) *Centralized assessment by IMWG criteria 2011 Primary endpoint Moreau P, et al. ASH Abstract 393.

7 Auto-Transplant vs. Novel Drugs - Modern Studies Group No Induction Comparator > VGPR GIMEMA NEJM 2014 MultiCente r Lancet Oncol 2015 IFM 2009 ASH 2015 EMN ASH RD x4 MPR x6 ASCT x2 389 RD x4 CDR x6 ASCT x2 700 VRD x3 VRD x5 ASCT + VRD x VCD x3-4 VMP x4 ASCT 1 or * 74 85* All of them are early vs. late transplant studies too PFS 22mo median 43mo* 29mo 43mo* 34mo 43mo* 3 yrs 65% HR 0.73* OS 65% 4y 81%* 68% 4y 77%* 83% 4y 81% NS (short fu)

8 Determination Trial Phase III IFM/DFCI 2009 Role of Early vs Delayed Transplant in the Era of Novel Agents MRD MRD N = 700 Pts 65 yrs of age Symptomatic, measurable NDMM VRd* 3 cycles VRd* 8 cycles MEL200 ASCT VRd* 2 cycles consolidation Lenalidomide Maintenance** Primary objective: PFS Secondary objectives: ORR, MRD, TTP, OS, Safety *VRD: bortezomib 1.3 mg/m 2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. ** till POD in US trial and 12 months in IFM trial Included PBSC collection with cyclophosphamide 3 g/m 2 + G-CSF after cycle 3. Avet-Loiseau H, et al. ASH Abstract 191.

9 IFM 2009 PFS / OS Response, % VRD Transplant CR VGPR MRD Neg FCM Attal M et al. N Engl J Med 2017;376:

10 IFM 2009 MRD Status

11 Treatment Schema MMRC U Chicago Protocols SCC + ASCT MRD at 8 cycles KRd+ASCT (4-week cycle) KRd induction (Cycles 1-4) KRd Consolidation (Cycles 5-8) KRd Maintenance (Cycles 9-18) MRD at 4 cycles Considered promising if scr improves from 30% to 50% at 8 cycles KRd w/o ASCT (4-week cycle) KRd induction (Cycles 1-4) KRd Consolidation (Cycles 5-8) KRd Maintenance (Cycles 9-24) SCC for eligible pts MRD at CR* MRD at 18 cycles LEN maintenance (off protocol) Zimmerman T et al ASH 2016; Abstract 675

12 Response Rates Over the Course of Treatment Aggressive Induction does not eliminate the need for ASCT KRd + ASCT KRd w/o ASCT Response, % cycles n=75 Response after ASCT (n=71) 11 8 cycles n=70 90% 44% 27% 21% 18 cycles n= cycles n= cycles 18 cycles n=44 n=41 VGPR ncr CR scr VGPR ncr CR scr KRd+ASCT shows high rates of deep responses in NDMM, with higher rates of scr compared with KRd w/o ASCT at pre-specified time point of 8 cycles 63% vs 30% Best response 74% vs 55%

13 Studies Included in Meta-Analysis CALGB (accrual 8/ /2009) IFM (accrual 6/2006 8/2008) GIMEMA (RV-MM-PI-209) (accrual 11/2007 7/2009) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD ASCT 2 2 DESIGN LEN + DEX 4 INDUCTION MPR: 6 COURSES LEN: 2 COURSES PLACEBO (n = 229) LEN Maint a (n = 231) PLACEBO (n = 307) LEN Maint a (n = 307) NO TREATMENT (n = 67) LEN Maint b (n = 67) NO TREATMENT LEN Maint b INTERIM ANALYSIS ANDINTERIM UNBLINDING ANALYSIS AND UNBLINDING Dec 2009 Dec 2009 Jan 2010 PRIMARY ANALYSIS CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT NO CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT ALL TREATMENT DISCONTINUED Jan 2011 CONTINUED TREATMENT Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day after 3 mos if tolerated and continued until PD. b Patients received 10 mg/day on days 1-21/28 until PD. ASCT, autologous stem cell transplant; LEN, lenalidomide; maint, maintenance; MPR, melphalan, prednisone, and lenalidomide; NDMM, newly diagnosed multiple myeloma; maint, maintenance; PD, progressive disease. CONTINUED TREATMENT Attal M et al ASCO 2016 McCarthy P et al EHA 2016 McCarthy P et al IMW 2017

