Updates in the Treatment and Management of Relapsed/Refractory Multiple Myeloma

Transcription

1 Updates in the Treatment and Management of Relapsed/Refractory Multiple Myeloma Rachid Baz, MD Associate Professor, Departments of Oncologic Sciences and Medicine University of South Florida Associate Member, Myeloma Section Head and Director of Clinical Research Department of Malignant Hematology H. Lee Moffitt Cancer Center and Research Institute Disclosures Research Funding: Celgene Millennium Sanofi Bristol Myers Squibb Karyopharm Therapeutic 1

2 Overview Selecting Therapy Based on Specific Patient and Disease Features Current Recommendations and Treatment Options for Relapsed/Refractory Myeloma Future Directions in the Salvage Setting Management of Adverse Events Selecting Therapy for Myeloma Based on Specific Patient and Disease Features 2

3 When to Consider Retreatment Need to consider biochemical vs symptomatic relapse Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of relapse Caveat: Patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of biochemical relapse Factors in Selecting Treatment For Relapsed/Refractory Myeloma Disease-related factors Duration of response to initial therapy Treatment-related factors Previous therapy exposure (relapsed or refractory) Toxicity of regimen (combination vs single agent) Mode of administration (eg, oral or intravenous) 3

4 How do We Synthesize These Variables? Does the patient NEED therapy? Defined by presence of symptoms similar to initial treatment Not all patients with biochemical relapse need therapy Aggressiveness of previous relapse, risk of organ damage, and magnitude of M-protein increase all play into this decision Relapsed/Refractory Myeloma: Preferred Regimens NCCN Category 1 Bortezomib SC vs IV administration Bortezomib/PLD Carfilzomib/lenalidomide/ dexamethasone Panobinostat/bortezomib/ dexamethasone Lenalidomide/dexamethasone NCCN Category 2A Repeat primary induction therapy if relapse at > 6 mos Bortezomib combinations With dex; len/dex; thalidomide Carfilzomib Cyclophosphamide High-dose or with bort/dex or len/dex Pomalidomide/dexamethasone Thalidomide/dexamethasone DCEP, DT-PACE, or VTD-PACE NCCN clinical practice guidelines in oncology: multiple myeloma: v

5 Treating Indolent, Slow-Growing Myeloma in First Relapse IMiD-Based Salvage Initial treatment with bortezomib May consider single agent without dexamethasone Underlying PN PI-Based Salvage Initial treatment with IMiD Previous bortezomib therapy but good or long response Renal dysfunction Transplant-Based Salvage Transplant not part of initial therapy Long remission post transplant Treating Relapsed/Refractory Myeloma Carfilzomib-Based Salvage Intolerance to bortezomib Dexamethasonesparing treatment as part of a combination Intolerance to IMiDs Pomalidomide-Based Salvage Lenalidomide refractory Refractory to standard-dose PI Pts with del(17p)? Other Salvage Refractory to pomalidomide and carfilzomib Monoclonal antibody candidate Clinical trials 5

6 Treating Aggressive Myeloma With Rapid, Multiple Relapses Likely Combination Therapy Do Not Wait for Symptomatic Relapse Chemotherapy-Based Salvage DCEP vs DT-PACE Oral vs IV chemo Performance status of patient plays important role Chemotherapy + Novel Agent Combinations of lenalidomide/ bortezomib and other chemotherapy agents Transplant-Based Salvage Likely to be short lived Rapid disease control Reconstitute marrow Current Recommendations and Treatment Options for Relapsed/Refractory Myeloma 6

