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9/27/2017 The Problem of Relapse in Myeloma PARAMESWARAN HARI Medical College of Wisconsin Relapse is the hallmark of multiple myeloma • Definitions • Relapse from CR / Biochemical Progression / Clinical Relapse • Biological Correlates • Choosing when to treat • Risk Stratification of Relapse Definitions- Relapse • From CR • Mainly used for clinical trials • Reappearance of serum or urine M-protein by immunofixation or electrophoresis or abnormal FLC ratio • Development of ≥5% plasma cells in BM • Any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) • Clinical relapse • • • • New CRAB findings New plasmacytomas or bone lesions (fractures do not necessarily count) Increasing size of existing plasmacytomas (>50%) Hyperviscosity related to paraprotein Kumar et al, Lancet Oncol, 2017 1 9/27/2017 Definitions- Progression • Increase of 25% from lowest confirmed response value in one or more of: – Serum M-protein (absolute increase must be ≥0.5 g/dL) – Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL – Urine M-protein (absolute increase must be ≥200 mg/24 h) – Light chain disease: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) • Non-secretory: 25% increase in bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%) • Appearance of a new lesion(s), ≥50% increase from nadir • ≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of disease Kumar et al, Lancet Oncol, 2017 Multiclonal disease with spatial and temporal heterogeneity • Acquired genomic events with progression Rasche L et al Nature Communications 8, Article number: 268(2017) Case presentation • 62 YO M with standard risk MM dx’d in 1/2013 – Received RVD x 3 nCR – Auto-HCT with melphalan 200 in 6/2013 sCR – Maintenance lenalidomide started in 9/2013 • On routine bloodwork 4/2017 SPEP shows reappearance of M protein at 0.1 g/dL Now what?? 2 9/27/2017 Importance of full re-staging at suspected relapse/progression • • • • History- determine co-morbidities Physical- determine PS Labs – including PB flow for PCs Bone marrow, including FISH, cytogenetics, +/- GEP – Determine new clones – Risk stratification – Possibly help with clinical decision making (BCMA, 11:14) • Imaging- beware of EMD – PET/CT – PET/MRI Dingli et al, Mayo Clin Proc, 2017 Loss of CR or Never CR or Sustained CR Never CR CR achieved and Lost Hoering A et al Blood. 2009 Aug 13; 114(7): 1299–1305. • Re-appearance of M protein/BJ • Reappearance of 5% PCs in BM • New CRAB event • New plasmacytoma • New hyperviscosity • 25% increase in M protein/BJ/ FLD difference • 10% increase in BM • 50% increase in plasmacytoma • 50% increase in circulating PCs Clinically relevant Measured Measured 3 9/27/2017 Making your decision • Immediate treatment for relapse • Closer follow-up • Regular follow-up Indications for treatment • Clinical relapse (CRAB or plasmacytomas) • Significant biochemical progression without clinical relapse • Doubling of the M-component in two consecutive measurements separated by 2 months with the reference value of 5 g/L, (=0.5 g/dL) or • In two consecutive measurements any of the following increases: – the absolute levels of serum M protein by ≥10 g/L (=1.0g/dL), or – an increase of urine M protein by ≥500 mg per 24 hours, or – an increase of involved FLC level by ≥20 mg/dL (= 200 mg/L) (plus an abnormal FLC ratio) or 25% increase (whichever is greater) Ludwig et al, The Oncologist, 2014 • Re-appearance of M protein/BJ • Reappearance of 5% PCs in BM • • • • New CRAB event New plasmacytoma New hyperviscosity 50% increase in plasmacytoma • Doubling of M protein or increase by >1 g/dL • Increase in > 500 mg/24 H BJ • Increase in LC > 200 mg/L • Circulating plasma cells • 25% increase in M protein/BJ/ FLD difference • 10% increase in BM • 50% increase in plasmacytoma • 50% increase in circulating PCs Treatment Indicated 4 9/27/2017 Dingli et al, Mayo Clin Proc, 2017 When to treat if only biochemical relapse/progression • Aggressive clinical disease at diagnosis • Short treatment-free interval/ suboptimal response to previous treatment line • Imminent risk for organ dysfunction (pts with previous light chaininduced renal impairment) • Unfavorable cytogenetics (t(4;14) or del17p) Ludwig et al, Oncologist, 2014 Natural History of early relapse after transplant No relapse by 2 years: 5-year OS 80% Relapse by 2 years: 5-year OS 32% 15 Kumar S et al Tandem BMT meetings 2017 5 9/27/2017 How many pts relapse early? 100 IFM 2009 10% of MRD Neg 90 MRD pos MRD neg 30% of MRD Pos 80 Patients (%) 70 60 50 P<0.001 40 30 20 10 0 0 12 65 172 57 166 24 36 48 30 86 4 17 Months of follow-up N at risk MRD pos MRD neg 43 151 Attal M et al NEJM 2017 Back to the case… • 62 YO M with standard risk MM dx’d in 1/2013 – Received RVD x 3 nCR – Auto-HCT with melphalan 200 in 6/2013 sCR – Maintenance lenalidomide started in 9/2013 • On routine bloodwork 4/2017 SPEP shows reappearance of M protein at 0.1 g/dL • BM: 5% involvement by plasma cells, normal cytogenetics/FISH • PET/CT negative • Followed q3 months with labs • 10/2013 M protein = 0.7 • 11/2013 M protein = 1.1 Gray areas • On maintenance with an M protein rise 0.20.6 – Should we treat earlier if the patient is already on maintenance? • High-risk patients with increasing light chains, but not quite at progression • Persistently PET avid plasmacytomas • True biochemical progression but questionable performance status 6 9/27/2017 Next Talks • Choosing a regimen at relapse – Early Relapse – Refractory Relapse • Options for the multirelapsed and refractory patient – Immunotherapy – Clinical Trials of Newer Novel Agents 7 10/1/2017 Early Relapse: Choosing Among Different Second Line Regimens Ajay K. Nooka, MD, MPH, FACP Associate Professor Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University Atlanta, Georgia 2 Disclosures ➢Advisory board: Celgene, Amgen, Novartis, Spectrum, Pharmaceuticals and Adaptive technologies Clinical Vignette 72-year-old female with diagnosis of standard risk myeloma (hyperdiploidy on FISH studies) received induction therapy with RVd regimen. She underwent upfront transplant and achieved stringent CR. She opted not to go for maintenance therapy, and was monitored closely. Four years from her transplant, she started showing evidence of biochemical progression, and now she is anemic. You suggest that the following second line regimen delivers the best depth of response (≥VGPR) based on the data from available lenalidomide based phase III studies: 1. 