7/7/2017. Speaker Disclosure. Myeloma Clinical Pearls. General Concepts

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1 Speaker Disclosure Myeloma 2017 I have no disclosures. I will discuss off Label use of drugs. Some data/slides have been reproduced from multiple meetings I have attended over the past few years. Clinical Pearls General Symptoms Epidemiology The Spectrum MGUSSMMMM Cytogenetics and Risks Staging Concept if Clonal Evolution Drugs Treatment Initial Relapse/Refractory Smoldering Miscellaneous Response/MRD Survival Future General Concepts Neoplastic Proliferation of Plasma Cells Producing a monoclonal protein resulting in- Skeletal Destruction Cytopenias Renal Failure Hypercalcemia CRAB 1% of all Cancers 32,000 NP ,000 Deaths 10% of Hematologic Malignancy 4.5/100,000 in US Year African Americans (2-3X) Median Age 66 10% < 50 Men: Women/1.4:1 Anemia 73% Bone Pain 58% Elevated Creatinine 48% Weakness 32% Hypercalcemia 28% Extramedullary 7% PET/CT-Valve Inferior Survival IgG 52% IgA 21% IgM 2% Kappa or Lambda only 16% Negative 6.5% Biclonal 2% IgD2% 1

2 Diagnosis of Myeloma Previous Disease Definitions Judgement CRAB Judgement Interpreting FLC Ratio Clinical Course Imaging Studies MGUS10 No Crab <10% BMPC <3 Gm M SMM No Crab >10% BMPC >3 Gm M Myeloma Crab >10% BMPC >3 Gm M New 60% BMPC FLCr 100 > 1 MRI Focal Lesion Revised IMWG Criteria MGUS SMM Myeloma < 10 % BMPC < 3 Gm M No MDE >10 % -60 % 3 Gm M 500 mg/24hr VrM and No MDE Plasma Cell Proliferation 1 or More MDE CRAB 60 % 100 FLCr > 1 MRI Focus Disease Progression MGUS 1% Low Risk SMM 5% High Risk 25% Smoldering Myeloma Low Risk Progression 5%/Year High Risk Progression 25%/Year Median Time to Progression- 2 years PROBABILITY OF PROGRESSION (%) 100 SMM versus MGUS MGUS YEARS SINCE DIAGNOSIS New High Risk Features 1. M > 3Gm 2. IgA SMM 3. Immunophoresis 4. FLCr involved: Uninvolved > 8 < Progressive incm or > 4 6. Clonal Marrow PC 50-60% 7. Abnormal PC Immunophenotype > 95% of Marrow PC 8. Cytogenetics t(4;14) del (17p) gain(1q) 9. Circulating Plasma Cell 10. MRI 1 Focal Lesion Diffuse Change 11. PET/CT Focal Lesion Diffuse Change 2

3 ISS I. B2 < 3.5 a > 3.5 II. Neither I or II III.B2 > 5.5 Revised ISS I. 28% Standard Risk by Cytogenetics/FISH Normal LDH II. Not I or II 62% III. 10% Either High Risk Cyto/FISH or high LDH Cytogenetics FISH High del 17p +/or t(14;16) ri rii riii 5 year PFS year OS Concept Clonal Evolution and Biologic Heterogeneity 3

4 Risk Factors 1. Host 2. Cytogenetics Host Factors Advanced Age Frailty Performance Status Comorbidities Renal Law Albumin Diabetes o Neuropathy Heart Disease High B-2 Micro globin Risk Factors in Newly Diagnosed MM HOST PLASMA CELL GENETICS Other Advanced Age, Frailty Deletion (17p) High S Phase, high LDH Performance Status t(4;14), t(14;16), t(14;20) Circulating PC s Comorbidities (renal failure, low albumin, high B2M) Deletion (1p); Addition (1q) Deletion (13q) by Metaphase Cytogenetics Hypdiploidy High Serum FLC; high B2M Extramedullary Disease Reduced Polyclonal BMPC s Cytogenetically Defined, Risk-Based Classification of SMM High Risk High-Intermediate Low- Intermediate Low-Risk Del 17p T(4;14) Gain(1q) Trisomies All Other No Cytogenetic Abnormalities High-Risk GEP Signatures Early Relapse; absence of response Median TTP-2 years Median TTP-3 years Median TTP-3 years Median TTP-10 years Molecular Classification of Myeloma Drugs Disease Aggressiveness Immuonomudaltors (imids) Trisomies t(11;14) (CCND1) t(6;14) (CCND3) t(4;14) (FGFR3/MMSET) t(14;16) (C-MAF) t(14;20) (MAF-B) Proteosome Inhibitors (PI) Steroids Cytotoxic HIDA Inhibitors Antibodies Small Molecule Inhibitors 4

