www.comtecmed.com/comy comy@comtecmed.com IMiDs (Immunomodulatory drugs) and Multiple Myeloma Xavier Leleu Service des Maladies du Sang Hôpital Huriez, CHRU, Lille, France
www.comtecmed.com/comy comy@comtecmed.com Disclosure of Conflict of Interest (List) Celgene Lecture fees, board, other honorarium Janssen Lecture fees, board Millenium/Takeda Lecture fees, board Onyx/Amgen Lecture fees, board LeoPharma Lecture fees, board Novartis Lecture fees
Patients (%) Approval of Novel Agents has Improved OS 1 Overall Survival from Time of Diagnosis 1971 26 8 6 1971-1976 1977-1982 1983-1988 1989 2 21-26 Diagnosis Period Median OS 1971 1996 1 3 months 1996 26 1,a 45 months p value p <.1 4 2 21 26 a 21 25 2 55 months 26-21 2 73 months p =.2 2 4 6 8 1 12 14 Time (months) Sustained improvement in OS seen over the 26-21 diagnosis period Improvement in OS over this period attributed to use of novel agents and ASCT a Approval of Bort-, Thal-, and Len-containing regimens occurred during this time. 1. Kumar SK, et al. Blood. 28;111:2516-2. 2. Kumar SK, et al. Leukemia. 213.
Proportion Surviving Proportion Surviving Continued Improvement in OS in Novel-Agent Era There are 138 patients grouped into 21 25 and 26 21 cohorts Use of novel agents in treatment regimens improved OS 1. 1..8.6 26-21.8.6 Received Novel agents.4 21-25.4 No Novel agents.2.2 1 2 3 4 5 6 Follow up from diagnosis (years) 1 2 3 4 5 6 Follow up from diagnosis (years) Survival 21 25 26 21 p Median OS, years 4.6 6.1.2 6-year estimated OS, % 4 51 <.1 Kumar SK, et al. Leukemia. 213.
Approval Timelines (EU) for Novel Therapies 28 June 213 Approved for RRMM 2 April 25 Bort (IV) as monotherapy for RRMM patients who received 1 prior treatment and who have undergone or are ineligible for BMT Approved for NDMM 29 August 28 Bort (IV) in combination with MP approved for NDMM patients ineligible for HDT with BMT 2 September 212 Bort (SC) as monotherapy for RRMM patients who received 1 prior treatment and who have undergone or are ineligible for BMT Bort in combination with TD approved for SCT-eligible NDMM patients 24 25 26 27 28 29 21 211 212 213 26 April 24 Bort (IV) approved for RRMM patients who failed to respond to 2 prior treatment 14 June 27 Len in combination with DEX in RRMM patients who received 1 prior treatment a EMA approval dates can only be verified from 24 to the present. BMT, bone marrow transplant; EMA, European Medicines Agency; EU, European Union; IV, intravenous; SC, subcutaneous. 16 April 28 Thal in combination with MP in NDMM patients aged 65 years or ineligible for HDT 5 August 213 Pom + LoDex in relapsed and refractory patients with 2 prior regimens including Len and Bort EMA. http://www.ema.europa.eu/ema/.
IMiDs (Immunomodulatory drugs)
IMiDs share a Phtaloyl ring Pthaloyl ring O N O H N O Glutarimide ring Lenalidomide O Thalidomide O N O H N O Additional amino group N H 2 Carbonyl removed Additional amino group Pomalidomide
IMiDs share mechanism of action: Overview Anti-myeloma Tumour suppressor gene upregulation and oncogene inhibition 1 4 Induction of cell-cycle arrest and apoptosis 1 5 Effects in drug-sensitive and drug-resistant cells 1 5 Stromal inhibition Inhibition of osteoclast differentiation 6,7 Inhibition of growth factor production 8 Inhibition of angiogenesis 9 IMiDs: Pomalidomide Immunomodulatory Enhanced immune function 8,1 14 Increased NK-mediated MM lysis 14,15 MM, multiple myeloma; NK, natural killer.