2. 3. 4. Elotuzumab with lenalidomide and dexamethasone Daratumumab with lenalidomide and dexamethasone Ixazomib with lenalidomide and dexamethasone Carfilzomib with lenalidomide and dexamethasone 1 10/1/2017 Why is it important to choose the best second line regimen? Relapsed myeloma: previously treated myeloma that progresses in the absence of any therapy and requires the initiation of salvage therapy. 6 4 2 0 Firs Second Third Fourth Fifth t Survival Outcomes at Emory[3] Survival Outcomes[2] Response Duration With Increasing Treatment[1] 1 2 1 0 8 Pts (%) Median Response Duration (Mos) Response duration in refractory myeloma 1 0 0 8 0 6 0 4 0 2 0 0 OS EFS 0 Sixth 12 Median, Mos Events, n/N (Range) 170/286 9 (7-11) 217/286 5 (4-6) 24 36 48 60 Mos Mos Treatment Regimen 1. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. 2. Kumar SK, et al. Leukemia. 2012;26:149-157. 3. Nooka A, et al. institutional data, unpublished. 5 Treatment Options for Relapsed and Refractory Myeloma (RRMM) Symptomatic relapse Consider clinical trial Relapse within first 12 months -Newer combination strategies CRD, CPD, RVD or clinical trial -Allogeneic transplant clinical protocol Subsequent relapse Factors to consider • Treatment related factors • Disease related factors • Patient related factors Prior SCT Yes No Relapse beyond the first 12 months *Bortezomib ± Dexamethasone *Lenalidomide + Dexamethasone *Bortezomib ± PLD RVD, VTD, CFZ, CRD, VCD, RCD, DCEP±V, DTPACE±V, Cytoxan, Pd, Td Relapse with maintenance therapy after SCT Relapse within 36 months Relapse without maintenance therapy after SCT Relapse beyond 36 months Relapse beyond 18-24 months Transplant eligible; has good PS • Primary refractory- SCT • Relapsed/refractory- SCT Subsequent relapse Relapse within 18-24 months * Subsequent relapse SCT2 Subsequent relapse Transplant ineligible -If patient has previously responded to the therapy, tolerated and relapsed at least 6 months after prior drug exposure • repeat prior therapy - Otherwise, consider • *Bortezomib ± Dexamethasone • *Bortezomib + PLD • *Lenalidomide + Dexamethasone • RVD, VTD, CFZ, CRD, VCD, RCD, DCEP, DT-PACE±V, Cytoxan, Pd, T Nooka, et al. Blood. 2015;125(20):3085-99. Factors to Consider to for Treatment Selection a Relapse: Disease related Factors ➢Nature of relapse ➢indolent vs aggressive ➢Risk stratification ➢Genetics of initial and relapsed marrow ➢Disease burden ➢High vs low ➢R-ISS staging ➢1 vs 2-3 1. 2. 3. 4. Nooka AK, et al. Blood. 2015;125:3085-3099. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. Palumbo A, et al. Blood. 2011;118:4519-4529. Orlowski RZ, Lonial S. Clin Cancer Res. 2016;22:5443. 2 10/1/2017 Factors to Consider to for Treatment Selection a Relapse: Treatment related Factors ➢ Previous therapy ➢ Pts with PD receiving IMiDs, PIs, or cytotoxic doublet/triplet therapies can benefit from next-generation regimens ➢ Avoid agents of previous regimen-related toxicity ➢ Maintenance therapy ➢ Regimen-related toxicity ➢ Toxicity profile should be considered in light of pt comorbidities ➢ Neuropathy: consider neuropathy sparing durgs (avoid bortezomib, thalidomide) ➢ Cardiac issues (uncontrolled HTN, CHF): careful consideration of carfilzomib ➢ COPD: monoclonal antibodies with caution (daratumumab) ➢ DVT/PE: use anticoagulation with IMiDs ➢ Depth and duration of previous response, tumor burden at relapse ➢ Retreatment with previous therapies an option if pt had previous response to the treatment, acceptable tolerance, and relapse occurred at least 6 mos after previous exposure 1. Nooka AK, et al. Blood. 2015;125:3085-3099. 2. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. 3. Palumbo A, et al. Blood. 2011;118:4519-4529. Factors to Consider to for Treatment Selection a Relapse: Patient related Factors ➢Renal insufficiency: disease related or due to comorbidities (hypertension, vascular disease, diabetes, nephrotoxicity)[1] ➢Hepatic impairment common in pts with RRMM [1] ➢Comorbidities and fraility[1] ➢Treatment decisions complicated in elderly ➢↑ toxicity due to ↓ organ function, physiologic reserve ➢European Myeloma Network vulnerability assessment algorithm anticipates regimen-related toxicities and assists individualizing therapy with least potential for interruption [2,3] ➢Patient preferences ➢Convenience, ease of travel, insurance and other social factors 1. Nooka AK, et al. Blood. 2015;125:3085-3099. 2. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. 3. Palumbo A, et al. Blood. 2011;118:4519-4529. 9 Lenalidomide and Bortezomib-Based Early Relapse Regimens: PFS and OS Trial ASPIRE1 N=792 TOURMALINE-MM-12 N=722 ELOQUENT-23 N=646 VGPR (%) PFS (HR, 95% CI) OS (HR, 95% CI) Rd + Carfilzomib Regimen PFS (mon) ORR (%) 26.3 87.1 69.9 .69 (.57-.83) P=.0001 .79 (.63-.99) P=.04 Rd 17.6 66.7 40.4 Rd + Ixazomib 20.6 78.3 48.1 Rd 14.7 71.5 39 Rd + Elotuzumab 19.4 79 33 Rd 14.9 66 28 POLLUX4 N=569 Rd + Daratumumab NR 93 75.8 Rd 18.4 76 44.2 PANORAMA5 N=768 Vd + Panobinostat 11.99 60.7 28 Vd 8.08 54.6 16 CASTOR6 N=498 Vd + Daratumumab NR 83 59 ENDEAVOR7 N=929 Vd 7.2 63 29 Carfilzomib + Dex 18.7 76.7 54 Vd 9.4 62.3 29 .74 (.59-.74) P=.01 NR .70 (.57-.85) P<.01 .78 (.63-.96) .37 (.28-.50) P<.0001 .63 (.42-.95) .63 (.52-.76) P<.0001 .87 (.69-1.10) P=.26 .39 (.28-.53) P<.0001 .63 (.42-.96) .53 (.44-.65) P<.0001 .79 (.58-1.08) P=.06 1. Stewart K, et al. N Engl J Med 2015;372:142-52. 2. Moreau P, et al. N Engl J Med 2016; 374:1621-1634. 3. Lonial S, et al. N Engl J Med 2015; 373:621-631. 