CME INFORMATION

GOAL

The goal of this activity is to provide education and tools that help oncology nurses provide optimal care for patients with multiple myeloma within a shared decision making framework.

TARGET AUDIENCE

This activity is intended for oncology nurses and other healthcare providers who provide care for patients with multiple myeloma.

LEARNING OBJECTIVES

Upon completion of this activity, participants should be able to:

n Describe specific strategies to engage patients with multiple myeloma and their caregivers in shared decision making to make them an active participant in their care

n Educate patients with multiple myeloma on the anticipated adverse events of various treatment options so that they will be empowered to participate in treatment decision making

n Interact with patients with multiple myeloma and caregivers to evaluate resources for continuous education and support as a source of empowerment

FACULTY AND STAFF INFORMATION

Core Faculty:

Beth Faiman, PhD, MSN, APRN-BC, AOCNNurse Practitioner Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio

Joseph D. Tariman, PhD, ANP-BCAssistant Professor DePaul University Chicago, Illinois

Faculty:

Page Bertolotti, RN, BSN, OCNClinical Practice NurseMultiple Myeloma and Amyloidosis ProgramSamuel Oschin Cancer Center at Cedars-Sinai Medical CenterLos Angeles, California

Donna Catamero, ANP-BC, OCN, CCRCNurse PractitionerMount Sinai HospitalNew York, New York

Elizabeth Finley Oliver, RN, BSN, OCNPrimary RNDepartment of HematologyMoffitt Cancer CenterTampa, Florida

Sandra E. Kurtin, RN, MS, AOCN, ANP-CHematology/Oncology Nurse PractitionerClinical Assistant Professor of NursingClinical Assistant Professor of MedicineArizona Cancer CenterUniversity of ArizonaTucson, Arizona

Patricia Mangan, APRN, BCNurse LeadHematologic Malignancies/Bone Marrow and Stem Cell TransplantAbramson Cancer CenterUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Kimberly Noonan, MS, RN, ANP, AOCNNurse Practitioner, Multiple MyelomaDana-Farber Cancer InstituteBoston, Massachusetts

Tiffany Richards, MS, ANP-BC, AOCNPNurse PractitionerDepartment of Lymphoma/MyelomaUniversity of Texas M. D. Anderson Cancer CenterHouston, Texas

Staff:

Terrence FaganAssociate Managing EditorClinical Care Options, LLC

Gordon KelleySenior Clinical EditorClinical Care Options, LLC

Kevin Obholz, PhDEditorial Director, Hematology/OncologyClinical Care Options, LLC

DISCLOSURE OF CONFLICTS OF INTEREST

The Annenberg Center assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by the Annenberg Center for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. The Annenberg Center is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The faculty and staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

DISCLOSURE OF FACULTY AND STAFF FINANCIAL AFFILIATIONS

Faculty:

Page Bertolotti, RN, BSN, OCN, has disclosed that she has received fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Amgen, Celgene, and Takeda Oncology.

Donna Catamero, ANP-BC, OCN, CCRC, has disclosed that she has received consulting fees from Celgene and Takeda Oncology and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Amgen, Celgene, Janssen, and Takeda Oncology.

Beth Faiman, PhD, MSN, APRN-BC, AOCN, has disclosed that she has received consulting fees and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Amgen, Celgene, and Takeda Oncology.

Elizabeth Finley Oliver, RN, BSN, OCN, has disclosed that she has received consulting fees from Celgene and Takeda Oncology and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Amgen and Celgene.

Sandra E. Kurtin, RN, MS, AOCN, ANP-C, has disclosed that she has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Takeda Oncology.

Patricia Mangan, APRN, BC, has disclosed that she has received consulting fees from Celgene and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Amgen, Celgene, Novartis, and Takeda Oncology.

Kimberly Noonan, MS, RN, ANP, AOCN, has disclosed that she has no real or apparent conflicts of interest to report.