Molecular Structure of IMiDs (Immunomodulatory drugs)
Antitumor Activity of Thalidomide in Refractory Multiple Myeloma Seema Singhal, et al 1999;341:1565
SYSTEMATIC REVIEW OF PHASE II TRIALS OF THALIDOMIDE MONOTHERAPY IN RELAPSED MM Glasmacher A, Br J Haematol 25-42 communications (24 full papers) - 1629 patients - median dose > 2 mg/d in 86% of cases CR or VGPR (> 9%) 1.6 PR (>5%) 27.8 43.2% MR 13.8 - Survival data 1 year EFS 35 %, median EFS : 3 to 16 months 1 year SV 6 %, median SV : 14 months
Proportion of patients Proportion of patients MP versus MPT and MP versus MEL1 in newly diagnosed elderly MM patients: response* 1..8 Overall survival MP MPT MEL1 1..8 Progression-free survival MP MPT MEL1.6.6.4.4.2.2 12 24 36 48 6 72 84 Time from randomization (months) 12 24 36 48 6 72 Time from randomization (months) Treatment PFS, months p value OS, months p value MP (n = 196) 17.8 ± 1.4 33.2 ± 5.8 <.1.1 MPT (n = 125) 27.5 ± 2.1 51.6 ± 4.5.2.4 MEL1 (n = 126) 19.4 ± 1. 38.3 ± 2.7 * Median follow-up time: 51.5 months (IQR 34.4 63.2). Facon T, et al. Lancet. 27;37:129-18.
MPT vs MP for previously untreated elderly patients with MM: Meta-analysis of 1685 individual-patient data from 6 randomized trials Survival proportion..2.4.6.8 1. PFS HR=.67 in favor of MPT, p<.1 Median 14.9 mos (14.-16.6) Median 2.3 mos (18.8-21.6) MPT MP 12 24 36 48 months..2.4.6.8 1. OS HR=.83 in favor of MPT, p=.5* Median 39.3 mos (35.6-44.6) Median 32.7 mos (3.5-36.6) MPT MP 12 24 36 48 months *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model Fayers et al. Blood 211;118:1239-1247
Phase III trial of Thal + Dex compared with Dex alone in NDMM (MM-3) Multi-centre phase III study 47 patients with untreated symptomatic MM R A N D O M I Z A T I O N Thal/Dex (n = 235) Thalidomide: 5 mg/day escalating to 1 mg/day on day 15, and to 2 mg/day from day 1 of cycle 2 + dexamethasone: 4 mg on days 1 4, 9 12, and 17 2 (cycles 1 4), and days 1 4 (cycle 5 + ) Placebo/Dex (n = 235) Placebo: as for thalidomide above + dexamethasone: as for above 28-day cycles repeated until disease progression or unacceptable toxicity Stratification according to age, ECOG performance status, and 2 -microglobulin Primary end-point TTP ECOG = Eastern Cooperative Oncology Group; NDMM = newly diagnosed MM. Data from Rajkumar SV, et al. J Clin Oncol. 28;26:2171-7.
Proportion of subjects with no progression Thal + Dex vs Dex in newly diagnosed MM (MM-3): TTP and overall survival Proportion of subjects surviving 1.9.8.7.6.5.4.3.2.1 Time to progression (TTP) HR (95% CI):.43 (.32.58) Thal + Dex Placebo + Dex Censored p <.1 2 4 6 8 1 12 14 16 Time (weeks) Thal + Dex median time to progression: 22.6 months Placebo + Dex median time to progression: 6.5 months 1.9.8.7.6.5.4.3.2.1 Overall survival Thal + Dex Placebo + Dex Censored 2 4 6 8 1 12 14 16 Time (weeks) Data from Rajkumar SV, et al. J Clin Oncol. 28;26:2171-7.
Molecular Structure of Imids (Immunomodulatory drugs) 18
N Engl J Med 27;357:2123 MM9 Weber et al. NEJM 27
Lenalidomide + Dexamethasone in RRMM: Two Phase 3 Trials North American MM-9 (48 centres in the US, Canada; n = 353) 1 International MM-1 (5 centres in Europe, Australia, Israel; n = 351) 2 Mean follow-up length of MM-9: 17.6 months, MM-1: 16.4 months Len: 25 mg, Days 1 21 a Placebo: Days 1 21 a Dex: 4 mg, Days 1 4, 9 12, 17 2 for the first 4 cycles; 4 mg, Days 1 4 for subsequent cycles a Dex: 4 mg, Days 1 4, 9 12, 17 2 for the first 4 cycles; 4 mg, Days 1 4 for subsequent cycles a Continue until disease progression a Each course of treatment lasted 28 days. Len, Lenalidomide; Dex, dexamethasone 1. Weber DM, et al. N Engl J Med. 27;357:2133-42. 2. Dimopoulos M, et al. N Engl J Med. 27;357:2123-32.