14 Overall Survival: Median Follow-Up of 80 Months There is a 25% reduction in risk of death, representing an estimated 2.4- year increase in median survival (March 2015 data cutoff) a yr OS Survival Probability Events/n Median OS HR (95% CI) (95% CI), mo P value LEN maint 215/605 NR (NR-NR) 0.75 ( ) Placebo/.001 Observation 275/ ( ) Overall Survival (Months) No. at Risk LEN maint Placebo/ Observation a Log-rank test and Cox model stratified by study to assess impact of lenalidomide maintenance on overall survival. Median for lenalidomide treatment arm was extrapolated to be 115 months based on median of the control arm and HR (median, 86 months; HR = 0.75). HR, hazard ratio; maint, maintenance; NR, not reached; OS, overall survival. 50% 62% Attal M et al ASCO 2016 McCarthy P et al EHA 2016 McCarthy P et al IMW 2017

15 Summary Transplant is key Early better than collect and hold Induction matters as induction improves post transplant outcomes improved Lenalidomide maintenance benefits >> risk Standard of Care 3 drug induction (PI / IMID / Steroid) Melphalan based Auto Lenalidomide maintenance

16 Multiple Myeloma, Circa 2017 Treatment initiation dictated by presence of morbidity Therapy anchored on proteasome inhibitors, IMId and corticosteroids Treatment stratification based mostly in age One size fits all treatment approach Success defined by improvement in surrogates of gross disease Continuous therapy until failure/intolerance Most patients will die from MM

17 Newer Studies EU and US

18 Myeloma XI+ TE TNE R 1:1:2 Induction CTD Cyclophosphamide: 500mg d1,8,15 Thalidomide: mg daily Dexamethasone: 40mg d1-4,12-15 To max response/intolerance Dose reduced for TNE CRD Cyclophosphamide: 500mg d1,8 Lenalidomide: 25mg d1-21 Dexamethasone: 40mg d1-4,12-15 To max response/intolerance Dose reduced for TNE CCRD Cyclophosphamide: 500mg d1,8 Carfilzomib: 20/36 mg/m 2 d1-2,8-9,15-16 Lenalidomide: 25mg d1-21 Dexamethasone: 40mg d1-4,8-9,12-15 To max response/intolerance Not for TNE R 1:1 * Consolidation CVD Cyclophosphamide: 500mg d1,8,15 Velcade: 1.3mg/m 2 d1,4,8,11 Dexamethasone: 20mg d1-2,4-5,8-9,11-12 Dose reduction for TNE No further treatment ASCT (TE only) R 2:1 Lenalidomide No maintenance TE: Transplant eligible TNE: Transplant non-eligible Decision based on individual patient factors including age, co-morbidities and patient/clinician discussion. * Patients with NC/PD response to initial IMiD all received CVD consolidation

19 Transplant eligible Significant improvement in PFS from 28 to 50 months, HR=0.47 Median PFS, months [95% CI] 100 Lenalidomide (n=451) 50 [44, ] Patients alive and progression-free (%) Observation (n=377) 28 [23, 32] HR=0.47; 95% CI 0.38, 0.60 Log-rank p< Time since randomisation (months) No. of patients at risk: Lenalidomide Observation Jackson GH et al ASH 2016, Courtesy G Morgan

20 Daratumumab ASCT Hovon/IFM R Induction 4 cycles VTD + Dara VTD Endpoints: scr PFS, OS HDM ASCT Consolidation 2 cycles VTD + Dara VTD Stratify by: dara treatment, response, MRD status R Maintenance Until progression Dara Observation Courtesy P Sonneveld

21 Alliance Len +/-Daratumumab post ASCT for NDMM MEL 200 Auto Transplant RESTAGE D MRD & IP Lenalidomide Lenalidomide Daratumumab 1 year 2 years

22 Multiple Myeloma: US Cooperative Group Trials E3A06 Phase II S0777- Rd vs VRd E1A06 - MPT vs. MPR CTN 0702 Phase III CALGB Len vs PBO Stem Cell Transplant Asymptomatic & Early E3A06 R vs. Obs A Plasmacytoma Z vs ZI Induction Rx E1A11: CRd vs VRd S1211: VRd vs. VRd Elo BMTCTN 1302: High risk Allo DETERMINATION: RVD Early vs Late HSCT A:Rd vs Rd Dara for HSCT Ineligible A: RVd vs RVd Dara HSCT Eligible Non Transplant Consolidation Maintenance E1A11 R 2 yrs vs until PD BMT CTN 1401 Len vs Len DC Vaccine post Extension of R 0702 S:R vs RI post Auto? A: R Dara vs R post HSCT? Relapse S1304: K high vs, low dose A061202: PDI vs PD RRMM: no prior BMT PDI vs HSCT?