Tiffany Richards, MS, ANP-BC, AOCNP, has disclosed that she has received consulting fees from Celgene and Onyx.

Joseph D. Tariman, PhD, ANP-BC, has disclosed that he has no real or apparent conflicts of interest to report.

Terrence Fagan, Gordon Kelley, and Kevin Obholz, PhD, have no real or apparent conflicts of interest to report.

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

The following planners and managers, Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CHCP; Judi Smelker-Mitchek, RN, BSN; and Jan Schultz, RN, MSN, CHCP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Charles E. Willis, Director of Continuing Education from the Annenberg Center for Health Sciences at Eisenhower; Amanda Sewell, MBA, Manager of Continuing Education; Debbie Price, Database Administrative Secretary; and Alma Perez, Accreditation Specialist, from the Annenberg Center for Health Sciences at Eisenhower have no relevant commercial relationships to disclose.

DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The Annenberg Center, Clinical Care Options, and activity supporters do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the Annenberg Center, Clinical Care Options, and activity supporters. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

NURSING CONTINUING EDUCATION

Accreditation StatementAnnenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Credit Designation 1.0 contact hour may be earned for successful completion of this activity.

California Board of Registered NursingProvider approved by the California Board of Registered Nursing, Provider Number 13664, for 1.0 contact hour.

INSTRUCTIONS FOR CREDIT (CME/CE) Participants wishing to receive continuing education credit must perform all of the following:

1. Sign in upon arrival with meeting staff and attend the full session.

2. Complete the program evaluation form verifying your attendance at the session and return to meeting staff prior to departure. No credit can be given without this documentation of attendance.

Final deadline for original CME/CE activity evaluation form submission: August 31, 2016

If you do not turn in the evaluation on site at the activity, pleaseSend to: Postgraduate Institute for Medicine, 304 Inverness Way South, Suite 100, Englewood, CO 80112 Attn: Errin Bilek or fax to: 303-790-4876

Certificates will be emailed within 4 weeks following the program.

There are no fees required to participate in this activity.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

1

New Approaches to Myeloma Treatment: What You Need to Know and What You Need to Tell Your Patients

Supported by educational grants from Amgen, Celgene Corporation, and Novartis.

Image: fotostorm/Copyright©2016 iStockphoto LP. All Rights Reserved

Core Faculty

Beth Faiman, PhD, MSN, APRN-BC, AOCNNurse Practitioner Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio

Joseph D. Tariman, PhD, ANP-BCAssistant Professor DePaul University Chicago, Illinois

Agenda

The New Era of Shared Decision Making in Oncology

Clinical Updates in Multiple Myeloma

Advances in Therapy for Newly Diagnosed and Relapsed/Refractory MM

Moving Forward: Implementing SDM in Current Practice

2

The New Era of Shared Decision Making

i O lin Oncology

What is Shared Decision Making?

SDM is a model of treatment decision making in the pt encounter

4 essential elements:

1. 2 participants: healthcare providers (MD/APP/RNs) and pt

2. Both parties share information

3. Both parties take steps to build consensus about preferred treatment

4. Mutual agreement is reached between pt and healthcare member on treatment approach

Slide credit: clinicaloptions.com

The New Era of Shared Decision Making

In the past, paternalistic or provider-driven decision making model was dominant

Increased pt burden on cost and healthcare consumerism in US and elsewhere shifted the model from provider-driven to pt-centered care

All oncology nurses are involved in shared decision making[1]; nurses are a trusted source of pt information[2]

1. Tariman J, et al. Clin J Oncol Nurs. 2015;19:548-556. 2. Tariman J, et al. Ca Treat Comm. 2014;2:34-37. 3. http://www.ahrq.gov. 4. Institute of Medicine Committee on Quality of Health Care in America. 5. Patient Protection and Affordable Care Act. 6. AACN Competencies for Baccalaureate and Graduate Nurses.