Patients, % Lenalidomide + Dexamethasone Significantly Prolonged TTP vs Placebo + Dexamethasone 1,2 1 8 6 Study Treatment n Median TTP p value MM-9 Len + Dex 177 11.1 months 1 <.1 MM-9 Placebo + Dex 176 4.7 months 1 MM-1 Len + Dex 176 11.3 months 2 <.1 MM-1 Placebo + Dex 175 4.7 months 2 4 2 5 1 15 2 25 TTP, Months TTP with Lenalidomide + dexamethasone was significantly longer compared to placebo + dexamethasone in both trials (p <.1) 1. Weber DM, et al. N Engl J Med. 27;357:2133-42. 2. Dimopoulos M, et al. N Engl J Med. 27;357:2123-32.
Patients, % Pooled MM-9/MM-1 Analysis: Lenalidomide + Dexamethasone Significantly Prolonged OS 1 8 Treatment Median OS p value Len + Dex 38. months.45 Placebo + Dex 31.6 months 6 4 2 2 4 6 8 OS, Months Cross-over rate from Placebo + dexamethasone to Lenalidomidebased therapy was 47.6% Dimopoulos MA, et al. Leukemia. 29;23:2147-52.
Safety Profile of Lenalidomide + Dexamethasone in RRMM AE, n (%) Lenalidomide + Dex Placebo + Dex Neutropenia 125 (35.4)** 12 (3.4) Thrombocytopenia 46 (13.)** 22 (6.3) Anaemia 38 (1.8)* 21 (6.) Pneumonia 32 (9.1) 19 (5.4) All thromboembolic events 56 (15.9)** 19 (5.4) Hyperglycaemia 27 (7.6) 27 (7.7) Fatigue 23 (6.5) 17 (4.9) Pooled analysis from MM-9 and MM-1: grade 3 AEs occurring in more than 5% of patients 1 *p <.1; ** p <.5. Dimopoulos MA, et al. Leukemia. 29;23:2147-52.
Average Incidence (per 1 Person-Months) Hazard Rates of Haematologic AEs in Patients Continuously Treated With Lenalidomide + Dexamethasone 3 2 MM-9 and MM-1 Subgroup Analysis: 212 (of 353) Patients Who Achieved PR Neutropenia Thrombocytopenia Thrombotic events 24 1 3 6 9 12 15 18 21 24 27 Time, Months Months 3 6 9 12 15 18 21 24 27 N 174 173 16 149 127 97 47 18 3 Neutropenia events 14 24 25 26 24 17 11 1 Thrombocytopenia events 1 5 3 1 2 1 1 Thrombotic events 12 13 1 3 1 San Miguel JF, et al. Clin Lymphoma Myeloma Leuk. 211;11:38-43.
Incidence Rate (per 1 Person-Months) Incidence Rate (per 1 Person-Months) Neuropathy Risk Decreased During Lenalidomide + Dexamethasone Treatment Regardless of History of Neuropathy 25 MM-9 and MM-1 Subgroup Analysis 5. 4.5 With History of Neuropathy 5. 4.5 Without History of Neuropathy 4. 4. 3.5 3. 2.5 Severity Grade 1 Grade 2 Grade 3 3.5 3. 2.5 Severity Grade 1 Grade 2 Grade 3 2. 2. 1.5 1.5 1. 1..5.5 3 6 9 12 15 18 21 24 27 Time, Months 3 6 9 12 15 18 21 24 27 Time, Months Delforge M, et al. Blood. 29;114:149. [abstract 3873].
Patients, % MM-9/1: Trend Toward Improved Median Survival With Continued Therapy After Achievement of Response 1 Patients discontinuing Len + Dex (n = 38) Patients continuing Len + Dex (n = 174) 8 6 4 2 Median OS: 5.9 vs 35. months; p =.594 1 2 3 4 5 6 OS, Months San Miguel JF, et al. Clin Lymphoma Myeloma Leuk. 211;11:34-43.