23 Survival and PFS after HCT Older patients derive similar benefit Sharma M et al; Biol Blood Marrow Transplant Nov;20(11):1796

24 Cox Regression Analysis of Overall Survival by HCT-CI score P=NS Cumulative Survival Out patient Transplant Experience at KU N= 448 pt ( ) Obiozor et al BBMT 2017 Follow Up (years)

25 Renal Impairment should not restrict HCT for MM Overall Survival (p-value=0.602) Probability, % Progression-free Survival (p-value=0.124) Normal/Mild Moderate Severe Years Mahindra A et al ASH abstract

26 Post induction + ASCT-1 followed by: BMT CTN0702 STaMINA Trial Results R Maint only n=257 RVD R n=254 Double ASCT R n=247 Median PFS, mos Median OS, mos High-risk patients, n mos mos Median PFS, Median OS, No significant difference between the study arms ClinicalTrials.gov. NCT

27 Dispenzieri A, et al. Mayo Clin Proc. 2007;82: Kumar SK, et al. Mayo Clin Proc. 2009;84: Mikhael JR, et al. Mayo Clin Proc. 2013;88: NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Chng WJ, et al. Leukemia. 2014;28: MM Risk Categories Risk Factors FISH Cytogenetics Standard Risk (80%) (Expected OS: 6-7 Yrs) t(11;14), t(6;14) Hyperdiploidy High Risk (20%) (Expected OS: 2-3 Yrs) del(17p), t(4;14)* t(14;16), +1q21 Hypodiploidy del(13q) β 2 -microglobulin* Low (< 3.5 mg/l) High ( 5.5 mg/l) PCLI < 3% High ( 3%) Gene expression profile Good risk High risk Other high risk features: Extramedullary disease Plasma cell leukemia Plasmablastic morphology *Patients with t(4;14), β 2 -microglobulin < 4 mg/l, and Hb 10 g/dl may have intermediate-risk disease.

28 VRd Maintenance After ASCT in High Risk Disease 45 patients received VRd maintenance after ASCT for 2 years Bortezomib 1.3mg/m 2 weekly Lenalidomide 10mg d1-21 Dexamethasone 40mg weekly. High-risk Features n (%) Del 17p 19 (42) Del 1p 9 (20) T (4;14) 2 (5) T (14;16) 5 (11) PCL 11 (24) Others (aggressive presentation) 7 (16) > 1 Cytogenetic abnormalities 34 (75) PFS: 32 months 3-year OS: 93% Post-induction Response Post-ASCT day 60 Best Response Response scr% scr+cr % VGPR % ORR % SD % PD % from: Nooka, AK, et al. Leukemia ,

29 Non-Transplant Candidates Carefully evaluate transplant eligibility Moving target on who is eligible Assess after induction Medicare: Age NOT a barrier Moving beyond Lenalidomide/ Dec

30 SWOG S0777 Survival and Safety RVd vs. Rd Survival VRd (n = 242) Rd (n = 229) HR P Value Median PFS, months ( ).0018* Median OS, months ( ).025 Adverse Event Grade 3 AE Neurologic Pain Sensory Gastrointestinal VRd,% (n = 241) Rd, % (n = 226) SPM P Value < NR Durie B, et al. ASH Abstract 25.

31 Ongoing Studies For Newly Diagnosed MM Patients Ineligible For Transplant Study Sponsor/Study Director Intervention Status Eloquent-1 NCT Bristol-Myers Squibb/AbbVie Len/dex +/- Elotuzumab Ongoing, but not recruiting MAIA Trial NCT Janssen Research & Development, LLC Len/dex +/- Daratumumab Currently recruiting KEYNOTE-185 NCT Merck Sharp & Dohme Corp. Len/dex +/- Pembrolizumab Currently recruiting

32 MODERN TRIPLETS FOR RELAPSE Carfilzomib Len Dex Ixazomib Len Dex Elotuzumab Len Dex Daratumumab Len -Dex Vs. LEN - Dex Bortezomib Panabinostat Dex Bortezomib - Daratumumab- Dex Vs. BTZ - Dex