4. Dimopoulus M, et al. N Engl J Med 2016; 375:1319-1331. 5. San Miguel J, Lancet Oncol 2014; 15: 1195–206. 6. Palumbo A, et al. N Engl J Med 2016; 375:754-766. 7. Dimopoulos M, et al. Lancet Oncol. 2016;17:27-38. 3 10/1/2017 10 FDA Approvals of Novel Agents for Patients with RRMM Novel Agent or Regimen FDA Approval Date Panobinostat + bortezomib/dexamethasone February 23, 2015 Patient Population • Patients with ≥2 prior standard therapies, including bortezomib and an IMiD agent • Patients with relapsed disease who had received 1-3 prior lines of therapy Daratumumab November 16, 2015 • Patients with at least 3 prior treatments Ixazomib + lenalidomide/dexamethasone November 20, 2015 Elotuzumab + lenalidomide/dexamethasone November 30, 2015 • Carfilzomib + lenalidomide/dexamethasone July 27, 2015 Carfilzomib + dexamethasone Daratumumab + bortezomib/dexamethasone Daratumumab + lenalidomide/dexamethasone January 21, 2016 November 21,2016 November 21,2016 Daratumumab + pomalidomide/dexamethasone • Patients who had received at least 1 prior therapy Patients with 1-3 prior therapies • Patients with relapsed disease and 1-3 prior therapies • Patients who had received at least 1 prior therapy • Patients who had received at least 1 prior therapy • Patients who had received ≥2 prior standard therapies, including bortezomib and an IMiD agent June 16, 2017 Orlowski RZ, Lonial S. Clin Cancer Res. 2016;22:5443. 11 Available Regimens in Early Relapse NCCN Guidelines Preferred Regimens Other Regimens Level 1 Regimens Level 1 Regimens • Bortezomib/liposomal doxorubicin • Panobinostat/bortezomib/dexamethasone Doublets • Bortezomib/dexamethasone • Carfilzomib/dexamethasone • Lenalidomide/dexamethasone Other Triplets • Elotuzumab/lenalidomide/dexamethasone • Daratumumab/lenalidomide/dexamethasone • Ixazomib/lenalidomide/dexamethasone • Carfilzomib/lenalidomide/dexamethasone • Daratumumab/bortezomib/dexamethasone Other Regimens • Repeat primary induction therapy (if relapse at >6 months) • Bortezomib/cyclophosphamide/dexamethasone • Bortezomib/lenalidomide/dexamethasone PI-Based • Ixazomib/dexamethasone • Elotuzumab/bortezomib/dexamethasone Alkylator-Based • Bendamustine/bortezomib/dexamethasone • Bendamustine/lenalidomide/dexamethasone • Cyclophosphamide/lenalidomide/dexamethasone • DCEP (dex/cyclophosphamide/etoposide/cisplatin) • DT-PACE (dex/thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide) ± bortezomib (VTDPACE) • High-dose cyclophosphamide Note: NCCN Guidelines do not break out regimens into separate categories of early and late relapse NCCN Guidelines, Version 3.2017. Accessed August, 2017. Depth of response ➢ MRD negative rate POLLUX MRD negative rates CASTOR Moreau P, et al. N Engl J Med 2016; 374:1621-1634 Palumbo A, et al. N Engl J Med. 2016;375(17):754-766. 4 10/1/2017 Benefit of antibodies as earlier lines of therapy: MRD negativity and PFS from CASTOR MRD –ve rate with DVd as 1st line vs ITT PFS with DVd as 1st line vs 2-3 Mateos MV, et al. Blood. 2016;128: Abstract 1150. Relative Benefit of PFS: Possibility of delivering therapy over long term Betts K, et al. haematologica. 2017;102: Abstract E1300. Salvage ASCT in the Relapsed Setting ➢ Data from Mayo Clinic Transplant Center suggests that ASCT2 appears safe and effective treatment for relapsed MM (N = 98) ➢ ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos ➢ Rate of TRM: 4%, suggesting a favorable benefit-to-risk ratio ➢ Shorter TTP after ASCT1 predicts shorter OS post–ASCT2 TTP After ASCT1 Median From ASCT2, Mos (Range) PFS OS < 12 mos 5.6 (3-8) 12.6 (4-23) < 18 mos 7.1 (6-8) 19.4 (10-42) < 24 mos 7.3 (6-10) 22.7 (13-62) < 36 mos 7.6 (7-12) 30.5 (19-62) Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573. 5 10/1/2017 Emory Approach to Early Relapse Early relapse (1-3 prior lines of therapy) Clinical trials Aggressive relapse/high risk Indolent relapse +Len maintenance - IRd - ERd -Len maintenance - DRd - KRd - ERd +Len maintenance -Len maintenance - DPd - KPd - DRd - DVd - KPd Car/Pan as second salvage if IMID used *increase dose of lenalidomide to 25 mg Clinical Vignette 72-year-old female with diagnosis of standard risk myeloma (hyperdiploidy on FISH studies) received induction therapy with RVd regimen. She underwent upfront transplant and achieved stringent CR. She opted not to go for maintenance therapy, and was monitored closely. Four years from her transplant, she started showing evidence of biochemical progression, and now she is anemic. You suggest that the following second line regimen delivers the best depth of response (≥VGPR) based on the data from available lenalidomide based phase III studies: 1. 2. 3. 4. Elotuzumab with lenalidomide and dexamethasone Daratumumab with lenalidomide and dexamethasone Ixazomib with lenalidomide and dexamethasone Carfilzomib with lenalidomide and dexamethasone Conclusions ➢Novel agents in combination can achieve prolonged responses even in relapsed disease ➢Depth of response is key even in relapsed disease ➢ There are many right ways to treat patients with multiple myeloma in relapse ➢There are also wrong ways to do it, know your options ➢Regimen with good tolerability, and efficacy (monoclonal antibodies) ➢Despite major advances and newer options, a few challenges that we face today are ‒ how to sequence the available regimens? ‒ how to personalize therapy to derive the maximize benefit (eg: biomarkers)? ‒ how to tailor therapy to minimize toxicity yet retain efficacy 6 10/1/2017 Questions?? anooka@emory.edu 7 10/1/2017 Approach to the Patient with Refractory and Multiply Relapsed Multiple Myeloma Peter Voorhees, M.D. Member, Plasma Cell Disorders Program Relapsed/Refractory Disease : Outcomes 100 Kumar SK, et al. 2012. Usmani S, et al. 2016. 