MM-9/1: Continuous Treatment With Lenalidomide and Dexamethasone Did Not Increase the Incidence of Gr 3 AEs Grade 3 Adverse Event, n (%) Patients (n = 174) 1 Total population (n= 351) 2 Neutropenia 72 (41) 125 (35) Thrombocytopenia 2 (12) 46 (13) Thrombotic events 19 (11) 56 (16) Hyperglycaemia 15 (9) 27 (8) Anaemia 13 (8) 38 (11) Pneumonia 13 (8) 32 (9) Hypokalaemia 1 (6) 2 (6) 112 patients (64%) required lenalidomide dose reductions/interruptions due to adverse events 42 patients (24%) received G-CSF support G-CSF, granulocyte-colony stimulating factor. 1. San Miguel JF, et al. Clin Lymphoma Myeloma Leuk. 211;11:34-43. 2. Dimopoulos MA, et al. Leukemia. 29;23:2147-52.
MM-15: Study Design * All patients received thromboprophylaxis during induction; thromboprophylaxis could be continued during maintenance at physician s discretion. Dex: dexamethasone; ISS: International Staging System; M: melphalan; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by Lenalidomide maintenance; P: prednisone; PBO: placebo; R: Lenalidomide. Palumbo A. N Engl J Med. 212;366:1759-69. MED/MM/REV/212.4/25
Patients (%) MM-15: Progression-Free Survival MPR-R significantly extended median PFS vs. MP and MPR 1 75 MPR-R MPR MP Median PFS 31 months 14 months 13 months 5 25 HR (P value) MPR-R vs. MPR:.49; P <.1 MPR-R vs. MP:.4; P <.1 5 1 15 2 25 3 35 4 Time (months) HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by Lenalidomide maintenance; N/A: not applicable; PFS: progression-free survival. Palumbo A. N Engl J Med. 212;366:1759-69. MED/MM/REV/212.4/25
Patients (%) MM-15: Overall Survival After a median follow-up of 3 months, the number of deaths was low (31% event rate) and comparable across all arms 3-year OS 1 75 MPR-R 7% MPR 62% MP 66% 5 25 HR (P value) MPR-R vs. MPR:.79; P =.25 MPR-R vs. MP:.95; P =.81 1 2 3 4 5 Time (months) HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by Lenalidomide maintenance; N/A: not applicable; OS: overall survival. Palumbo A. N Engl J Med. 212;366:1759-69. MED/MM/REV/212.4/25
FIRST Trial: Study Design RANDOMIZATION 1:1:1 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx Screening Active Treatment + PFS Follow-up Phase LT Follow-Up Arm A Continuous Rd LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 4mg D1,8,15 & 22/28 Arm B Rd18 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 4mg D1,8,15 & 22/28 Arm C MPT MEL + PRED + THAL 12 Cycles 1 (72 wks) MELPHALAN PREDNISONE THALIDOMIDE.25mg/kg D1-4/42 2mg/kg D1-4/42 2mg D1-42/42 Pts > 75 yrs: Lo-DEX 2 mg D1, 8, 15 & 22/28; THAL 2 (1 mg D1-42/42); MEL 2.2 mg/kg D1 4 Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1 Facon T, et al. Lancet 27;37:129-18; 2 Hulin C, et al. JCO. 29;27:3664-7. Facon T, et al. Blood. 213;122:abstract 2.
FIRST Trial: Final Progression-free Survival Patients (%) 1 8 6 Median PFS Rd (n=535) 25.5 mos Rd18 (n=541) MPT (n=547) Hazard ratio Rd vs. MPT:.72; P =.6 Rd vs. Rd18:.7; P =.1 Rd18 vs. MPT: 1.3; P =.7349 2.7 mos 21.2 mos 4 42% (Rd) 2 23% (Rd18) 23% (MPT) 6 12 18 24 3 36 42 48 54 6 Time (months) Rd 535 4 319 265 218 168 15 55 19 2 Rd18 541 391 319 265 167 18 56 3 7 2 MPT 547 38 34 244 17 116 58 28 6 1 mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 213;122:abstract 2.