7 Summary of Combination Therapy in RR MM ORR, % IMiD-Based ORR PFS OS 31 Rd [1] * CyRd [2] PomD [3] * CyPomD [4] PI-Based CD [5] CRd [6] * CPomD [7] CyCD [8] VD [9] * VRd [10] * VPomD [11] CyBorD [12] Survival, months IMiD-Based Rd [1] * PomD [3] * CyPomD [4] 4 20 CD [5] 26 NR PI-Based NR CRd [6] * CPomD [7] VRd [10] * VPomD [11] CyBorD [12] *Data from phase III trials, all others from phase I or II trials 1. Dimopoulos M, et al. N Engl J Med. 2007;357: Morgan JG, et al. Br J Haematol. 2007;137: San Miguel J, et al. Lancet Oncol. 2013;14: Baz R, et al. ASH Abstract Lendvai N, et al. Blood. 2014;124: Stewart AK, et al. ASH Abstract Shah JJ, et al. ASH Abstract Bringhen S, et al. Blood. 2014;124: Mikhael JR, et al. Br J Haematol. 2009;144: Richardson PG, et al. Blood. 2014;123: Lacy MQ, et al. ASH Abstract Monge J, et al. ASCO Abstract Summary of IMiD Combination Therapy Regimen Phase N Outcomes Len/dex vs dex [1] III 351 OS: NR vs 20.6 mo TTP: 11.3 mo vs 4.7 mo ORR: 60.2% vs 24% Len/cyclo/dex [2] II 21 ORR: 65% Pom/dex II [3] III [4] OS: 16.5 mo vs mo PFS: 4.2 mo vs 2.7 mo ORR: 33% vs 18% PFS: 4.0 mo vs 1.9 mo Pom/cyclo/dex vs pom/dex [5] II 70 OS: 16.4 mo vs 10.5 mo PFS: 9.2 mo vs 4.4 mo ORR: 65% vs 39% 1. Dimopoulos M, et al. N Engl J Med. 2007;357: Morgan JG, et al. Br J Haematol. 2007;137: Richardson PG, et al. Blood. 2014;123: San Miguel J, et al. Lancet Oncol. 2013;14: Baz R, et al. ASH Abstract

8 Summary of Proteasome Inhibitor Combination Therapy Regimen Phase N Outcomes Carfilzomib ± dex [1] II 44 OS: 20.3 mo PFS: 4.1 mo ORR: 55% Carfilzomib/len/dex vs len/dex [2] III 792 PFS: 26.3 mo vs 17.6 ORR: 87.1% vs 66.7% (Interim 24-mo OS: 73.3% vs 65.0%) Carfilzomib/pom/dex [3] I/II 79 PFS: 9.7 mo ORR: 70% Carfilzomib/cyclo/dex [4] II 58 2-yr OS: 87% 2-yr PFS: 76% ORR: 95% 1. Lendvai N, et al. Blood. 2014;124: Stewart AK, et al. ASH Abstract Shah JJ, et al. ASH Abstract Bringhen S, et al. Blood. 2014;124: Summary of Proteasome Inhibitor Combination Therapy Regimen Phase N Outcomes Bortezomib ± dex [1] IIIb 638 ORR: 67% Bortezomib/len/dex [2] II 64 OS: 30 mo PFS: 9.5 mo ORR: 64% Bortezomib/pom/dex [3] I/II 47 PFS: 10.7 mo ORR: 85% Bortezomib/cyclo/dex [4] II 55 OS: 29 mo PFS: 9.2 mo ORR: 71% 1. Mikhael JR, et al. Br J Haematol. 2009;144: Richardson PG, et al. Blood. 2014;123: Lacy MQ, et al. ASH Abstract Monge J, et al. ASCO Abstract

9 Phase III ASPIRE: Len/Dexamethasone ± Carfilzomib in RR MM Randomized, open-label, multicenter phase III trial Stratified by: β 2 -microglobulin, prior bortezomib, and prior lenalidomide Pts with symptomatic RR MM after 1-3 prior treatments with PR to 1 prior regimen (N = 792) KRd Carfilzomib* 27 mg/m 2 IV Days 1, 2, 8, 9, 15, 16 (20 mg/m 2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15, 22 (n = 396) Rd Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15, 22 (n = 396) *After cycle 12, carfilzomib given on days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued. Stewart AK, et al. ASH Abstract 79. Len/Dexamethasone ± Carfilzomib in RR MM (ASPIRE): PFS (ITT) Proportion Surviving Without Progression KRd Rd (n = 396) (n = 396) Median PFS, mo HR (KRd/Rd) (95% CI) 0.69 ( ) P value (one-sided) <.0001 KRd Rd Months Since Randomization Risk Group by KRd (n = 396) Rd (n = 396) HR P Value FISH n Median PFS, mo n Median PFS, mo High Standard Stewart AK, et al. ASH Abstract 79. Reproduced with permission. 9