5 Drugs Old Older Recently Approved Future Drugs Drugs OLD Alkylators Steroids Interferon Anthracyclines Drugs OLDER ( ) Bortezomib(Velcade) Thalidomide Lenalidomide(Revlimid) Liposomal Doxorubicin Drugs Recently Approved ( ) Carfilzomib(Krypolis) Pomalidomide(Pomalyst) Daratumumab(Darzalex) Ixazomib(Nilaro) Elotuzumab(Empliciti) Selected New Classes and Targets 2016 Drugs Future PI Oprozomib Marizomib Monoclonal Antibodies NivolumabPD1 Pembrolizumab PD1 Durvalumab Small Molecule Inhibitors AMG17c Selinexor Vemuramob (Zelboraf) Venetoclax 5

6 Questions 1. Combination 2. Which combination? 3. The Puzzle Combinations can achieve better depth and duration of response. Treatment 1. Initial Transplant Eligible Transplant Ineligible Future 2. Relapse/Refractory 3. SMM 4. Concepts ASCT Consolidation Maintenance Goals of Initial Therapy 1. High Response Rate Rapid Response 2. Depth of Response 3. Improve Performance Status and QOL 4. PBSC Mobilization for younger patients What is young? Treatment Paradigm for Newly Diagnosed MM Transplant Eligible Patients Transplant Ineligible Patients Induction Therapy First Line Therapy Transplant Consolidation Initial Therapy/Maintenance Supportive Care Maintenance Treatment of Relapsed Disease Should We Tailor Therapy? By Genetic Risk Category Proteasome Inhibitors improve but not overcome poor prognosis of high-risk genetics By Age with Comorbidities Dose Modification and intensity modulation For Severe Renal Impairment Choose Bortezomib, Thalidomide, Pomalidomide, Cyclophosphamide Dexamethasone 6

7 Choice of Drugs for Initial Therapy Aim for deep and durable response MRD measurements insightful in clinical trials Continuous therapy improves outcome Induction, upfront transplant and maintenance Initial Treatment for 12 months followed by maintenance Prognostic factors are evolving High Risk disease needs new drugs Immuno-oncology will play an important role Tailor Therapy for Age and Frailty Renal Impairment Supportive Care Bone Health Thromboprophylaxis 1. Immunomodulatory (lmids) Thalidomide Lenalidomide 2. Protostome Inhibitors Bortezomib(Velcade) No IV-SQ-Yes Carfilzomib (Krypolis) IV Ixazomib PO 3. Cytotoxic Alkylating Melphalan Cyclophosphamide Bendamustine Doxorubicin Combinations VD-PACE DCEP HDAC 4. Steroids Dexamethasone 5. Approved < Not front Line > Ixazomib Carfilzomib Pomalidomide Elotuzumab (Empliciti) Daratumumab(Darzalex) Three Drugs Are Better Than Two in Novel Agent Era 100 ORR VGPR RVD 21 Day R <Renal Adjuisted> 25 mg 114 V 1.3 mg/m 2 1,4,8,11 DEX 20 mg 1&2 4&5 8&9 11& TD RD VD VTD VCD RVD RVD Lite 35 Day R 15x21d V 1.3mg/m 2 D 1,8, 15, mg 1&2, 8&9, 15&16, 22&23 10 mg 1,5,22 Initial Therapy Transplant Eligible Non Transplant New dx Transplant Intermediate Risk T (4;14) VRD x 4 ASCT? tandem High Risk del 17p T(14;16) T(14;20) KRD x 4 VRD Rd If frail Age 75 VRD # Cycles 4? ASCT + Maintenance L STD Risk B High Risk VRD X 4 L Maintenance Maintenance 2 Years Bortezomib based ASCT? tandem Maintenance Carfilzomib or Bortezomib for 2 Years 7