Patients (%) FIRST Trial: Overall Survival Interim Analysis 1 8 574 deaths (35% of ITT) 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% 6 4 2 Hazard ratio Rd vs. MPT:.78; P =.168 Rd vs. Rd18:.9; P =.37 Rd18 vs. MPT:.88; P =.184 Rd Rd18 MPT 6 12 18 24 3 36 42 48 54 6 Overall survival (months) 535 541 547 488 55 484 457 465 448 433 425 418 43 393 375 338 324 312 224 29 25 121 124 16 43 44 3 5 6 3 Facon T, et al. Blood. 213;122:abstract 2.
IFM 25-2: Study Design and Endpoints Primary endpoint: PFS Secondary endpoints: ORR, EFS, OS Consolidation 2 28-day cycles Maintenance until progression N = 614 NDMM; < 65 years of age SD within 6 months of ASCT Stratified according to β 2 -M, del(13),* VGPR post-asct R 1:1 Lenalidomide 25 mg/day days 1-21 Lenalidomide 1-15 mg daily (n = 37) Placebo (n = 37) * As measured by FISH; Consolidation phase added at first protocol amendment (Sept 26); Thromboprophylaxis was not mandatory; 1 mg/day for the first 3 months, then increased to 15 mg/day if tolerated. ASCT: autologous stem cell transplant; β 2 -M: β 2 -microglobulin; del: deletion; EFS: event-free survival; FISH: fluorescence in situ hybridisation; IFM: Intergroupe Francophone du Myélome; NDMM: newly diagnosed multiple myeloma; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; R: randomisation; SD: stable disease; VGPR: very good partial response. Attal M. N Engl J Med. 212;366:1782-91. MED/MM/REV/212.4/22
Patients (%) Patients (%) IFM 25-2: Progression-Free Survival Lenalidomide maintenance significantly prolonged median PFS vs. placebo 1 Cut-off: July 21 Cut-off: Oct 211 Median PFS HR (P value) LEN 41 months.5 (<.1) PBO 23 months N/A 1 4-year PFS HR (P value) LEN 43%.5 (<.1) PBO 22% N/A 75 75 5 5 25 25 6 12 18 24 3 36 42 48 Follow-Up 6 12 18 24 3 36 42 48 54 6 Follow-Up HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: Lenalidomide; N/A; not applicable; PBO: placebo; PFS: progression-free survival. Attal M. N Engl J Med. 212;366:1782-91 and Supplementary Appendix. MED/MM/REV/212.4/22
Patients (%) Poor Prognosis in Patients Ineligible for Novel Agents RRMM patients who are intolerant of or refractory to treatment with Lenalidomide, thalidomide, or bortezomib have a poor prognosis Median EFS: 5 months Median OS: 9 months 1 8 Survival Outcomes From Time Zero OS EFS Events/N 17/286 217/286 Median (range) in months 9 (7,11) 5 (4,6) 6 4 2 12 24 36 48 6 Months From Time Zero Kumar SK. Leukemia. 212; 26:149-57.
Molecular Structure of Imids (Immunomodulatory drugs)
RANDOMIZATION 2:1 Dimopoulos MA, et al. Updated Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival in MM-3, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM). Oral presentation at: American Society of Hematology. 213; December 7-1; New Orleans, LA. MM-3 Design: POM + LoDEX vs. HiDEX 28-day cycles (n = 32) POM: 4 mg/day D1-21 + LoDEX: 4 mg ( 75 yrs) 2 mg (> 75 yrs) D1, 8, 15, 22 PD a or Unacceptable AE Follow-Up for OS and SPM Until 5 Years Post Enrollment HiDEX: (n = 153) 4 mg ( 75 yrs) 2 mg (> 75 yrs) D1-4, 9-12, 17-2 PD a or Unacceptable AE Companion trial MM-3C POM 21/28 days Stratification Age ( 75 vs. > 75 yrs) Number of prior Tx ( 2 vs. > 2) Thromboprophylaxis was required for those receiving POM or at high risk for DVT Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure) a Progression of disease was independently adjudicated in real time.
MM-3: Overall Survival (ITT) Proportion of Patients 1. Median OS.8 POM + LoDEX (n = 32) HiDEX (n = 153) 13.1 mos 8.1 mos.6.4 HR =.72 P =.9.2. 4 8 12 16 2 24 28 OS (mos) 85 pts (56%) on the HiDEX arm received subsequent POM Dimopoulos MA, et al. Updated Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival in MM-3, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM). Oral presentation at: American Society of Hematology. 213; December 7-1; New Orleans, LA.