80 Patients alive, % • Despite the introduction of IMiDs and PIs, most patients relapse and outcomes are poor in relapsed or refractory patients1 • Median OS of 9 months in patients refractory to bortezomib and ≥1 IMiD1 • Median OS of 8 months in patients with relapsed or refractory MM who were double refractory or had relapsed after ≥3 prior lines of therapy, including pomalidomide and carfilzomib2 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time, months MM, multiple myeloma; IMiD, immunomodulatory drug; PI, proteasome inhibitor; OS, overall survival. 1.Kumar SK, et al. Leukemia. 2012;26(1):149-157. 2.Usmani S, et al. Oncologist. 2016. doi:10.1634/theoncologist.2016-0104. Outline • Available Therapeutic Regimens for later relapse • General Principles to Guide Therapy Decisions • Treatment of Later Relapse / Progression (≥2 prior lines of therapy and/or lenalidomide/bortezomib refractory) • Emerging therapeutics • Conclusions 1 10/1/2017 Available Regimens in Late Relapse: NCCN Guidelines Preferred Regimens Other Regimens Late Relapse (≥2 prior lines or len/bort refractory) Level 1 Regimens Doublets • Pomalidomide/dexamethasone Other Regimens • Pomalidomide/bortezomib/dexamethasone • Pomalidomide/carfilzomib/dexamethasone • Pomalidomide/daratumumab/dexamethasone • Daratumumab Late Relapse (≥2 prior lines or len/bort refractory) • Panobinostat/bortezomib/dexamethasone • Panobinostat/carfilzomib • Pomalidomide/cyclophosphamide/dexamethasone • DCEP (dex/cyclophosphamide/etoposide/cisplatin) • DT-PACE (dex/thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide) ± bortezomib (VTD-PACE) • High-dose cyclophosphamide Note: NCCN Guidelines do not break out regimens into separate categories of early and late relapse NCCN Guidelines, Version 3.2017, accessed August, 2017. • • • 55 pts with relapsed and bortezomib-refractory multiple myeloma (54 prior lenalidomide tx) Median prior regimens: 4 (2 – 11) Median time since diagnosis: 54.8 mos (7.5 – 263.6) 21-day cycle. Bort 1.3 mg/m2 IV D1, 4, 8, 11 (D1, 8 for cycle 9+); Dex 20 mg day of and after bort; Pano/Placebo 3x/week for the first 2 weeks of the cycle. Response Category Time (months) % ORR (≥PR) 34.5 CBR (≥MR) 52.7 CR Median PFS: 5.4 mos 0.0 nCR 1.8 PR 32.7 MR 18.2 SD 36.4 PD 5.5 Overall Survival • Progression-free Survival PANORAMA-2: A Phase 2 Study of Bortezomib, Dexamethasone and Panobinostat Median OS: Not reached (Median F/U: 8.3 mos) Time (months) Richardson PG et al. Blood 2013;122:2331-7. Pomalidomide-Dex vs Dex for Relapsed/Refractory Multiple Myeloma • Randomized, phase III study of Pom-Dex vs Dex in relapsed/refractory myeloma • Baseline characteristics: 1) Median number of prior therapies = 5; 2) Len and bort refractory 75% • ORR: 31% vs. 10% • Median PFS 4.0 vs. 1.9 mos • Median OS: 12.7 vs. 8.1 mos Dex Pom-Dex Miguel JS, et al. Lancet Oncol. 2013;14:1055-1066. 2 10/1/2017 Carfilzomib, Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma • MTD in phase I: 4-week cycle. CFZ 27 mg/m2 D1, 2, 8, 9, 15, 16; Pom 4 mg D1-21; Dex 40 mg D1, 8, 15, 22 • Median lines of therapy: 6 (2–12) • Len-refractory: 100% • Bortezomib-refractory: 93.5% Best Overall Response N=32 VGPR 16% PR 34% MR 16% SD 25% PD 9% Median PFS 7.2 months, Median OS 20.6 months Shah JJ, et al. Blood. 2015;261:2284-2290. Phase 1/2 Trial: Pomalidomide, Bortezomib and Dexamethasone Median 2 prior lines Prior lenalidomide 100%, prior bortezomib 57% Refractory to immediate prior line 28% Median 2 prior lines Prior lenalidomide 100%, prior bortezomib 97% ORR and DOR 2 OS and PFS1 Median follow-up: 12 months N = 47 Median follow-up: 12 months Response rate, n (%) 40 (85) Response rate, n (%) 22 (65) NA 100 95 Median DoR, months 7.4 (95% CI 4.4–9.6) Median OS Event free at 6 months (%) Event free at 12 months (%) 80 Median PFS, months 10.7 (95% CI 9.4–18.5) 60 Median DoR, months 13.7 (95% CI 8.5–16.8) 40 Success (%) 100 10 33 25 20 8 0 6 12 18 24 Time (months) 30 sCR/CR VGPR PR 24 MTD With IV BORT (n = 10) MTD With SC BORT (n = 12) 1.1 Median TTR, mos (95% CI) (0.7-5.1)a 1.4 (0.9-3.2)a 0.8 (0.7-1.0)a 1.0 (0.7-5.1) 5.8 Median DOR, mos (95% CI) (1.2-10.1) 7.4 (4.1-NE) NE (3.2-NE) 7.4 (4.4-9.6) 40 OS PFS 32 Escalation (n = 12) 60 00 9 17 40 42 20 80 20 N = 34 Total (N = 34) 8 1. Lacy MQ, et al. Blood. 2014;124 (suppl, abstr 304). 2. Richardson PG, et al. Blood. 2015;124 (suppl, abstr 3036). Phase 1/2 Trial: Pomalidomide, Cyclophosphamide and Dexamethasone • Median number of prior therapies 4 • Must have been refractory to lenalidomide • Refractory to bortezomib 71% 1.0 POM-LoDEX POM-LoDEX + cyclo Proportion 0.8 Median PFS: 9.5 vs 4.4 months (P = .1078) Median OS a: not reached vs 16.8 months (P = .1308) 0.6 0.4 0.2 Log-rank p = 0.1078 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) Arm POM-LoDEX POM-LoDEX + cyclo Baz R, et al. Blood. 2016;127(21):2561-8. N 36 34 Event 30 (83%) 26 (76%) Censored 6 (17%) 8 (24%) Median (95% CI) 4.4 (2.3, 6.0) 9.5 (4.6, 13.6) 9 3 10/1/2017 Daratumumab as Monotherapy for Relapsed/Refractory Multiple Myeloma PR 35 30 ORR, % 25 VGPR CR Progression-Free Survival sCR 2% 1% 3% CR or better 13% VGPR or better 10% 20 15 10 18% 5 0 16 mg/kg N = 148 • Median OS: 19.9 months Usmani S, et al. Blood. 2016;128:37-44. Pomalidomide, Dexamethasone and Daratumumab for Relapsed/Refractory MM Median number of prior lines of therapy: 4 (range 1 – 13), 71% PI and IMiD refractory, 25% with high risk CGs Of 17 pts in ≥CR, 35%, 29% and 6% were MRD- at thresholds of 10-4, 10-5 and 10-6, respectively Median PFS in high risk CG disease (N=22): 3.9 months (95% CI 2.3 – NE) Median OS = 17.5 months (85% CI 13.3 – NE) Chari, A, et al. Blood 2017;130:974-81. Analysis of Daratumumab, Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma Best Response ORR, n % sCR, n % CR, n % VGPR, n % PR, n % MR/SD, n % PD, n % Median cycles of tx, n (range) Dara and Pom Naive (n = 19) Dara and/or Pom Refractory (n = 22) Dara and Pom Refractory (n = 12) 17 (89.0) 7 (36.8) 1 (5.3) 3 (15.8) 8 (42.1) 1 (5.3) 1 (5.3) 9 (40.9) 0 0 1 (4.5) 8 (36.4) 9 (40.9) 4 (18.2) 4 (33.3) 0 0 1 (8.3) 3 (25.0) 6 (50.0) 2 (16.7) 15 (1-23) 3 (1-8) 3 (1-8) 12 Nooka AK, et al. Blood. 2016;128:492. 