Multiple Myeloma. Dr. Janet MacEachern BA, MD, FRCP(C) Grand River Regional Cancer Center Kitchener, Ontario

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1 Multiple Myeloma Dr. Janet MacEachern BA, MD, FRCP(C) Grand River Regional Cancer Center Kitchener, Ontario

2 Disclosures Relationships with financial sponsors: Grants/Research Support: n/a Speakers Bureau/Honoraria: n/a Consulting Fees: n/a Patents: n/a Other: n/a

3 Objectives Review the diagnosis and pathophysiology of multiple myeloma Establish rationale for current standard treatment approach Review evidence for 3 new agents (carfilzomib, daratumomab, lenalidomide) Review the logistics and side effect profiles of new regimens A word on lenalidomide maintenance A brief review of MGUS

4 Myeloma Neoplasm of plasma cells Aberrant Immunoglobulin production IgG, IgA (rarely IgM), light chain myeloma (Kappa, Lamda), non-secretory Impaired hematopoiesis (ESAs, prbc support) Cortical bone loss, lytic lesions, fractures (pami, kyphoplasty) Renal failure Immunosuppression (hypogammaglobulinemia, IVIg and scig replacement, immunizations, vigilance) HSV immunization and prophylaxis Cytogenetic risk stratification (t(11;14) for example)

5 Myeloma Treatment Approach ASCT eligible Doublet or triplet induction Rev/dex Rev/velcade/Dex CyBORD ASCT (usually one, rarely tandem) Revlimid maintenance At relapse KRD, KD Pom dex or cyclo/pom/dex Dara (alone or in combination) ASCT ineligible First line: VMP Rev/dex MP At relapse KRD KD Rev/dex Pom/dex Pom/cyclo/dex Daratumomab

6 Carfilzomib (Kyprolis) Currently has a place in the relapsed/refractory setting Kd kyprolis/dex vs Velcade/dex: Endeavor trial PFS 18.7mo vs 9.4mo KRd (kyprolis/revlimid/dex) vs Rd: Aspire trial After 1 prior line of therapy PFS 29.6 mo vs 17.6 mo After 2 prior lines of therapy PFS 25.8 mo vs 16.7 mo Median OS 48 months vs 40 months Doses, schedules and duration of therapy are different between the two regimens

7 ABSTRACT 743 Overall Survival of Patients with Relapsed/Refractory Multiple Myeloma Treated with Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone: Final Analysis from the Randomized Phase 3 ASPIRE Trial A. Keith Stewart, 1 David Siegel, 2 Heinz Ludwig, 3 Thierry Facon, 4 Hartmut Goldschmidt, 5 Andrzej Jakubowiak, 6 Jesus San-Miguel, 7 Mihaela Obreja, 8 Julie Blaedel, 8 Meletios A. Dimopoulos 9 1 Mayo Clinic, Scottsdale, AZ, USA; 2 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 3 Wilhelminen Cancer Research Institute, Vienna, Austria; 4 CHRU Lille Hôpital Claude Huriez, Lille, France; 5 University of Heidelberg, Heidelberg, Germany; 6 University of Chicago, Chicago, IL, USA; 7 Clinica Universidad de Navarra-Centro de Investigación Médica Aplicada, IDISNA, CIBERONC, Pamplona, Spain; 8 Amgen Inc., Thousand Oaks, CA, USA; 9 National and Kapodistrian University of Athens School of Medicine, Athens, Greece Stewart AK, et al. Oral presentation at ASH 2017 [abstract 743].

8 ASPIRE: LEN + Dex ± CFZ In RRMM Study Design Relapsed or progressive MM 1 3 prior therapies PR to 1 prior regimen N = 792 Stratification: β2-macroglobulin, Prior BORT, Prior LEN 1:1 KRd CFZ: 27 mg/m 2 D1, 2, 8, 9, 15, mg/m 2 D1, 2 for cycle 1 only After cycle 12, CFZ given on D1, 2, 15, 16 After cycle 18, CFZ discontinued LEN: 25 mg D1-21 DEX: 40 mg D1, 8, 15, day cycles Rd LEN: 25 mg D1-21 DEX: 40 mg D1, 8, 15, day cycles Key exclusion criteria: CrCl < 50 ml/min, LEN or DEX intolerance, PD on BORT, PD during the first 3 months of Tx if previously treated with Rd, PD at any time if Rd was the most recent Tx Primary endpoint: PFS Secondary endpoints: OS, ORR, DOR, HRQoL, safety Stewart AK, et al. Oral presentation at ASH 2017 [abstract 743]. 8