MM-3. OS Forest Plot of Subgroup Analyses Updated March 1 213 Subgroup ITT Population HR (95%CI).74 (.56-.97) POM + LoDEX* 145/32 HiDEX* 82/153 LEN and BORT Refractory.77 (.56-1.5) 113/225 62/113 LEN as Last Prior Tx.53 (.33-.87) 41/85 29/49 BORT as Last Prior Tx.87 (.56-1.36) 56/132 3/66.25.5 1 2 Favors POM + LoDEX Favors HiDEX * Number of events/number of pts San Miguel JF, et al. ASCO 213 [abstract 851].
MM-3 Phase 3: Safety Event Grade 3/4 haematological AEs, % POM + LoDEX (N = 3) HiDEX (N = 15) Neutropenia 48 16 Febrile neutropenia 9 Anaemia 33 37 Thrombocytopenia 22 26 Grade 3/4 non-haematological AEs, % Infection 3 24 Pneumonia 13 8 Bone pain 7 5 Fatigue 5 6 Asthenia 4 6 Glucose intolerance 3 7 Grade 3/4 AEs of interest, % DVT/PE 1 Peripheral neuropathy a 1 1 Discontinuation due to AEs, % 9 1
Survival distribution function estimate Pomalidomide IFM 29-2: superior Comparison to any between approach TTP on-protocol & TTP post on Bortezomib last prior line and (ITT Lenalidomide N = 84) 1..9.8.7.6.5.4.3.2.1. TTP last prior line TTP pomalidomide TTP last prior line (IRC responders) TTP pomalidomide (IRC responders) IRC = Independent review committee; ITT = intent-to-treat; TTP = time-to-progression. 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 Time from first intake (weeks) 2
IMiDs A new backbone of therapy: Lenalidomide Proteasome inhibitors Rd + carfilzomib in RRMM, phase 3 (US/EU), phase 1/2 (US) Rd + MLN978 in RRMM: phase 3 (USA, Canada, EU) Rd + MLN978 in NDMM: phase 3 (USA, Canada, France, Belgium, Japan) HDAC inhibitors Rd + vorinostat in RRMM: multiple phase 1/2 (US, EU), 1 phase 3 (USA) Rd + panobinostat in RRMM: 2 phase1/2 (USA, Australia, EU) Rd + ACY-1215 in RRMM: phase 1 (USA) Monoclonal antibodies Rd + elotuzumab in RRMM: multiple phase 1/2 (EU, USA, Japan), 1 phase 3 (ELOQUENT-2) Rd + elotuzumab in NDMM: phase 3 (ELOQUENT-1) Rd + daratumumab in RRMM: 1 phase 3 Rd + SAR65984 in RRMM: phase 1 (USA) Rd + IPH211 in RRMM: phase 1 (USA)
IMiDs in numbers Trials (as per clinicaltrials.gov, dd 12 May 214) Open Total Thalidomide 136 33 Lenalidomide 117 254 Pomalidomide 29 45 Publications (as per pubmed, dd 12 May 214) 213 212 total (no date filter) Thalidomide 299 315 2422 Lenalidomide 275 244 1232 Pomalidomide 53 21 132
Model of the disease course in Pattern of disease multiple in myeloma multiple myeloma M protein (g/dl) 1 Asymptomatic Symptomatic Active myeloma 5 2 MGUS or smouldering myeloma Plateau remission Relapse Refractory relapse Time Durie BGM. 211. Concise review of the disease and treatment options. Multiple myeloma. North Hollywood, CA: International Myeloma Foundation. Available from: http://myeloma.org/pdfs/ph21- Eng_l2.pdf. Accessed November 212.
M-protein (g/l) Proposed Updated Model Multiple myeloma: changing the paradigm in the RRMM setting 1 Active MM Lenalidomide FIRST RELAPSE SECOND RELAPSE Pomalidomide THIRD RELAPSE REFRACTORY RELAPSE 5 2 MGUS or SMM Plateau remission First-line therapy Second-line therapy Third-line therapy ACTIVE MYELOMA
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