10 ASPIRE: Interim OS Analysis Proportion Surviving KRd Rd (n = 396) (n = 396) 0.4 Median OS, mos NR NR HR (KRd/Rd) (95% CI) 0.79 ( ) P value (1 sided) KRd Median follow-up: 32 months Rd Mos Since Randomization OS results did not meet prespecified statistical boundary (P =.005) at interim AEs consistent with previous studies; no unexpected toxicities observed Grade 3 cardiac failure and ischemic heart disease: 3.8% and 3.3% in KRd arm vs 1.8% and 2.1% in Rd arm, respectively Stewart AK, et al. ASH Abstract 79. Reproduced with permission. ASPIRE: Select Adverse Events AE, % KRd (n = 392) Rd (n = 389) All Grade Grade 3 All Grade Grade 3 Non-hematologic AEs occurring in 25% of patients Diarrhea Fatigue Cough Pyrexia Upper respiratory tract infection Hypokalemia Muscle spasms Hematologic AEs occurring in 25% of patients Anemia Neutropenia Thrombocytopenia Other AEs of Interest Peripheral neuropathy* Hypertension Acute renal failure* Cardiac failure* Ischemic heart disease* Stewart AK, et al. ASH Abstract 79. Reproduced with permission. 10

11 Phase III PANORAMA 1: Bort/Dex ± Panobinostat in RR Myeloma Randomized, double-blind trial Stratified by prior lines of therapy, and prior bortezomib Treatment Phase I: Eight 21-d cycles (24 wks) Pts with symptomatic RR MM after 1-3 prior treatments (bortezomibrefractory excluded) (N = 768) Panobinostat 20 mg (3x/wk) Bortezomib 1.3 mg/m 2 IV (d1,4,8,11) Dexamethasone 20 mg (d1,2,4,5,8,9,11,12) (n = 387) Placebo (3x/wk) Bortezomib 1.3 mg/m 2 IV (d1,4,8,11) Dexamethasone 20 mg (d1,2,4,5,8,9,11,12) (n = 381) Richardson P, et al. ASCO Abstract 8510^. Patients with SD in tx phase I can proceed to tx phase II Treatment Phase II: Four 42-d cycles (24 wks) Panobinostat 20 mg (3x/wk) Bortezomib* 1.3 mg/m 2 IV Dexamethasone* 20 mg *reduced frequency Placebo (3x/wk) Bortezomib* 1.3 mg/m 2 IV Dexamethasone* 20 mg *reduced frequency k17 Bort/Dex ± Panobinostat in RR Myeloma (PANORAMA 1): PFS Primary endpoint reached: median PFS by 3.9 months GK6 Richardson P, et al. ASCO Abstract 8510^. 11

12 Slide 22 GK6 k17 Design: For the PFS and OS slides, change to Pan/bort/dex and placebo/bort/dex both here and in legend. Also, hyphenate CI ranges. Change PFS column header to "Median PFS, mo (95% CI)" Gordon Kelley, 3/19/2015 Creative, please redraw krosenthal, 3/31/2015

13 Bort/Dex ± Panobinostat in RR Myeloma (PANORAMA 1): OS Interim OS analysis; final analysis forthcoming k18 Richardson P, et al. ASCO Abstract 8510^. PANORAMA 1: Safety Cardiac GI Other Heme Select AEs ( 10% incidence and Pano + Bort/Dex (n = 381) Pbo + Bort/Dex (n = 377) 5% greater Incidence with Pano), % All grades Grade 3/4 All grades Grade 3/4 Arrhythmia Diarrhea Nausea Vomiting Fatigue Peripheral edema <1 Pyrexia Weight loss Decreased appetite Thrombocytopenia Anemia Neutropenia Leukopenia Lymphopenia Richardson P, et al. ASCO Abstract 8510^. San-Miguel JF, et al. Lancet Oncol. 2014;15:

14 Slide 23 k18 Creative, please redraw krosenthal, 3/31/2015

15 ENDEAVOR: Comparing Carfilzomib/Dex vs Bortezomib/Dex in Relapsed MM Randomized, Open-label, Phase III Study Patients with MM Relapsed after 1-3 prior regimens (primary refractory disease excluded) (N = 768) Carfilzomib* Dexamethasone* Bortezomib Dexamethasone *Carfilzomib: cycle 1 only, administered at 20 mg/m 2 IV on Days 1, 2 followed by escalation to 56 mg/m 2 on Days 8, 9, 15, and 16; then Days 1, 2, 8, 9, 15, and 16 on 28 day cycle. *Dexamethasone: administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28 day cycle. On days when carfilzomib is administered, dexamethasone is to be given 30 minutes to 4 hours prior to carfilzomib. Bortezomib: 1.3 mg/m 2 administered IV or SC on Days 1, 4, 8, and 11 of a 21-day cycle Dexamethasone: 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle Clinicaltrials.gov NCT Salvage Auto-Transplant in the Relapsed Setting: Reasonable Option? Recent data from Mayo Clinic Transplant Center suggests that auto- SCT2 appears safe and effective treatment for relapsed MM (N = 98) ORR: 86%; median PFS: 10.3 months; median OS: 33 months Rate of TRM: 4%. suggesting a favorable benefit-to-risk ratio Shorter duration of TTP after auto-sct1 predicts shorter OS post auto-sct2 TTP after auto-sct1 Median from auto-sct2, months (range) PFS OS <12 months 5.6 (3-8) 12.6 (4-23) <18 months 7.1 (6-8) 19.4 (10-42) <24 months 7.3 (6-10) 22.7 (13-62) <36 months 7.6 (7-12) 30.5 (19-62) Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:

16 Future Directions in the Salvage Setting Ixazomib (MLN9708): Phase I Studies in Relapsed/Refractory Myeloma N = 50 evaluable Dose: mg/m 2 on days 1,8,15 q28d ORR: 9 pts (1 VGPR, 8 PR) MR: 1 pt SD: 15 pts Disease control up to 9 mos Safety: generally well tolerated Heme, GI AEs manageable Low rate of discontinuation Infrequent PN; 1 grade 3 PN PK profile supports wkly dosing Kumar S, et al. Blood. 2014;124:

17 Phase III TOURMALINE-MM1: IRD vs RD in Relapsed and/or Refractory MM Patients with relapsed/refractory MM; 1-3 prior therapies; ECOG PS 0-2 (Planned N = 703) Ixazomib 4 mg PO D1,8,15 + RD* 28-day cycles Placebo PO D1,8,15 + RD* 28-day cycles Treatment continued until disease progression or unacceptable toxicity *Lenalidomide 25 mg PO Days 1-21; dexamethasone 40 mg PO Days 1,8,15,22 Primary Endpoint: PFS Secondary Endpoints: OS, OS and PFS in high-risk patients, response (ORR, PR, VGPR, CR, DOR), safety, pain response, global health outcomes, PK analysis, association between response or resistance to ixazomib and cytogenetics ClinicalTrials.gov. NCT Single-Agent Oprozomib in RR MM: Summary of Efficacy 2/7 Schedule 5/14 Schedule Phase Ib mg/d (n = 16) Phase Ib + II mg/d (n = 43) PD SD MR PR VGPR CR CBR: 50.0% ORR: 31.3% CBR: 32.6% *ORR in 11 carfilzomib-refractory patients (phase II): 18.2% Response data not shown for step-up cohorts due to limited treatment exposure Vij R, et al. ASH Abstract 34. Reproduced with permission. ORR: 23.3%* 15