Emphasis on pt-centered care

– Agency for Healthcare Research and Quality[3]

– Institute of Medicine Committee on Quality of Health Care in America[4]

– Patient Protection and Affordable Care Act[5]

– American Association of Colleges of Nursing competency[6]

Slide credit: clinicaloptions.com

3

Implementing SDM in MM

Study on preferences for participation in treatment decision making in pts newly diagnosed with active myeloma (N = 20)

– 95% preferred to have some role

Breakdown of role preferences:

– 55% preferred a shared role with provider

– 40% preferred to make decisions after seriously considering opinion of their provider

– 5% (n = 1) preferred to leave decisions to provider, as long as pt’s treatment preferences are considered

Tariman JD, et al. Oncol Nurs Forum. 2014;41:411-419. Slide credit: clinicaloptions.com

Short-term Benefits Long-term Outcomes

Increased confidence with treatment decisions

Higher satisfaction with treatment decisions Enhanced trust in healthcare team Improved self-efficacy

Treatment adherence Better quality of life Improved treatment

outcomes: disease remission

Pt Benefits of SDM

Avoidance of decisional regrets Decreased pt/caregiver stress and anxiety

related to cancer treatment decisions

Kane HL, et al. CA Cancer J Clin. 2014;64:377-388. Slide credit: clinicaloptions.com

What Are the Roles of the Nurse in SDM?

Patient

Patient Education

Psychological Support

Information Sharing With

Multidisciplinary Team

Adapted from Tariman JD, et al. Clin J Oncol Nurs. 2015;19:548-556.

Assessment, Monitoring,

Management of Treatment Side

EffectsAdvocacy

Outcomes Evaluation

Slide credit: clinicaloptions.com

4

Information Sharing With Multidisciplinary Team

Role of nurse in SDM needs to be strengthened to improve the representation of pts’ interests[1]

Multidisciplinary team approach common in many tumor types: lung,[2] head and neck,[3] colorectal,[4]

breast cancer [5] and othersbreast cancer,[ ] and others

1. Lamb BW, et al. Urol Nurs. 2014;34:83-91. 2. Leo F, et al. J Thorac Oncol. 2007:2:69-72. 3. Stalfors J, et al. Acta Otolaryngol. 2007;127:82-87. 4. Wood JJ, et al. Colorectal Dis. 2008;10:769-772. 5. Jenkins VA, et al. Qual Health Care. 2007;10:70-75. Slide credit: clinicaloptions.com

Pt Education and Information Giving

Study on treatment decision making in older adults diagnosed with symptomatic myeloma identified nurses as one of the sources of information[1]

Clinical nurse specialists are a reliable source of information for pts[2]

The nurse is THE MOST TRUSTED healthcare team member di t th 2015 G ll [3] i ll taccording to the 2015 Gallup survey,[3] so nurses are in an excellent

position to advocate for pts[1,2,4]

– Practice implications:

– Respect pt’s autonomy

– Acknowledge pt’s right to self-determination

– Ensure informed treatment decisions

1. Tariman JD, et al. Cancer Treat Commun. 2014;2:34-47. 2. Thornton M, et al. Int J Palliat Nurs. 2011;17:68-74. 3. Gallup.com. Accessed April 8, 2016. 4. Tariman JD, et al. Oncol Nurs Forum. 2014;41:411-419. Slide credit: clinicaloptions.com

Advocacy

Nurses have a critical role in encouraging pt autonomy related to ethical discussions[1]

1. Breier-Mackie S. Nurs Ethics. 2001;8:510-521. Slide credit: clinicaloptions.com

5

Psychological Support Role

Pivotal role in helping pts achieve decision satisfaction during phase I trials by allowing them to talk about what is important in their lives and searching a way to live life until the end satisfactorily[1]

During end-of-life care, nurses provide guidance and support to pts and families during their difficult decisions on artificial feeding[2] and withholding life-supporting measures[3]