8 Non-Transplant Eligible msmart-transplant Eligible Standard Risk trisomies t(11;14) t (6;14) VRD x 12 months Rd if > 75 or frail 1 year Intermediate Risk All others VRD X 12 Months BortezomibMaintenance 1 year High Risk Del 17p t(14;16) t(4;14) amp(1q) t(14;20) KRD X 12 Months Intermediate Risk High-Risk 4 cycles of VRd 4 cycles of KRd Autologous Stem Cell Transplant (ASCT); Consider tandem ASCT Autologous Stem Cell Transplant (ASCT); Consider tandem ASCT Car or B Maintenance 1 year Bortezomib-based Maintenance for 2 years Carfilzomib or Bortezomib-based maintenance for 2 year Important Trials 1. SWOG S0777 VRdvd Ld Previously Untreated No intent for Transplant Improved PFS and OS 2. First 1623 Patients Ld28 days cycle until prog* Ld72 weeks MPT 72 Weeks 3. IFM/DFCI 2009 First Trial: Age Adjusted Treatment IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT Candidates) Randomize RVDx3 RVDx3 CY (3g/m2) MOBILIZATION Goal: 5x 10 cells/kg CY (3g/m2) MOBILIZATION Goal: 5x 10 cells/kg Melphalan 200 mg/m2 + ASCT RVDx5 RVDx2 Len until Progression Len until Progression ASCT at relapse MEL 200 mg/m2 if < 65 yrs 8

9 Conclusion Young Patients: o Bortezomib-based induction o ASCT o Consolidation o Maintenance Maintenance Therapy Standard Risk t(11; 14), t(6;14), Trisomies High Risk Del 17p, t(4;14), t(14;16), t(14;20) Elderly Fit Patients o 3 Drug Combinations BortezomibMelphalan/Cyclophosphamide Corticosteroids BortezomibLenalidomide/thalidomide low-dose dexamethasone Elderly Frail Patients o 2 Drug Combinations Lenalidomide-low dose-dexamethasone Lenalidomide Maintenance VRd/VTd and Autologous stem cell transplant Bortezomib-based Maintenance Summary RVD +/- Transplant is Standard CyBorDex in some (renal failure) Current Understanding Combinations will allow us to improve responses and cure a higher fraction of patients. Drugs with different MOA will overcome genetic heterogeneity. KRD versus RVD is under investigation High Risk disease can be identified and specifically targeted. 9

10 3 Drug Induction Now STANDARD Should we add a 4 th drug? EVOLUTION Trial: CRVD- NOT Better Ongoing Trials for Newly-Diagnosed Patients Ongoing Phase II Studies Dara-IRD Elo-RVD Pano-RVD Dara-KRD Alliance RVD DARA RVD t(4;14) 1 Translocation upregulates MMSET + FGFR3 Found in 15% of patients Associated with IgA Myeloma Immature Morphology Often Associated with del17 Tendency for less lytic-bone disease, younger age t(11:14) 2 Translocation upregulates CyclinD1 Found in 20% of patients Associated with IgD, IgM, and nonsecretorymm LymphoplasmacytoidMorphology Often associated with B lineage-associated Ag Enriched for amyloid/plasma cell leukemia Support 50% PR VGPR scr CR 40% 30% ORR 21% 20% 3% ORR 40% 3% 7% 17% 1. Hypercoag ASA 325 or other 2. Acyclovir Prophylaxis 3. PCP Prophylaxis 10% 3% 9% ORR 6% 4. Bisphosphonate 0% 6% All Patients (n=6) 13% t(11;14) (n=30) 3% 3% Non-t(11;14) or undetermined (n=36) 5. Monitor 6. PI SQ 10