18 Single-Agent Oprozomib in RR MM: Safety Phase Ib study identified MTD of oprozomib for 2/7 dosing schedule (300 mg/day) and 5/14 dosing schedule (240 mg/day) 4 dose-limiting AEs observed: grade 3 diarrhea and grade 4 thrombocytopenia (2/7 schedule), grade 3 tumor lysis syndrome and grade 3 vomiting (5/14 schedule) Overall safety improved in phase II, step-up dosing with introduction of extended-release oprozomib Incidence of grade 3 hematologic AEs declined Incidence of gastrointestinal AEs declined, except for grade 1/2 nausea and diarrhea in the 5/14 schedule Serious AEs occurred in approximately 30% to 33% of patients in phase II study (3 patients with each schedule) Overall fewer pts required dose reductions, discontinuations in phase II, but more discontinued treatment in phase II vs phase Ib with 2/7 schedule Vij R, et al. ASH Abstract 34. MAb-Based Targeting of Myeloma Antibody-dependent cellular cytotoxicity (ADCC) Complement-dependent cytotoxicity (CDC) C1q Apoptosis/growth arrest via targeting signaling pathways Effector cells: CDC C1q FcR MM 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:

19 Phase Ib/II 1703 Trial: Elotuzumab in Combination with Len/Dex in RR MM Patients treated with elotuzumab 10 or 20 mg/kg + lenalidomide/dexamethasone Approximately 60% of pts received previous treatment with bortezomib and/or thalidomide and 20% to 30% were refractory to previous treatment Percent of patients, % ORR 92% ORR 76% ORR 84% Richardson PG, et al. ASH Abstract 302. Phase 2 efficacy: progression-free survival Progression-free patients (%) Median time to progression/death: 10 mg/kg (n=36): mos mg/kg (n=37): mos 10 Total (n=73): mos Time (months) Number at risk: 10 mg/kg 20 mg/kg Total

20 Elotuzumab in Combination with Len/Dex in RR MM (Phase Ib/II): Safety Grade 3/4 AEs, n (%) Elo 10 mg/kg (n = 36) Elo 20 mg/kg (n = 37) Lymphopenia 10 (28) 5 (14) Diarrhea 5 (14) 2 (5) Neutropenia 7 (19) 7 (19) Thrombocytopenia 7 (19) 6 (16) Anemia 6 (17) 5 (14) Hyperglycemia 2 (6) 5 (14) Fatigue 3 (8) 2 (5) Back pain 3 (8) 1 (3) Dyspnea 3 (8) 1 (3) Muscle spasms 2 (6) 0 Insomnia 0 2 (5) Asthenia 1 (3) 1 (3) URI 1 (3) 1 (3) Pyrexia 1 (3) 1 (3) Peripheral edema 0 1 (3) Nausea 0 1 (3) Richardson PG, et al. ASH Abstract 302. Infusion reactions: if pts tolerated 2 ml/min, flow rate increased to 5 ml/min 33% of infusions were at 5 ml/min 11% experienced infusion reactions 7 at < 2 ml/min rate 1 at 2 ml/min rate Most common events included pyrexia (3), nausea (1), rash (3) Phase III ELOQUENT-2: Len/Dex ± Elotuzumab in RR MM Randomized 1:1 Patients with relapsed/refractory MM and 1-3 prior therapies (Planned N = 640) Elotuzumab + RD 28-day cycles RD 28-day cycles Treatment continued until disease progression, death, or withdrawal of consent Elotuzumab 10 mg/kg IV weekly D1,8,15,22 (Cycles 1-2) and D1,15 (Cycles 3+); Lenalidomide 25 mg PO D1-21; Dexamethasone 40 mg D1,8,15,22 (8 mg IV + 28 mg PO during elotuzumab dosing) Primary endpoints: PFS and ORR Secondary endpoints: OS, pain response Exploratory endpoints: Safety, time to response, DOR, time to subsequent therapy, health-related QoL, PK and immunogenicity of elotuzumab Lonial S, et al. ASCO Abstract TPS8112; ClinicalTrials.gov. NCT