33 Summary of PFS Rd 10 KRd IRd EloRd 5 0 ASPIRE TOURMALINE ELOQUENT-2 Trial Design PFS Invest. arm PFS Rd arm HR ASPIRE Rd vs KRd 26.3mo 17.6mo 0.69 TOURMALINE Rd vs IRd 19.4mo 14.9mo 0.70 ELOUQUENT-2 Rd vs EloRd 20.6mo 14.7mo 0.74 Moreau, P. et al. ASH 2015 Abstract 727 Lonial, S. et al. N Engl J Med. 2015; 373: Stewart, et al. N Engl J Med. 2015;372:

34 VGPR Rates/PFS with Triplet vs Doublet Regimens Odds of Achieving VGPR in Early Relapse Trial Odds Ratio Lower Limit Upper Limit P-Value PANORAMA MM VAR/IFM ELOQUENT ASPIRE POOLED ODDS RATIO Odds Ratio and 95% CI for Achieving VGPR Doublet Better Triplet Better Pooled Hazards Ratio: PFS Trial Hazard Ratio Lower Limit Upper Limit z-value P-Value PANORAMA MM VAR/IFM Hazard Ratio and 95% CI for PFS ELOQUENT ASPIRE POOLED ODDS RATIO Nooka, et al. Blood. 2015;126: Triplet Better Doublet Better 34

35 MAb-Based Targeting of Myeloma Antibody-dependent cellular cytotoxicity (ADCC) Effector cells: FcR Complement-dependent cytotoxicity (CDC) C1q CDC MM C1q Apoptosis/growth arrest via targeting signaling pathways MM ADCC MM Daratumumab (CD38) SAR (CD38) Daratumumab (CD38) SAR (CD38) Elotuzumab (SLAMF7) Daratumumab (CD38) SAR (CD38) Tai YT, et al. Bone Marrow Res. 2011;2011:

36 CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study Key eligibility criteria RRMM 1 prior line of therapy Prior bortezomib exposure, but not refractory R A N D O M I Z E 1:1 DVd (n = 251) Daratumumab (16 mg/kg IV) Every week - cycle 1-3 Every 3 weeks - cycle 4-8 Every 4 weeks - cycles 9+ Vel: 1.3 mg/m 2 SC, days 1,4,8,11 - cycle 1-8 dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 Vd (n = 247) Vel: 1.3 mg/m 2 SC, days 1,4,8,11 - cycle 1-8 dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 Primary Endpoint PFS Secondary Endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Cycles 1-8: repeat every 21 days Cycles 9+: repeat every 28 days Daratumumab IV administered in 1000 ml to 500 ml; gradual escalation from 50 ml to 200 ml/min permitted RRMM, relapsed or refractory multiple myeloma; DVd, daratumumab/bortezomib/dexamethasone; IV, intravenous; Vel, bortezomib; SC, subcutaneous; dex, dexamethasone; PO, oral; Vd, bortezomib/dexamethasone; PFS, progression-free survival; TTP, time to progression; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 36

37 Proportion surviving without progression No. at risk Vd DVd Progression-free Survival Months Median : 7.2 months HR: 0.39 (95% CI, ); P< *KM estimate; HR, hazard ratio Median : not reached year PFS* % 26.9% Vd 0 0 DVd 61% reduction in the risk of disease progression or death for DVd vs Vd

38 POLLUX LENALIDOMIDE + DARA

39 POLLUX STUDY

40 4 Major Triplets for Relapsed MM

41 We don t know which triplet is better KRD IRD ERD DRD DVD DPD Comparison of HR across trials is not the answer Odds of winning does not inform us about the margin of victory Triplet vs. Doublet designs looking at PFS are of marginal benefit to the field

42

43 ROLE OF RETRANSPLANTATION

44 Myeloma X: High-dose Melphalan + Salvage ASCT vs Cyclophosphamide in R/R MM R/R MM; > 18 mos after prior ASCT (N = 293) PAD induction 2-4 cycles Melphalan 200 mg/m2 IV + ASCT (n = 89) Cyclophosphamide 400 mg/m2/wk PO x 12 cycles (n = 85) PAD induction therapy: bortezomib + doxorubicin + dexamethasone 2-4 cycles PBSC mobilization and harvesting if applicable Removed from study if PD or CD34+ cells < 2 x 106/kg Primary endpoint: time to disease progression Secondary endpoints: OR, PFS, OS, toxicity, safety, pain, QoL Cook G, et al. Lancel Oncol. 2014;15:

45 Myeloma X: Salvage Transplant at Relapse Randomized 1:1 R/R MM; >18 mos after prior ASCT (N = 293) Cook G et al; Lancet Haematol Jul;3(7):e PAD induction 2-4 cycles Melphalan 200mg/m2 IV + ASCT (n = 89) Cyclophosphamide 400mg/m2 PO/wk x12 cycles (n = 85)

46 KEYNOTE-023: Efficacy of Pembrolizumab + Len/Dex in R/R MM All ResponseEvaluable Pts (n = 17) LenalidomideRefractory Pts (n = 9) ORR, n (%) VGPR PR 13 (76) 4 (24) 9 (53) 5 (56) 2 (22) 3 (33) Disease control rate, n (%) 15 (88) 7 (78) Outcome Median time to first response, mos (range) 1.2 ( ) M-protein reduction 50% from baseline, % 76.5 Median DoR, mos 9.7 San Miguel J, et al. ASH Abstract 505.

47 CHECK POINT INHIBITION AFTER ASCT Correlative Studies Effects of anti-pd-1 on T- and NK-cell function Correlation of immune cell phenotypes in the autologous graft and outcomes Study Schema Lenalidomide Transplant Pembrolizumab 200 mg IV Melphalan 0 * * Graft Sample Blood Samples CR conversion rate at day 180

48 Newer and Fancier Immunotherapy BCMA CAR-T cells CAR-BCMA T cells specifically recognized BCMA Exhibited antimyeloma activity in humans. Reliable Elimination of MM plasma cells Even works in chemotherapy refractory Need higher doses than CART19? Deep Remissions induced Toxicity incl. CRS Relapses noted despite CR Soluble BCMA Not a factor Syed Abbas Ali et al. Blood 2016;128:

49 BCMA CART early data 11 pts screened, and 6 treated in cohort 1. Grade 4 PRES Grade 3 CRS Adam D. Cohen et al. Blood 2016;128:1147

50 Allogeneic Transplantation can cure some patients with MM Graft versus Tumor Effect ( Allo Effect ) Graft versus Myeloma effect? Donor Lymphocyte infusion induce Tail of survival remission Chronic GVHD lowers relapse risk CRUDEST and OLDEST Immunotherapy for MM Prospect of long term disease control Agnostic to traditional risk markers Gahrton G et al N Engl J Med Oct 31;325(18):1267

51 Are there any pts who benefit from AlloHCT now? 1. High risk subset is allo better? Risk defined by.? When should allo be done? 2. Is an allogeneic immune system better for some pts? Can we use an allo immune system better as a platform for immune modulation?

52 Can upfront Allotransplant cure high risk? Author N HIGH RISK DEFINITION High risk Allo vs. Auto EBMT NMAM 92 Deletion 13 q PFS - 8 years 21% vs. 5% OS - 8 years 47% vs. 31% Knop 199 DEL 13q + DEL 17p Median PFS NR vs. 6 mo Median OS NR vs. 23 mo Hi Risk MM < 65 years N Tandem AUTO 1:1 Auto #1 Flu MEL +-ATG ALLO with Sib or URD (incl 9/10) Knop S et al; ASH abstract 2014 Dec #43 2-year PFS 59% vs. 47% with Auto. 2 Yr PFS

53 Post-relapse Survival: Is relapse after Allo different? Adjusted Probability, % 100 AUTO/AUTO vs. AUTO/ALLO ( 12 months after relapse) HR = 0.72( ) p-value = AutoAllo (n=178) AutoAuto (n=404) Identical 60 Results from randomized EBMT study Gahrton et al Blood Novel therapies augment immune response vs. MM and help in the setting of post allo relapse AUTO/AUTO vs. AUTO/ALLO (>12 months) 20 HR = 1.55( ) p-value = Years Htut et al 2016 ASH abstract

54 Patient selection: Early Relapse after Auto Consider Allo

55 Additional Agents Currently in Early Phase Development Agent MOA Clinical Trial Phase Ibrutinib Tyrosine kinase inhibitor (BTK, ERK1/2, others) I and II Filanesib Kinesin spindle protein inhibitor II Indatuximab ravtansine CD138 antibody-drug conjugate I and II HDAC inhibitor I and I/II XPO1 nuclear transport inhibitor I and II anti-cd38 antibody I/II Selective BCL-2 inhibitor I Ricolinostat Selinexor (KPT-330) MOR202 (MOR03087) Venetoclax Clinicaltrials.gov 55