9 ASPIRE: LEN + Dex ± CFZ In RRMM key efficacy results Outcome KRd Rd HR (95% CI) (n = 396) a (n = 396) a 1-sided P Value Median PFS, months Median OS, months ( ) P < ( ) P =.0045 Outcome Post-KRd (n = 167) Post-Rd (n = 200) HR (95% CI) 1-sided P Value Median OS beyond progression, months ( ) P =.4473 Data cutoff: April 28, 2017 Median PFS follow-up: 48.8 months (KRd), 48.0 months (Rd) Median OS follow-up: 67 months Median OS was 11.4 months longer with KRd vs Rd in patients at first relapse (47.3 vs 35.9 months, respectively) a ITT population. Stewart AK, et al. Oral presentation at ASH 2017 [abstract 743]. 9

10 ASPIRE: LEN + Dex ± CFZ In RRMM SAFETY TEAEs, (%) KRd (n = 392) Rd (n = 389) All Grade Grade 3 All Grade Grade 3 Hematologic Anemia Neutropenia Thrombocytopenia Nonhematologic a Diarrhea Fatigue Cough Pyrexia Upper respiratory tract infection Hypokalemia Muscle spasms a 25% in either arm. Stewart AK, et al. Oral presentation at ASH 2017 [abstract 743]. 10

11 Carfilzomib: cheat sheet Risk of tumour lysis in first cycle only Dose escalation in cycle 1 Day 1,2 20mg/m2/d Day 8,9,15,16 27mg/m2/d Cycle 1 days 1 and 2 only Aggressive oral hydration 30ml/kg/d (~2L) x 48h NS 500cc pre dose and 500cc post dose Monitor for tumour lysis days 2,3,4 For all other days and cycles NS 250cc pre dose is common. Post dose hydration optional (I do not give one)

12 Carfilzomib: cheat sheet Thrombocytopenia expected (class effect) For velcade hold if plts <50 For carfilzomib hold if plts <25 4-6% incidence of cardiac events. No specific guidelines, but be mindful Acyclovir prophylaxis mandated in the trials ASA 81mg/d mandated if Revlimid is used (effective VTE prophylaxis in this setting)

13 Daratumomab

$RRMM LEN in Combination with DARA (POLLUX) Study Design 1,2 1 prior therapy Prior LEN exposure, but not refractory CrCl 30 ml/min 1:1 DRd (n = 286) DARA 16 mg/kg IV Cycles 1-2: QW Cycles 3-6: Q2W$ ISS stage, LEN exposure Primary endpoint: PFS Secondary endpoints: TTP, OS, ORR, VGPR, MRD, TTR, and DOR Median duration of study Tx: 24.5 months for DRd and 16.

ISS stage, LEN exposure Primary endpoint: PFS Secondary endpoints: TTP, OS, ORR, VGPR, MRD, TTR, and DOR Median duration of study Tx: 24.5 months for DRd and 16.

14 RRMM LEN in Combination with DARA (POLLUX) Study Design 1,2 1 prior therapy Prior LEN exposure, but not refractory CrCl 30 ml/min 1:1 DRd (n = 286) DARA 16 mg/kg IV Cycles 1-2: QW Cycles 3-6: Q2W Cycles 7: Q4W LEN 25 mg PO D1-21 DEX a 40 mg PO weekly 28-day cycles Rd (n = 283) LEN 25 mg PO D1-21 DEX 40 mg PO weekly 28-day cycles Tx until PD or unacceptable toxicity Stratification: prior Tx, ISS stage, LEN exposure Primary endpoint: PFS Secondary endpoints: TTP, OS, ORR, VGPR, MRD, TTR, and DOR Median duration of study Tx: 24.5 months for DRd and 16.0 months for Rd a On DARA dosing weeks, 20 mg DEX on D1 (as premedication) and D2. CrCl, creatinine clearance; DARA, daratumumab; DEX, dexamethasone; DOR, duration of response; DRd, daratumumab, lenalidomide, dexamethasone; ISS, International Staging System; IV, intravenously; LEN, lenalidomide; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, every week; Rd, lenalidomide, dexamethasone; RRMM, relapsed or refractory multiple myeloma; TTP, time to progression; TTR, time to response; Tx, treatment; VGPR, very good partial response. 1. Bahlis NJ, et al. Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM): Efficacy and Safety Update (POLLUX). ASCO 2017, abstract # ClinicalTrials.gov. NCT Accessed June 7,