11 Relapse Disease Important Issues and Questions 1. Biochemical or Clinical 2. Do I really need to treat perhaps min tweaking 3. Are there High-Risk Features? 4. What line of treatment? o 1 3 o > 3 } 5. What has happened to Chemotherapy Combinations? i.e; DCEP DEX 40 X 4d Cytoxan 400/m Etoposide 40/m 2 Cisplatinum 15/m 2 Relapse Disease Important Issues and Questions 6. What Drugs Used? 7. Response to Previous Drugs? 8. How well is Patient s Performance? 9. Comorbidities? 10. Goals Concept of Clonal Evolution Myeloma: Scope of The Disease Confronting Disease Relapse in Myeloma Early Relapse 1-3 Prior Lines 1. ImidBased L + D- if L Naïve or Sensitive P + D KRD IRD How would I sequence therapy? Transplant Eligible Transplant Ineligible RVD/KRD-Transplant-Maintenance RVD lite/rid 2. PI Based B+2 if BT2 Naïve or Sensitive KD KRD IRD V+ clara R+ clo 3. Immune Based Chemo Resistant DARA + V elo+ R PomDex= Pl Dara + Pl/IMiD Cellular Therapy Clinical Trial Pom/Pl Dara + Pl/IMiD Clinical Trial 11

12 Relapse 3 lines 1. Pom + Dex(mm-003) Median prior #5 ORR 31 % PFS 4 mo Median or 12.7 mo IRD 2. Dara Sirius Study Median #5 ORR 31% PFS 3-7 months * Median or 17.5 mo 3. Re Treatment Even if progressed on previous requires combination 3 Important Trials 1. CASTOR NETM 8 10 Relapse Refractory 498 Patients VD vs DARA v D o Improved PFS o Infusion Reaction o Tponia 2. Pollox 498 Patients Vd+/- DARA DARA VD Doubled VGPR & SCR 3. Aspire NEJM Patients K + LD vs LD Improved PES Selected Phase III Trials in Relapsed Disease Name of Trial No. of Prior Arm N PFS (Months) ORR VGPR CR Times ENDEAVOR 1-3 Kd % 54% 13% Vd % 29% 6% TOURMALINE- 1-3 IRd % 48% 12% MM1 Rd % 39% 7% ELOQUENT Elo-Rd % 33% 4% Rd % 28% 7% ASPIRE 1-3 KRd % 70% 32% Rd % 40% 9% PANORAMA Pano-Vd % 11% Vd % 6% NAMBUS 2 Pd % 6% 1% (MM-003) D % 1% 0% CASTOR 1 Vd-dara 251 NE 82.9% 59.2% 19.2% Vd % 29.1% 9% POLLUX 1 Rd-dara 286 NE 93% 76% 43% Rd % 44% 19% CASTOR: Median Progression-free Survival and Median Time to Disease Progression POLLOX: Progression-free Survival Aspire Early Survival Analysis 12