Vital roles in providing emotional support to women following early breast cancer treatment in order to help them feel satisfied with their decisions and prevent psychological distress[4]

1. Ohara K, et al. Oncol Nurs Forum. 2010;37:E124-E132. 2. Bryon E, et al. J Adv Nurs. 2008;63:2-14. 3. Bouley G. Dimens Crit Care Nurs. 2011;30:321-325. 4. Budden LM, et al. Int J Nurs Pract. 2014;20:8-16. Slide credit: clinicaloptions.com

Complex Role of Nurses in SDM

Community nurse role in bereavement care in context of uncertainty[1]

Influenced by many variables, including:

l ti hi hi h

TaskTask

Task

TaskTask

Task

Task

Task

Task

Task

Task

Role

Role Role

S f

Reason

P relationships, hierarchy, power, leadership, education, experience, and responsibility[2]

Complex role during difficult and controversial treatment decisions[3]

1. Brownhill S, et al. Br J Community Nurs. 2013;18:133-139. 2. Hancock HC, et al. Int J Nurs Stud. 2006;43:693-705.3. Tariman JD, et al. Clin J Oncol Nurs. (In press.)

Task

Task

Task

TaskTask

TaskTask

Task

Task

Task

Task

Task

TaskRole

Role

Role

Role

Role

Self Purpose

Self-Esteem

Slide credit: clinicaloptions.com

Clinical Updates in Multiple MyelomaMultiple Myeloma

6

What Is Multiple Myeloma?

Cancer of the plasma cells

2016: 30,330 new cases

Median age: 69 yrs

Abnormal plasma cells

Produce

Causes: chemicals, environment

44.9% will survive at 5 yrs; MM pts are survivors

Faiman B, et al. Multiple myeloma. In: Hematologic malignancies in adults. ONS Publishing. 2014.SEER stat fact sheets: myeloma. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30.

↑ circulating abnormal serum proteins

Genetic and molecular defects

Slide credit: clinicaloptions.com

100

80

60

res

sio

n (

%)

51

6673

78

MGUS

Smoldering MM

Progression to Symptomatic MM

15% more will convert over next 5 yrs and then 1% per yr thereafter

40

20

0

51% will convert in first 5 yrs~ 10% per yr

0 5 10 15 20 25

Pro

gr

4 1016

21

Strategy: identify pts with high risk of progression; suggest early treatment before organ damage occurs

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590.Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Yrs Since Diagnosis

Slide credit: clinicaloptions.com

MM: Clinical Manifestations

Series of genetic mutations, translocations, normal cell turns malignant.Hallmarks of myeloma: CRAB (also known as myeloma defining events).

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. Slide credit: clinicaloptions.com

R = RenalInsufficiency

B = Bone Disease

A = Anemia

C = Calcium Elevation

Recurrent infections*

*Not an MDE, yet relatively common

7

Updated IMWG Criteria for Diagnosis of Multiple Myeloma

•MGUS

M protein < 3 g/dL

Clonal plasma cells in BM < 10%

No myeloma-defining events

•Smoldering Myeloma

M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine)

Clonal plasma cells in BM ≥ 10% to 60%

No myeloma-defining events

•Multiple Myeloma

Underlying plasma cell proliferative disorder

AND 1 or more myeloma-defining events

≥ 1 CRAB* feature

Cl l l ll i BM

*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)R: Renal insufficiency (CrCl < 40 mL/min or serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET/CT)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Clonal plasma cells in BM ≥ 60%

Serum free light-chain ratio ≥ 100

> 1 MRI focal lesion

Slide credit: clinicaloptions.com

Lab tests: Serum protein electrophoresis (SPEP)

Urine protein electrophoresis (UPEP)

Complete metabolic panel (CMP)

CBC + differential

Plasma ratio of free kappa/lambda light chains

Diagnostic Workup

pp g

Monoclonal protein analysis (MPA)

Bone marrow biopsy: FISH, cytogenetics, and gene expression profiling (GEP)

Imaging: Skeletal survey

MRI, CT

PET scan ± MRI, CT

Genetic changes occur

Ghobrial IM, et al. Blood. 2014;124:3380-3388. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-3548. Faiman B. Clin Lymphoma Myeloma Leuk. 2014;14:436-440. Slide credit: clinicaloptions.com

When and Why Should a Clinical Trial Be Considered?