4 10/1/2017 Analysis of Daratumumab, Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma 0.8 0.6 0.4 0.2 0 PFS Dara/Pom/Dex: SD or Better vs No Response PFS Dara/Pom/Dex: Cohort 3 SD or Better vs No Response 1.0 Cumulative Survival 1.0 0.8 Cumulative Survival Cumulative Survival PFS Dara/Pom/Dex: All Cohorts 1.0 ≥ SD 0.6 0.4 No response 0.2 0 0 6 12 Mos Efficacy, Mos 18 24 0.8 ≥ SD 0.6 0.4 0.2 No response 0 0 6 12 Mos 18 24 0 6 12 Mos 18 All Cohorts (N = 41) Dara and Pom Naive (n = 19) Dara and Pom Refractory (n = 12) 7 NR 3 16 17 8 Median PFS Median follow-up 24 Nooka AK, et al. Blood. 2016;128:492. General Treatment Principles • Overlap between early and late relapse treatment choices • An early or late relapse regimen may be appropriate as 2nd – 4th line therapy (1 – 3 prior lines) depending on the circumstances • The role of doublets and monotherapy is limited • Several novel triplets now available with good toxicity profiles • Consider in the more frail, heavily pretreated patients • Prior treatment toxicity, disease resistance patterns and comorbidities figure particularly prominently into the decision making process for these patients • Assess for the presence of t(11;14) • Always think about a clinical trial PABST: The Blue Ribbon Approach to Therapy Decisions for Previously Treated Multiple Myeloma • Past medical history • What co-morbidities will impact tolerability of therapy? • Adverse events • What toxicities were experienced with prior therapy? • Biochemical vs clinical relapse/progression • Standard vs high-risk disease biology • Treatment history • Is the disease resistant to specific drug classes? 5 10/1/2017 Biochemical vs Clinical Progression IMWG Consensus Criteria for Response in MM • Biochemical progression: • Progression of disease based on M protein parameter increase only • Timing of therapy institution / escalation dependent on numerous factors • • • • Pace of progression Original clinical presentation Standard vs high-risk disease biology Patient / physician comfort level • Clinical relapse: • “Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder” • Mandates immediate institution / escalation of therapy Biochemical Progression ↑ of ≥25% from nadir response value in one or more of the following: 1) Serum M protein (absolute increase ≥0.5 g/dL, ≥1 g/dL if nadir ≥5 g/dL) 2) Urine M protein (absolute increase ≥200 mg/24 hours) 3) Measurable by serum FLC testing only: difference between involved and uninvolved FLCs (absolute increase ≥10 mg/dL) 4) Non-secretory: bone marrow PC % (absolute increase ≥10%) Clinical Relapse 1) 2) 3) 4) 5) 6) Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression) Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and >=1 cm) increase as measured serially by the SPD§§ of the measurable lesion Hypercalcaemia (>11 mg/dL); Decrease in haemoglobin of >=2 g/dL not related to therapy or other nonmyeloma-related conditions Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma Hyperviscosity related to serum paraprotein ≥50% increase in circulating plasma cells (minimum 200 cells / uL) if this is the only disease measure available Kumar S et al. Lancet Oncol 2016;17:328-46 Standard vs High-Risk Disease Biology: IMWG Consensus on Risk Stratification Parameters % of Patients Median OS High-Risk Standard-Risk Low-Risk ISS II/III and t(4;14) or del(17p13) Others ISS I/II and absence of t(4;14), del(17p13) and +1q21 and age <55 20% 60% 20% 2 years 7 years >10 years • Other factors: Gene expression profile, LDH. circulating plasma cells, response to prior therapy Chng WJ et al. Leukemia 2014;28:269-77 Revised International Staging System R-ISS stage 1: normal LDH, no high risk cytogenetic abnormality (CA)*, ISS stage 1 disease R-ISS stage 2: not stage 1 or 3 R-ISS stage 3: ISS stage 3 disease PLUS high LDH OR high risk CA Non Transplant-Based Tx IMiD-Based Tx Transplant-Based Tx Bortezomib-Based Tx *High risk CA = del(17p) and/or t(4;14) and/or t(14;16) Palumbo et al. JCO 2015;33:2863-2869 6 10/1/2017 Treatment History • What regimen(s) has the patient had in earlier lines of therapy? • Is the disease refractory to a specific treatment? • Refractory per the IMWG guidelines: disease progression on or within 60 days of the last dose of therapy • Lack of response (stable disease) with prior therapy has been included in the definition of refractory in some studies • Carfilzomib has activity in bortezomib-refractory disease but the reverse has not been well studied • Pomalidomide has activity in lenalidomide-refractory disease but the reverse has not been well studied • If refractory, did the patient have disease progression on standard dosing, reduced dosing due to prior toxicity or maintenance dosing? • If dose reduced for toxicity, what were the toxicities, and how could they be better managed? • For patients on maintenance, it is common practice to optimize therapy prior to changing to a noncross resistant regimen. • Increase the doserdof lenalidomide and reincorporate dexamethasone for a patient with progression on lenalidomide maintenance. A 3 agent is often included in such a scenario (e.g. elotuzumab) but patients with lenalidomiderefractory disease were not allowed to participate in the ELOQUENT-1 study and the additional impact of this maneuver has not been well studied Treatment Choice Algorithm • First Step • Review resistance pattern with prior therapy • Determine biochemical vs clinical relapse • Assess standard vs high risk disease • High risk FISH: del(1p), gain 1q, t(4;14), t(14;16), t(14;20), del(17p) • High LDH, circulating plasma cells, plasma cell leukemia, extramedullary disease • Second Step • Refine choice based on co-morbidities and tolerability of previously used drug classes Disease Progression (≥2 prior lines of therapy) Disease Progression on Standard Dose Therapy Len/Bort Refractory Disease Progression on Maintenance Biochemical Progression or Early Clinical Relapse with Minimal Morbidity Escalate to standard dose, add back dex Biochemical Progression or Clinical Relapse Clinical Relapse