13 Aspire LEN-based Triple Therapy Combinations in RRMM (under study/recently completed in Phase 1/2/3 Trials Novel Agents In RR MM Innovations (Pls, IMiDs) to date have produced significant improvements in PFS and OS: recent approvals (e.g. Ixazomib) will augment this. Next wave of therapies ~ mutation-driven, as well as plasma cell biology-related Daratumumab and Elotuzumab: first in class MoAbs, and paradigm agents. Baseline immune function appears to also be a key barrier to success but may be targetable (e.g. use of PD1/PDL1 blockade) MoAbshave activity in high risk disease, represent true new novel mechanisms, as well as other immuno-therapeutics (e.g. checkpoint inhibitors, vaccines) New insights to mechanisms of drug action (e.g. panobinostat) are further expanding therapeutic opportunities with combinations. Numerous other small molecule inhibitors show promise (e.g. HDAC, CXCR4, BCL, AKT, CDK, HSP 90, Nuclear Transport, KSP, BET bromodomain proteins/myc, DUBs, MEK) Control Arm Comparator Arm Trial Name Lenalidomide and Dexamethasone Bortezomiband Dexamethasone Dexamethasone Carfilzomib,lenalidomide, and dexamethasone Elotuzumab, lenalidomide, and dexamethasone Ixazomib, lenalidomide, and dexamethasone Carfilzomib and Dexamethasone Panobinostat,bortezomib, and dexamethasone Pomalidomideand Dexamethasone ASPIRE ELOQUENT 2 TOURMALINE 1 ENDEAVOR PANORAMA 1 MM03NIMBUS No Transplant High-Dose Melphalan Myeloma X Patient Population Dosing Keynote-023: Pembrolizumab+ Lenalidomide and Dexamethasone RRMM for whom 2 prior therapies, including a proteasome inhibitor and an IMiD, have failed. Phase2 of Pembrolizumab+ Pomalidomideand Dexamethasone 2 RRMM for whom 2 prior therapies, including a proteasome inhibitor and an IMiD, have failed. Pembrolizumab 200 mg fixed dose* 200 mg IV every 2 weeks IMiD Lenalidomide: 25 mg Pomalidomide: 4 mg daily X 21 days Dexamethasone 40 mg (low-dose) 40 mg weekly Response 17 patients; 76% response rate 11 of 22 evaluablepatients (50% response rate) *Used in the phase 2portion of study based on MTD/MAD 1. San Miguel J et al Blood 2015, 126. Abstract Badros AZ et al Blood 2015, 126. Abstract 506 Immune Checkpoint Inhibitors in MM Nuclear Transport Inhibitors (Selinexor) Bromodomain Inhibitors Antibody Drug Conjugates Bispecific Antibodies TCELL (BCMA, CD19) 13

14 2017 Trends in MM Rx: Restoring Immune Function Immunomodulatory drugs, other small molecules (eg, HDACi s) Monoclonal Antibodies Checkpoint Inhibitors Vaccines Cellular Therapies Challenges and Opportunities in Relapsed Myeloma Many new treatments available Initial treatment options are changing (LEN moving frontline) Use of continuous treatment means that patients are refractory at progression (LEN Maintenance) Data supports triplet combinations of novel agents in early relapse (exposure to multiple novel agents occurs earlier) Data from pivotal trials is lagging behind clinical practice Treatment Smoldering Excess Protein Production Target Protein Degradation Genomic abnormalities and acquired resistance Target Protein Degradation Immune Suppression Restore anti-mm Immunity High Risk o Evolving or multiple high risk features o Consider MM Therapy o Trail or OBS Q 3 months Low Risk o Observation Len/Dex versus Observation in High Risk SMM: OS 14

15 High Risk SMM Trials-Mateos 1. Len 25/d cl 1-21 dex20 mg d cycles Maintenance Len 10/d years V1 OBS 1. PFS/Survival 2. Prevents irreversible damage to kidneys and bones High Risk Trials 2. Carfilzomib x 8/Rd Landgren Carfilzomib 20/3l mg/m 2 1, 2; 8, 9; 15, 16 L D 20/10 (cycles 5-8) 1,2; 8,9; 15,16 Q 28 days StemCell Harvest 4 CRd 24 cycles rev extended L 10/d 121 MRD 58% Cycle 4 100% Cycle 8 3. Elotuzumab+ L +/- dex IMWG Response Grid Combinations can Achieve Better Depth and Duration of Response CR neg immunofixation < 5% Plasma Cells ncr Serum/urine immunofixation < 5% Plasma Cells VGPR Serum/urine ummunofixation > 90% Dec serum M on SPE < 100 mg urine M or > 90% Dec involved/uninvolved light PR > 50% M > 90% urine 24 hour protein or < 200 MRD Sensitivity Should MRD Negativity be the goal? 15

16 The Effect of MRD Status on PFS and OS-( Meta Analysis) Progression-Free Survival in MRD-Molecular Response Survival Improvement Variable Outcomes in MM 16