21 GEN 501: Daratumumab Monotherapy Pts with R/R MM; 2 prior lines of therapy; ineligible for ASCT Part 1 (dose escalation) Daratumumab 3+3 dose escalation to 24 mg/kg (N = 32) Part 2 (expansion cohorts) Daratumumab (N = 50) ORR=35% Manageable safety profile ORR=10% n=3 n=2 n=1 n=4 Quality of responses better in the 16 mg/kg vs. 8 mg/kg group 8 mg/kg 16 mg/kg ORR, % Median PFS, wks Lokhorst et al. ASCO Abstract 8513 Phase I/II Trial: Daratumumab + Len/Dex in RR MM Phase I/II dose-escalation trial of daratumumab in combination with len/dex in RR MM (safety cohort: n = 45; efficacy cohort: n = 43) k16 Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 patients refractory to len MTD: Daratumumab 16 mg/kg + len 25 mg and dex 40 mg weekly Plesner T, et al. ASH Abstract

22 Slide 38 k16 Creative, please redraw krosenthal, 3/31/2015

23 Daratumumab + Len/Dex in RR MM: Overall Best Response Overall Best Response VGPR or Better Response (Part 2) Percentage (%) CR 31% CR 6.7% VGPR 46% PR 23% Part VGPR 43% PR 37% Part 2 Percentage (%) CR 6.7% VGPR 43.3% 2 Cycles (n = 30) 60 CR 8.0% VGPR 52% 4 Cycles (n = 25) 64.7 CR 11.8% VGPR 52.9% 6 Cycles (n = 7) PR VGPR CR Daratumumab-related serious AEs: pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program); laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program) 19/45 patients reported infusion-related reactions; mostly grade 1 and 2 Plesner T, et al. ASH Abstract 84. Reproduced with permission. Phase Ib Trial: SAR in Combination with Len/Dex in RR MM SAR650984: humanized IgG1 antibody to the CD38 receptor widely expressed in many heme malignancies Dose escalation: SAR mg/kg IV D1,15 of 28-day cycle + lenalidomide 25 mg on D dexamethasone 40 mg weekly Expansion cohort: SAR mg/kg IV MTD not reached Previous MM Treatment SAR dose, mg/kg q2w Overall 3 (n = 4) 5 (n = 3) 10 (n = 24) (n = 31) Median prior regimens (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14) Median prior lines (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11) Median time on last lenalidomide, mo (range) 7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54) Relapsed/refractory to IMiD, n (%) 3 (75) 2 (67) 21 (88) 26 (84) Martin TG, et al. ASH Abstract

24 SAR in Combination with Len/Dex in RR MM (Phase Ib): Efficacy DoR: 9.13 mo (range: ) Response, % Total (N = 31) ORR 58 scr 6 VGPR 23 PR 29 CBR 65 MR 6 SD 19 PD 13 Patients, % 100 Martin TG, et al. ASH Abstract 83. Reproduced with permission MR ORR 67% CBR 67% ORR 25% CBR 50% mg/kg (n = 4) PR 67 5 mg/kg (n = 3) Most common treatment-related grade 3/4 AEs: neutropenia, anemia, thrombocytopenia, and febrile neutropenia 15 incidences of infusion reaction, all occurring in the first 2 cycles VGPR ORR 63% CBR 67% mg/kg (n = 24) scr ORR 58% CBR 65% Overall (N = 31) JS10 Additional Agents Currently in Development Agent MOA Phase in Development Ibrutinib Tyrosine kinase inhibitor Phase I and II (BTK, ERK1/2, others) Filanesib Kinesin spindle protein Phase II (KSP) inhibitor Indatuximab ravtansine CD138 antibody-drug Phase I and II conjugate Ricolinostat HDAC inhibitor Phase I and I/II Selinexor (KPT-330) XPO 1 nuclear transport inhibitor Phase I and II 21

25 Slide 41 JS10 The relative size of the PR and VGPR bars in the "overall" column need to be adjusted. Jill Sakai, 3/18/2015