Before organ damage occurs (preferred)

Clinical trials (preferred)

– Emphasize pros—benefits—of clinical trials

– Access to new drugsAccess to new drugs

– Collect information in logical manner

– Can benefit pt, others

– Cons and risks also exist and should be discussed with pts, caregivers

– Stringent monitoring, placebo, etc

Ghobrial IM, et al. Blood. 2014;124:3380-3388. Slide credit: clinicaloptions.com

8

Advances in Therapy for Newly Diagnosed and

R l d/R f t MMRelapsed/Refractory MM

NCCN Preferred Regimens

Other NCCN Regimens

Initial therapy (induction) for transplantation-eligible pts (response assessment

Category 1 Bort/dox/dex Rd RVd VD

Category 2A IRd KRd

Category 2B Dexamethasone

Induction and Maintenance Therapy for Transplantation-Eligible Pts With MM

p ( pafter cycle 2) VTD

Category 2A CyBorD

Liposomal dox/vin/dex Thal/dex

Maintenance therapy

Category 1 Lenalidomide Thalidomide

Category 2A Bortezomib

Category 2B VP VT Interferon Steroids Thal + pred

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016. Slide credit: clinicaloptions.com

NCCN Preferred Regimens

Other NCCN Regimens

Initial therapy (induction) for transplantation-ineligible pts (response

Category 1 Rd RVd MPR MPT

Category 2A IRd MP

Category 2B Dexamethasone

Induction and Maintenance Therapy for Transplantation-Ineligible Pts With MM

ineligible pts (response assessment after cycle 2)

MPVCategory 2A

VD CyBorD

Liposomal dox/vin/dex Thal/dex Vin/dox/dex

Maintenance therapy

Category 1 Lenalidomide Thalidomide

Category 2A Bortezomib

Category 2B VP VT Interferon Steroids Thalidomide + prednisone

Slide credit: clinicaloptions.comNCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016.

9

“Best” Treatment for the Pt?

With so many available therapies, how does one choose the “best”?

Guidelines exist to “guide” decision making

Consider:

– Prevention of further organ damage (if present)

– Age, morbidities, desire, financial, social status

– Biomarkers/cytogenetic risk group (high or low)

– 2 drugs, 3 drugs, or more?

– Pt preferences and goals

– Clinical trial availability

– Quality of life

Palumbo A, et al. J Clin Oncol. 2014;32:587-600. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-3548. Slide credit: clinicaloptions.com

IP CR

sCR

mCR

CR

Monitoring Disease is Essential: IMWG Myeloma Response Criteria

Category Response Criteria

sCR Normal FLC ratio; no clonal BM plasma cells

CR Negative IFX and < 5% BM plasma cells

VGPR Positive IFX and negative SPEP; ≥ 90% urine protein decrease; urine M-protein level

100 /24 h

Better

VGPR

PR

MR

SD

Slide credit: clinicaloptions.comPalumbo A, et al. J Clin Oncol. 2014;32:587-600. Durie BM, et al. Leukemia. 2006;20:1467-1473.