Len/Bort Ref only Standard Risk - KPd - DPd - Kd - Pd - CyPD - Dara High Risk / Clin Relapse - KPd - DPd + Pom Ref Standard or High Risk - Kd - KCyD - Dara - DPd - Vtx-based** + CFZ Ref Standard or High Risk - DPd - CyPd - Pd - Dara - Vtx-based** Quad Ref Standard or High Risk - Dara - DPd* - Pano-based tx - Alkylatorbased therapy if not resistant - Vtx-based** Vtx = venetoclax *Only if disease resistant to prior pom-dex and dara in separate lines of therapy. **If + for t(11;14) (off label use) 7 10/1/2017 Venetoclax Monotherapy (N=66) Design: Phase I, open label, study of venetoclax monotherapy Study Population: RRMM • Median age: 63 yrs • ISS stage II/III: 62% • Median prior therapies: 5 (1-5) • Prior BTZ: 94% (70% ref) • Prior REV: 94% (77% ref) Dosing & Schedule: VEN: initial 2 week lead in period with weekly dose-escalation • Final doses: daily at 300 mg, 600 mg, 900 mg, or 1200 mg • Patients who progressed could receive VEN + dex and remain on study • Median time on VEN: 2.5 mo (0.2-23); 26% received VEN + dex for a median of 1.4 mo (0.1-11) Safety, n (%) Venetoclax Gr 3/4 (≥10%) Thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%) SAEs ≥2 pts Pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each) Deaths 8 (all considered unrelated to VEN) Kumar S, et al. ASH 2016. Abstract 488. Venetoclax + Vd (N=66) Design: Phase Ib, open label, dose escalation study of venetoclax + Vd Study Population: RRMM • Median age: 64 yrs • ISS stage II/III: 59% • Median prior therapies: 3 (1-13) • Prior BTZ: 32% ref • Prior REV: 56% ref Dosing & Schedule: VEN: daily, 50 mg – 1200 mg dose escalation • RP2D: 800 mg qd Vd: Dose and schedule not reported Safety, n (%) Venetoclax Gr 3/4 (≥10%) Thrombocytopenia (29%), anemia (15%) and neutropenia (14%) SAEs ≥2 pts Febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension 1 DLT: lower abdominal pain (1200 mg Ven) Deaths Efficacy All 1-3 Priors DOR 8.8 mo V non-ref: 10.6 mo V naïve: 15.8 mo TTP 8.6 mo V non-ref: 11.3 mo V naïve: 17.1 mo Efficacy With t(11;14) 78% ORR Without t(11;14) 66% • Discontinuations: 43 (65%), PD (33), AE (5), withdrawn consent (2), not specified (3) 5 (4=PD, 1=RSV infection) Moreau P, et al. ASH 2016. Abstract 975. STORM: Selinexor + Dex (N=79) Design: Phase II study of Sd Efficacy Study Population: RRMM • 48 pts refractory to REV, POM, V, K (Quad) • 33 pts refractory to above + anti-CD38 mAbs (Penta) Dosing & Schedule: S: 80 mg BIW for 6 or 8 doses of a 28 d cycle D: 20 mg BIW ORR CBR All Quad Penta 21% 32% 21% 29% 20% 37% Efficacy ORR, n (%) Standard Risk High Risk (17p13) t(14;16) t(4;14) 4 (17) 6 (33) 3 (38) 1 (100) 2 (50) Median age: 68 yrs Safety, n (%) Gr 3/4 (≥10%) All patients Thrombocytopenia Neutropenia Anemia Fatigue Hyponatremia 58 21 25 14 20 • Efficacy mOS PFS DOR All Responders Nonresponders 9.3 mo 2.1 mo NR (>11 mo) 5.7 mo 5 mo Most quad patients (83%) received 6 doses/cycle; penta patients (65%) received 8 doses/cycle Vogl DT, et al. ASH 2016. Abstract 491. 8 10/1/2017 PAVO: SC Daratumumab (N=41) Design: Ph Ib, open label, multicenter, dose-escalation study of SC Dara with rHuPH20 (Dara-PH20) Efficacy 1200 mg 1800 mg 25% 41% ORR Study Population: N=41 • ≥2 prior lines of therapy • Prior therapy included an IMiD and a PI Safety Gr 3/4 Fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome Dose & Schedule: D (cohort 1): 1200 mg in 60 mL over 20 min (n=8) D (cohort 2): 1800 mg in 90 mL over 30 min (n=33) ONLY SEEN IN 1200 MG DOSE Dara-PH20 was infused via a syringe pump in rotating areas on the abdomen in 4-week treatment cycles: QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter IRR (most Gr 1/2) Chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain, and wheezing; all occurred at 1st infusion and were controlled with treatment NO GRADE 3 IRR SEEN IN 1800 MG DOSE • • Part 2 of the study will examine the RP2D of Dara-PH20 vs IV Dara monotherapy 1800 mg was selected as the RP2D Usmani S, et al. ASH 2016. Abstract 1149. First in Human Study with GSK2857916, An Antibody Drug Conjugated to Microtubule-disrupting Agent Directed Against B-cell Maturation Antigen (n=30) – BCMA expression is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells – BCMA is broadly expressed at variable levels on malignant plasma cells – GSK2857916 was well tolerated with no DLTs up to 4.6 mg/kg q3w; MTD was not reached – AEs were manageable with ocular toxicity emerging as the most frequent reason for dose modifications – Hematologic toxicities such as thrombocytopenia and anemia are expected in the disease under study – 66.7% ORR including a stringent CR observed at higher doses of GSK2857916 in this refractory population – 3.4 mg/kg was selected as the dose to investigate in the expansion phase of the study based on the totality of the data from Part 1 – Pharmacodynamic and correlative analyses are ongoing Cohen A, et al. ASH 2016. B-cell Maturation Antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for MM Group/Company Binder/co-stimulatory signaling Transfection Trial ID BCMA expression required? Median prior lines of therapy Latest efficacy Safety summary Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA NCI Bluebird/Celgene/NCI Nanjing Legend Biotech Novartis/UPenn Murine/CD3 & CD28 Murine/CD3 & 41-BB Murine/CD3 & 41-BB Fullay human/CD3 & 41-BB Gamma-retroviral Lentiviral Lentiviral Lentiviral NCT02215967 NCT02658929 NCT03090659 NCT02546167 Yes Yes Yes No 7 7 3 9 1 CR (relapsed), 7 PRs in 16 patients 4 CRs, 12 PRs in 18 patients 15 CRs and 13 PRs in 35 patients 1 CR, 3 PRs in 9 patients Substantial but reversible 1 death, cardiopulmonary arrest (unrelated) Transient CRS 1 death – progressive disease/candidaemia 9 10/1/2017 Conclusions • There are many right ways to treat patients with multiple myeloma in relapse • There are also wrong ways to do it • As long as you have a PABST (review PMHx, adverse events, biochemical vs clinical relapse, standard vs high-risk disease, treatment history), you will come to a good answer