26 Management of Adverse Effects Peripheral Neuropathy: Risk Factors and General Considerations General Considerations Endocrine disorders Hypothyroidism Diabetes Nutritional disease Connective tissue disease Vascular disease Medications Herpes zoster Most common symptoms Sensory deficits Neuropathic pain Disease- and Treatment-Related Factors Hyperviscosity syndrome Hypergammaglobulinemia Incidence of peripheral neuropathy in untreated patients: 39% Incidence of grade 3/4 CIPN with novel agents Bortezomib: 26% to 44% with weekly vs twice weekly dosing with SC administration Thalidomide: 28% to 41% with higher doses and prolonged therapy Carfilzomib: overall 14% Gleason C, et al. J Natl Compr Cancer Netw. 2009;7: Palumbo A, et al. J Clin Oncol. 2014;32: Kurtin S, et al. J Adv Pract Oncol. 2013;4:

27 How Should Neuropathy Be Managed? Patient education Causes No clear established preventive guidelines, but exercise appears to be effective Provider interventions Duloxetine, pregabalin, gabapentin Glutamine, alpha lipoic acid Investigate comorbid conditions SC bortezomib vs IV (if allowed by the study) Bortezomib: SC vs IV Administration Subcutaneous FDA approved SC in 2012 Equivalent efficacy as IV (numerous studies) Reduced neuropathy, GI AEs Consider for patients with preexisting or high-risk PN 67.8% of patients prefer SC over IV 54 mins less chair time on average 46 mins less clinic time on average Intravenous FDA approved IV in 2003 Highly effective myeloma therapy Neuropathy a notable AE For SC administration, add 1.4 ml 0.9% sodium chloride Reconstituting bortezomib (3.5 mg vial) For IV administration, add 3.5 ml 0.9% sodium chloride Hydration: a key nursing consideration, especially in patients with renal compromise Barbee MS, et al. ASCO Abstract E Mateos MV, et al. Ther Adv Hematol. 2012;3: Bortezomib [package insert]

28 Risk Assessment for VTEs in Patients Receiving Thalidomide or Lenalidomide VTE prophylaxis for individual risk factors (eg, age or obesity) or myeloma-related risk factors (eg, immobilization or hyperviscosity) If 1 risk factor present: aspirin mg/day If 2 risk factors present: LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) VTE prophylaxis for myeloma therapy related risk factors (eg, high-dose dexamethasone, IMiDs, doxorubicin, multiagent chemotherapy) LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) Palumbo A, et al J Clin Oncol. 2014;32: Palumbo A, et al. Leukemia. 2008;22: Myelosuppression and Infection Myelosuppression is associated with both myeloma and the drugs used to treat it Risk of infection increased due to hypogammaglobulinemia Dose-modification guidelines are available in package inserts Infection prophylaxis Patients should remain up-to-date on appropriate vaccinations VZV prophylaxis when receiving PIs Use of IVIG or prophylactic antibiotics is controversial, and should only be used when warranted Patient education emphasizing importance of alerting treating clinicians of potential infection can reduce unnecesary antibiotics 24

29 Current Management of Bone Disease Treat the myeloma Novel therapies have benefits Direct effect on inflammatory cytokines Inhibition of bone resorption Osteoclast stimulation Bisphosphonates Pamidronate Zoledronic acid Supplement with calcium and vitamin D3 to maintain calcium homeostasis Radiotherapy (low dose) Impending fracture Cord compression Plasmacytomas Orthopedic consultation Impending or actual long-bone fractures Bony compression of spinal cord Vertebral column instability Niesvizky R, et al. J Natl Compr Canc Netw. 2010;8(suppl 1):S13-S20. Christoulas D, et al. Expert Rev Hematol. 2009;2: Drake MT. Oncology (Williston Park). 2009;23(14 suppl 5): Terpos E, et al. J Clin Oncol. 2013;31: Webb SL, et al. British J Pharmacol. 2014;[Epub ahead of print]. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy Incidence between 3%-4% with zoledronic acid or pamidronate 25

30 Overall Conclusions Doublet or triplet combination approaches should be considered Combination treatment with either bortezomib, carfilzomib, and/or pomalidomide with dexamethasone active and well tolerated Novel agents in combination can achieve prolonged responses even in relapsed disease Optimal management approaches should emphasize improving QoL by identifying potential complications of therapy and minimizing long-term toxicity New classes of agents and second-generation agents have activity and are of considerable interest 26