< 100 mg/24 hrs

PR ≥ 50% decrease serum M-protein and ≥ 90% decrease in 24-hr urinary M-protein

SD Not meeting criteria for CR, VGPR, PR, or progressive disease

IP CR: sCR AND BM negative by next gen flow (10-6)

sCR: CR AND normal FLC ratio, BM negative by flow, 2 measures

mCR: CR AND negative PCR (10-5)

CR: negative IFX; < 5% PC in BM; 2 measures

PDWorse

NCCN Preferred Regimens Other NCCN Regimens

Category 1 Bortezomib Bortezomib/liposomal doxorubicin Elotuzumab/len/dex Ixazomib/len/dex KRd Rd Pan/bort/dex

Category 2A Bendamustine Bortezomib/vorinostat Bendamustine/len/dex

Recommended Regimens for Pts With Relapsed/Refractory MM

Pan/bort/dex Pom/dex

Category 2A CyBorD, RVd, VD, VCD, VTD Carfilzomib, carfilzomib/dexamethasone Cyclo/len/dex Daratumumab DCEP DT-PACE ± bortezomib High-dose cyclophosphamide Thalidomide/dexamethasone Repeat primary induction Tx if relapse at > 6 mos

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016. Slide credit: clinicaloptions.com

10

Factors in Selecting Treatment for Relapsed/Refractory Myeloma

Disease-related factors

– Duration of response to initial therapy

– High-risk vs low-risk status

– Biochemical disease progression, or symptomatic?

Other comorbid conditions– Other comorbid conditions

– PATIENT PREFERENCE

Treatment-related factors

– Previous therapy exposure (relapsed or refractory)

– Toxicity of regimen (combination vs single agent)

– Mode of administration (ie, oral or IV)

– Cost and convenience (out of pocket copays for IV vs oral)

Slide credit: clinicaloptions.com

New Agents and Regimens Approved for RRMM in 2015

TreatmentNumber of Previous

Lines of Therapy

Carfilzomib (proteasome inhibitor) + lenalidomide + dexamethasone*

1-3

Elotuzumab (anti-SLAMF7 mAb) + lenalidomide + dexamethasone

1-3

Ixazomib (proteasome inhibitor) + lenalidomide + dexamethasone

≥ 1

Panobinostat (HDAC inhibitor) + bortezomib + dexamethasone

≥ 2

Daratumumab (CD38-targeted mAb) monotherapy

≥ 3

Slide credit: clinicaloptions.com

*Carfilzomib monotherapy 20/56 mg/m2 IV previously approved for pts with RRMM.

ASPIRE: Rd ± Carfilzomib in RRMM

Outcome KRd(n = 396)

Rd (n = 396)

Significance

ORR, % 87.1 66.7 P < .001

Median PFS, mos 26.3 17.6 HR: 0.69; P = .0001

Phase III trial

Interim OS results did not meet prespecified statistical boundary (P = .005)

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. N Engl J Med. 2015;372:142-152. Slide credit: clinicaloptions.com

2-yr OS, % 73.3 65.0 HR: 0.79; P = .04

11

PANORAMA 1: Bort/Dex ± Panobinostat in RRMM

Subgroup analysis of phase III trial of pts who received ≥ 2 previous treatments, including bortezomib and an IMiD

Outcome Pan/Bort/Dex(n = 73)

Bort/Dex(n = 74)

Significance

1. Richardson PG, et al. Blood. 2016;127:713-721.2. San Miguel J, et al. ASH 2015. Abstract 3026. Slide credit: clinicaloptions.com

(n = 73) (n = 74)

ORR, %[1] 58.9 39.2 P = .017

Median PFS, mos[1] 12.5 4.7 HR: 0.47

Median OS, mos[2] 25.5 19.5 Not significant

TOURMALINE-MM1: Rd ± Ixazomib in RRMM—Efficacy

CharacteristicIxazomib + Rd

(n = 360)Placebo + Rd

(n = 362)P Value

Median PFS, mos 20.6 14.7 .012*

ORR, % CR

78.311.7

71.56.6

.035

.019

Phase III trial (N = 722)

PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed

Moreau P, et al. ASH 2015. Abstract 727.