for your patient • Use your local/regional Myeloma Specialists as a resource when questions arise about risk status, when to change treatment in biochemical relapse, optimal therapy when the preferred regimens may not be good options • Always consider a clinical trial, especially in increasingly refractory and / or high risk disease. We have gotten better at treating this disease but have a long ways to go! 10 9/28/2017 2017 Trends in MM Rx: Restoring Immune Function • Immunomodulatory drugs, other small molecules (eg, HDACi’s) • Monoclonal antibodies • Checkpoint inhibitors • Vaccines • Cellular therapies Monoclonal Antibodies Kill MM Through Multiple Mechanisms ELOQUENT 2: Elotuzumab-Rd (ERd) vs Rd ERd (n = 321) N=646 RRMM ELO: 10 mg/kg, d1, 8, 15, 22 (cycles 1–2); d1, 15 (cycles ≥ 3); LEN: 25 mg, d1–21 DEX: weekly equivalent, 40 mg 28-day cycles until progression 1–3 prior lines Not LEN-refractory Rd (n = 325) LEN: 25 mg, d1–21 DEX: 40 mg, d1, 8, 15, 22 28-day cycles until progression • Primary end points: PFS, ORR • Secondary end points: OS, DoR, QoL, safety Lonial S et al. N Engl J Med. 2015;373:621. 1 9/28/2017 ELOQUENT-2: ERd vs Rd Progression-Free Survival ERd (n=321) Median PFS, mos (95% CI) Rd (n=325) 19.4 (16.6−22.2) 14.9 (12.1−17.2) HR=0.73 (95% CI 0.60−0.89; P=0.0014) 3-yr PFS, % 26 18 Dimopoulos MA et al. Blood. 2015;126: Abstract 28. ELOQUENT-2: ERd vs Rd Efficacy Responses1 ERd Rd HR; (n=321) (n=325) P value P<0.001 100 ORR 79%a Patients (%) 80 60 4 ORR 66%* 28 7 21 40 20 46 38 0 ERd Rd n=321 n=325 *Values may not sum due to rounding. CR VGPR PR Median PFS, months2 19.4 14.9 Median TTNT, months2 33 21 0.73; 0.0014 0.62 (95% CI 0.50– 0.77) 0.77; 0.0257 Median OS, 43.7 39.6 months2 Median DoR, 20.7 16.7 NR 1. Lonial S et al. N Engl J Med. 2015;373:621-31. months1 2. Dimopoulos MA et al. Blood. 2015;126: Abstract 28. Daratumumab: Mechanism of Action 2 9/28/2017 Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR Phase 3 Randomized Controlled Study of DVd vs Vd in Pts With Relapsed or Refractory MM: CASTOR Overall Response Ratea P <0.0001 90 Response rate, % 20 83 80 63 70 60 16 14 59 50 P = 0.0012 40 29 30 10 9 4 10 2 0 0 Response-evaluable population. ≥VGPR ≥CR DVd Vd 8 6 19 ORR 14 12 20 a 18 P <0.0001 % 100 3 MRD-neg (10-4) 11 3 9/28/2017 Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX Phase 3 Randomized Controlled Study of DRd vs Rd in Pts With Relapsed or Refractory MM: POLLUX MRD-negative Rate 50 45 40 P <0.0001 MRD-negative rate (%) 35 30 P <0.0001 30% 23% 25 P <0.0001 20 15 10 10% 8% DRd Rd 5% 5 2% 0 MRD-neg (10-4) MRD-neg (10-5) MRD-neg (10-6) Significantly higher MRD-negative rates for DRd vs Rd Response-evaluable set. Assessed by next generation sequencing in bone marrow. 12 4 9/28/2017 Daratumumab in High-Risk Patients Rationale for DARA + POM-D • In a randomized, Phase 3 study, pomalidomide plus low-dose dexamethasone (POM-D) in patients relapsed from or refractory to previous treatment with bortezomib or lenalidomide1 resulted in the following: – ORR = 31% – Median PFS of 4.0 months – Median OS of 12.7 months • Pomalidomide increases CD38 expression in a time and dosedependent fashion in multiple myeloma cells 2 1. San Miguel J, et al. Lancet Oncol. 2013;14(11)1055-1066. 2. Boxhammer R, et al. Presented at 51st American Society of Clinical Oncology (ASCO) Annual Meeting; May 29 -June 2, 2015; Chicago, IL. Abstract 8588. 14 MMY1001: DARA + POM-D Arm Eligibility criteria • Refractory to last line of therapy • ≥2 prior lines of therapy, including 2 consecutive cycles of lenalidomide and bortezomib • Pomalidomide naïve • ECOG score ≤2 • Absolute neutrophil count ≥1.0×109/L, and platelet count ≥75×109/L for patients with <50% plasma cells (>50×109/L, otherwise) • Calculated creatinine clearance ≥45 mL/min/1.73 m2 Open-label, multicenter, six-arm, Phase 1b study (28-day cycles) DARA* IV 16 mg/kg + Pomalidomide 4 mg (Days 1-21) + Dexamethasone 40 mg QW *QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond. Treat 6 patients with DARA + POM-D If ≤1 patient has DLTs Enroll 6 additional patients Expand up to 88 patients 15 5 9/28/2017 Overall Response Rate: DARA + POM-D PR DARA + POM-D (N = 75) 53 (71) 59.0-80.6 Best response sCR CR VGPR PR MR SD PD 4 (5) 3 (4) 25 (33) 21 (28) 2 (3) 17 (23) 3 (4) 1.5-13.1 0.8-11.2 22.9-45.2 18.2-39.6 0.3-9.3 13.8-33.8 0.8-11.2 VGPR or better (sCR+CR+VGPR) 32 (43) 31.3-54.6 7 (9) 3.8-18.3 CR or better (sCR+CR) CR sCR ORR = 71% 70 9% CR or better 60 5% 4% 50 ORR, % 95% CI Overall response rate (sCR+CR+VGPR+PR) VGPR 80 n (%) 33% 40 43% VGPR or better 30 20 28% 10 0 16 mg/kg N = 75 • • • ORR = 71% ORR in double-refractory patients = 67% Clinical benefit rate (ORR + minimal response) = 73% 16 Progression-free Survival at 6 Months: DARA + POM-D Patients progression-free and alive, % 100 80 60 40 6-month PFS rate = 66% (95% CI, 52.3-75.9) 20 0 0 2 4 6 Time from first dose, months Patients at risk 98 67 39 19 • Median follow-up of 4.2 months 17 Coming Soon?;Recombinant Human Hyaluronidase ▪ ▪ ENHANZE™ platform of recombinant human hyaluronidase (rHuPH20) temporarily breaks down the hyaluronan barrier, allowing rapid absorption of injected drugs1 Schematic of rHuPH20 1 Herceptin SC® and MabThera SC® are approved in Europe as co-formulate products with rHuPH202,3 – Dosing time is 5 to 8 minutes with SC versus 0.5 to 6 hours with IV4-6 Aim: To determine the safety, pharmacokinetics, and efficacy of DARA as SC administration 1. 2. Halozyme Therapeutics. Mechanism of action for Hylenex recombinant (hyaluronidase human injection). www.hylenex.com/mechanism-of-action. Accessed 11/8/2016. European Medicines Agency. Herceptin: EPAR – product information. 2016 3. 4. 5. 6. European Medicines Agency. MabThera: EPAR – product information. 2016. Ismael G, et al. Lancet Oncology. 2012;13(9):869-878. Shpilberg O, et al. Br J Cancer. 2013;109(6):1556-1561. De Cock E, et al. Plos One. 2016;11(6):e0157957. 