15 LEN in Combination with DARA (POLLUX) Key Efficacy and Safety Data a DRd (n = 286) Rd (n = 283) P Value Median PFS, months NR 17.5 <.0001 Median OS, months NR NR Response, % b PR VGPR CR <.0001 <.0001 <.0001 Median DOR, months NR 26.0 Median TTNT, months NR 22.7 <.0001 Most common grade 3/4 hematologic TEAEs ( 5%), % c Neutropenia Febrile neutropenia Anemia Thrombocytopenia Lymphopenia Most common grade 3/4 non-hematologic TEAEs ( 5%), % c Pneumonia Diarrhea Fatigue Discontinued Tx due to TEAEs, % c SPMs, % c 6 d 6 e a Median follow-up, 25.4 months. b n = 281 and n = 276 response-evaluable patients in the DRd and Rd arms, respectively. c n = 283 and n = 281 for the safety populations in the DRd and Rd arms, respectively. d Includes 5 patients with SCC, 1 with acute monocytic leukemia, and 1 with EBV-associated lymphoproliferative disorder. e Includes 4 patients with SCC and 1 with sideroblastic anemia. See slide notes for abbreviations. Bahlis NJ, et al. Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM): Efficacy and Safety Update (POLLUX). ASCO 2017, abstract #

16 PFS a Median follow-up: 32.9 months (range, months) month PFS b % surviving without progression No. at risk Rd DRd Months % 35% HR 0.44; 95% CI, ; P < DRd Median: not reached Rd Median: 17.5 months % reduction in risk of progression/death for DRd versus Rd HR, hazard ratio; CI, confidence interval. a Exploratory analyses based on clinical cut-off date of October 23, b Kaplan-Meier estimate. Dimopolous M, et al. American Society of Hematology (ASH) 2017, #739 16

17 PFS With Subsequent Line of Therapy (PFS2) month PFS2 a % surviving without progression No. at risk Rd DRd Months HR 0.51; 95% CI, ; P < % 58% DRd Rd Median: 32.3 months 0 0 DRd does not negatively impact outcomes of subsequent therapy a Kaplan-Meier estimate. Dimopolous M, et al. American Society of Hematology (ASH) 2017, #739 17

18 Daratumomab Anti-CD38 antibody After drug infused, all blood bank serological tests will be positive: DAT (Coomb s) Antibody screen Crossmatch Before giving first dose of daratumomab alert blood bank to have patient s blood Phenotyped at CBS so they can in future issue phenotypically compatible blood products.

19 Lenalidomide (Revlimid) Oral agent 25mg/d x21 days q28d (monotherapy or in combination) Evidence to support its use first line and in relapsed/refractory population Health Canada Mandated Safety Program REVAID (patient, prescriber, dispensing pharmacy) Dose adjust for renal impairment/dialysis

20 Lenalidomide (Revlimid) Cytopenias common Hold if plts <50 ESA support for anemia Rash Benadryl, low dose prednisone, Hold drug Desensitization protocol GI (diarrhea) Increased risk VTE (ASA prophylaxis)

21 Lenalidomide Maintenance McCarthy CALGB. NEJM 2012;366(19) n=568, 47 centers Median TTP 50 months vs 27 months 7y OS 62% vs 50%; at the cost of no treatment break and doubling of the rate of secondary primary malignancies from 6% to 12% Attall et al IFM. NEJM 20212; patients <65y, 77 centers 10mg/d x 3months then escalated to 15mg/d Median PFS 41 months vs 23 months ***4y OS no different SPM: 3.1 per 100 patient years vs 1.2

22 Lenalidomide Maintenance Should be routinely discussed and offered as an option Funding climate must be considered If progress on maintenance lenalidomide, may not be eligible for a triplet (DRD, KRD) Comes at a substantial resource cost (~$10 000/mo) and significant increase in second primary malignancies Conversation needs to be balanced

23 MGUS

24 Multiple Myeloma Dr. Janet MacEachern BA, MD, FRCP(C) Grand River Regional Cancer Center Kitchener, Ontario

COMy Congress The case for IMids. Xavier Leleu. Hôpital la Milétrie, PRC, CHU, Poitiers, France

COMy Congress The case for IMids. Xavier Leleu. Hôpital la Milétrie, PRC, CHU, Poitiers, France Xavier Leleu Hôpital la Milétrie, PRC, CHU, Poitiers, France The case for IMids COMy Congress 21 Disclosures Grants/research support: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium/Takeda, Novartis,