CR VGPR PR

11.736.466.7

6.632.364.9

.019

Median time to response, mos 1.1 1.9

Median DoR, mos 20.5 15.0

Median TTP, mos 21.4 15.7 .007†

*HR: 0.742. †HR: 0.712.

Slide credit: clinicaloptions.com

ELOQUENT-2: Rd ± Elotuzumab—Efficacy

OutcomeElotuzumab + Rd

(n = 321)Rd

(n = 325)HR (95% CI)

PFS Median, mos 1 yr, % 2 yrs, %

19.46841

14.95727

0.73 (0.60-0.89;P = .0014)

PFS benefit seen with elotuzumab in all predefined subgroups

Dimopoulos MA, et al. ASH 2015. Abstract 28.

3 yrs, % 26 18

Median time to next treatment, mos

33 21 0.62 (0.50-0.77)

ORR, % 79 66

Interim OS, mos 43.7 39.60.77 (0.61-0.97;

P = .0257)

Slide credit: clinicaloptions.com

12

Elotuzumab + Rd: Dose and Schedule

Cycles 1 and 2 (28-Day Cycles)

Day of cycle 1 8 15 22

Elotuzumab, mg/kg (IV) 10 10 10 10

Lenalidomide, 25 mg (PO) QD

Dexamethasone, mg (PO/IV) 28/8 28/8 28/8 28/8

Cycles 3 and Beyond (28-Day Cycles)

Implications: Infusion reaction prevention: Dex 28mg 3-24 hrs prior; Dex 8 mg IV 1 hr prior; H1, H2,

and acetaminophen premed 45-90 mins prior

HSV prophylaxis

DVT prophylaxis (lenalidomide)

Elotuzumab [package insert]. 2015.

Day of cycle 1 8 15 22

Elotuzumab, mg/kg (IV) 10 10

Lenalidomide, 25 mg (PO) QD

Dexamethasone, mg (PO/IV) 28/8 40/0 28/8 40/0

Slide credit: clinicaloptions.com

SIRIUS: Daratumumab in R/R Myeloma

Phase II trial; pts were heavily pretreated

Reductions in paraprotein occurred in majority of pts

Responses observed across subgroups

Deepening of responses with continued treatment

– Median time to response: 1 mo– Median time to response: 1 mo

Lonial S, et al. Lancet. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

Outcome Daratumumab(n = 106)

95% CI

ORR, % 29.2 20.8-38.9

Median PFS, mos 3.7 2.8-4.6

1-year* OS, % 65 51.2-75.5

Median DoR, mos 7.4 5.5-NE

*Median OS not reached.

Daratumumab: Safety, Dose, and Schedule

Daratumumab-related sAEs[2]

Dosing Schedule (16 mg/kg IV)[1] Wks

Weekly 1-8

Every 2 wks 9-24

Every 4 wks 25+ until disease progression

1. Daratumumab PI. 2015.2. Lonial S, et al. Lancet. 2016;[Epub ahead of print].

– 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 of 45 pts reported infusion-related reactions; mostly grade 1/2

Must pre/post medicate with hydrocortisone

Montelukast 10 mg and loratadine 10 mg night before and for 48 hrs after infusion

Type/cross match and antibody workup necessary

Slide credit: clinicaloptions.com

13

Promising Agents in Clinical Trial for MM

Agent MOA Phase in Development

Ibrutinib Tyrosine kinase inhibitor III

Oprozomib Proteasome inhibitor III

Filanesib Kinesin spindle protein

inhibitorII

MOR202 (MOR03087) Anti-CD38 mAb I/II

Indatuximab ravtansine CD138 antibody–drug

conjugateI/II

Ricolinostat HDAC inhibitor I/II

Selinexor (KPT-330)XPO1 nuclear transport

inhibitorI/II

Isatuximab (SAR650984) Anti-CD38 mAb Ib

Venetoclax Selective BCL-2 inhibitor I

Clinicaltrials.gov Slide credit: clinicaloptions.com

AEs Commonly Associated With MM Therapeutic Agents

X X X X X X X

X X X X X X X X X

X X X X X X X X

X X X X X X X X X X X X

Bortezomib

Carfilzomib

Thalidomide

Lenalidomide

PIs

IMiDs

Colson K. Support Care Cancer. 2015;23:1431-1445.