18 6 9/28/2017 PAVO: Study Design Phase 1b, open-label, multicenter, dose-finding, proof of concept study Key eligibility criteria • RRMM with measurable disease • ≥2 prior lines of treatment • Not received anti-CD38 therapy Group 1 (n = 8) DARA: 1,200 mg rHuPH20: 30,000 U Dosing schedule ▪ Approved schedule for IV ▪ 1 Cycle = 28 days Infusion time ▪ 1,200 mg: 20-min infusion (60 mL) ▪ 1,800 mg: 30-min infusion (90 mL) Group 2a (n = 45) DARA: 1,800 mg rHuPH20: 45,000 U Primary endpoints Secondary endpoints • Ctrough of DARA at Cycle 3/Day 1 • Safety • • • • Pre-b/post-infusion medication ▪ Acetaminophen, diphenhydramine, montelukast, and methylprednisolone ORR CR Duration of response Time to response RRMM, relapsed or refractory multiple myeloma; QW, weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; Ctrough, trough concentration; ORR, overall response rate; CR, complete response; PK, pharmacokinetic. aGroup 2 comprises 4 distinct cohorts, each treated with DARA 1,800 mg and rHuPH20 45,000 U. C trough on Cycle 3/Day 1 in Group 1 supported dose selection for Group 2. The study evaluation team reviewed safety after Cycle 1 and PK after Cycle 3/Day 1 for each group. bAdministered 1 hour prior to infusion. 19 IRRs 1,200 mg n=8 1,800 mg n = 45 ▪ All IRRs in the 1,800-mg group were grade 1 or 2 IRR, % (n) 13 (1) 24 (11) Chills Pyrexia Pruritus Dyspnea Flushing Hypertension Hypotension Nausea Non-cardiac chest pain 13 (1) 0 (0) 0 (0) 13 (1) 0 (0) 0 (0) 0 (0) 0 (0) 9 (4) 9 (4) 4 (2) 0 (0) 2 (1) 2 (1) 2 (1) 2 (1) ▪ One grade 3 IRR of dyspnea in the 1,200-mg group ▪ No grade 4 IRRs were observed ▪ All IRRs occurred during or within 4 hours of the first infusion ▪ No IRRs occurred during subsequent infusions in either group ▪ Abdominal wall SC injections were well tolerated 13 (1) 0 (0) Oropharyngeal pain 0 (0) 2 (1) Paresthesia Rash Sinus headache Tongue edema Vomiting Wheezing 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) Low IRR incidence and severity with DARA SC 20 Immune Checkpoint Inhibitors in MM 7 9/28/2017 Immune Checkpoint Inhibitors for Relapsed/Refractory Multiple Myeloma Pneumonitis Type CAR T Trial Patient Types Study Phase Site(s) CART-19 for multiple myeloma Relapsed/ refractory 1 University of Pennsylvania Safety study of CAR-modified T cells targeting NKG2D-ligands Relapsed/ refractory 1 Dana-Farber Cancer Institute Study of T cells targeting B-cell maturation antigen (BCMA) for previously treated multiple myeloma Relapsed/ refractory 1 National Cancer Institute University of Pennsylvania Tadalafil and lenalidomide maintenance with or without activated marrow infiltrating lymphocytes (MILs) in high-risk myeloma Newly diagnosed; relapsed (without prior ASCT) 2 Sidney Kimmel Comprehensive Cancer Center Adoptive immunotherapy with activated marrow-infiltrating lymphocytes and cyclophosphamide graft-versus-host disease prophylaxis in patients with relapse of hematologic malignancies after allogeneic hematopoietic cell transplantation Relapsed/ refractory 1 Sidney Kimmel Comprehensive Cancer Center Affinityenhanced T cells Engineered autologous T cells expressing an affinity-enhanced TCR specific for NY-ESO-1 and LAGE-1 Relapsed/ refractory 1/2 City of Hope University of Maryland DLI CD3/CD28 activated Id-KLH primed autologous lymphocytes Post-transplant 2 University of Pennsylvania MILs 8 9/28/2017 Myeloma CAR Therapy • Which Target: – CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1 (SLAMF7), BCMA • Many questions remain about CAR design: – Optimal costimulatory domains – Optimal vector – Optimal dose and schedule – Need for chemotherapy – Perhaps “cocktails” of multiple CARs or CARs + chemotherapy will be required for best outcomes Which Target: BCMA B cell maturation antigen (BCMA) ▪ A member of the TNF receptor superfamily ▪ Expression is largely restricted to plasma cells and mature B cells ▪ Not detectable in any other normal tissues ▪ Expressed nearly universally on multiple myeloma cells ▪ Anti-MM efficacy validated in initial studies1 Multiple myeloma cells expressing BCMA (brown color = BCMA protein) 1. Ali et al., Blood 2016 128: 1688. Cohen et al., ASH 2016, abstract 1147 CRB-401 Study Design 9 9/28/2017 Adverse Events Generally Mild, No ≥ Grade 3 CRS* or Neurotoxicity ▪ No DLTs to date ▪ Cytopenias related to fludarabine/ cyclophosphamide lymphodepletion, as expected ▪ No ≥ Grade 3 cytokine release syndrome or neurotoxicity *CRS uniformly graded according to Lee et al., Blood 2014;124:188195 Best Response and Time Since bb2121 Infusion Cytokine Release Syndrome Summary 10 9/28/2017 UPENN; BCMA CAR TRIAL Cohort 1 1 - 5 x 108 CAR+ T cells (n=3-6) Up to n=9 Up to n=9 Feasibility Efficacy (response rates, PFS, OS, MRD) Exploratory: – – – – – – – 4 week delay between subjects 1) Flow Safety Secondary – – • Up to n=9 Primary objective – • Cohort 3 Cytox 1.5 g/m2 + 1 - 5 x 108 CAR+ T cells (n=3-6) Pre BCMA-CAR • Cohort 2 Cytox 1.5 g/m2 + 1 - 5 x 107 CAR+ T cells (n=3-6) CART-BCMA expansion, persistence, phenotype Impact on normal B cell and PC compartments BCMA expression pre- and post-treatment Cytokine/chemokine levels Soluble BCMA, BAFF, APRIL levels Assess for anti-CAR immune responses Impact on tumor microenvironment Day 7 CD8 2) qPCR Patient characteristics – Cohort 1 (n=9) Characteristic Median (range) or % Age 57 (44 – 70) Gender 67% male; 33% female Isotype IgG (33%), IgA (44%), LC (22%) Prior lines of therapy Lenalidomide 9 (4-11) 100% (refractory: 78%) Bortezomib 100% (refr: 89%) Pomalidomide 100% (refr: 89%) Carfilzomib 100% (refr: 89%) Autologous SCT 78% Cyclophosphamide 100% (refr: 67%) Daratumumab 44% (refr: 44%) Anti-PD1 33% (refr: 33%) High-risk genetics -17p or TP53 mutation 100% 67% Extramedullary dz 33% % BM plasma cells 80 (15 – 95) Day 0 absolute CD3 258/µL (117 – 1354) Bi-Specific Antibody (bsAb) Constructs 11 9/28/2017 Conclusions • Immunotherapy is an active strategy for myeloma therapy • Optimal targets for immunotherapy remain under study 12
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