X X X X X X X X

X X X X X X

X X X X X X

X X X X X X X X

X X X X X X X X

X X X X X X X

X X X X X

X X X X X X X

X X X

Pomalidomide

Cyclophosphamide

Melphalan

Dexamethasone

Prednisone

Panobinostat

Vorinostat

Elotuzumab

Daratumumab

Chemotherapy

mAbs

HDACis

Corticosteroids

Slide credit: clinicaloptions.com

MM Treatment: Key AEs, Considerations

Drug Class Name Key AEs Nursing Considerations

Proteasome inhibitorsBortezomib PN, T, M, F

IV, SC; monitor platelets; safe in renal failure

CarfilzomibPN, C, M, F,

DVTHydration,

cardio/pulmonary

ASA or LMWH if high risk

Immunomodulatory agents

LenalidomideDVT, M, BD, R,

D

ASA or LMWH if high risk for clots; weekly CBC x 8

wks

Thalidomide DVT, M, BD As above

Pomalidomide DVT, M, BD, F As above

Monoclonal antibodiesDaratumumab IR, M, RD

Infusion reaction risk; pre/post med as directed;

interrupt infusion if reaction

Elotuzumab IR, M, RD As above

US Food and Drug Administration. FDA approved drug products. Slide credit: clinicaloptions.com

14

MM Treatment: Key AEs, Considerations

Drug Class NameKey Side Effects

Nursing Considerations

Alkylating agentsMelphalan M, N

CBC diff monthly; renal dose adjustment

Cyclophosphamide M, N CBC diff monthly; renal

dose adjustment y p p j

CorticosteroidsPrednisone H, MS

Monitor blood sugar, insomnia, weight gain

Dexamethasone H, MS Above

HDAC inhibitors Panobinostat C, DBaseline EKG and mag/K+ monitoring;

loperamide for diarrhea

US Food and Drug Administration. FDA approved drug products. Slide credit: clinicaloptions.com

Proper Dosing of Drugs Can Minimize AEs

Drug

Dosing Based on Risk Factors* Including Age

No Risk FactorsAt Least 1 Risk Factor

Adjusted Dose

At Least 1 Risk Factor Plus Occurrence of Grade

3/4 Nonhematologic AE

Bortezomib1.3 mg/m2 2x/wk

Days 1, 4, 8, 11 q3w1.3 mg/m2 qw

Days 1,8,15,22 q5w1.0 mg/m2 qw

Days 1,8,15,22 q5w

Lenalidomide25 mg/day 15 mg/day 10 mg/day

*Geriatric assessment, risk factors:– Older than 75 yrs of age– Mild, moderate, or severe frailty (eg, weakness, poor endurance, weight loss, low physical

activity, and slow gait speed)– Comorbidities: cardiac, pulmonary, hepatic, or renal dysfunction

Slide credit: clinicaloptions.com

LenalidomideDays 1-21 of 28-day cycle Days 1-21 of 28-day cycle Days 1-21 of 28-day cycle

Dexamethasone40 mg/wk

Days 1, 8, 15, 22 q4w20 mg/wk

Days 1, 8, 15, 22 q4w10 mg/wk

Days 1, 8, 15, 22 q4w

Melphalan0.25 mg/kg or 9 mg/m2

Days 1-4 q4-6w0.18 mg/kg or 7.5 mg/m2

Days 1-4 q4-6w0.13 mg/kg or 5 mg/m2

Days 1-4 q4-6w

Thalidomide 100 mg/day 50 mg/day 50 mg/day

Palumbo A, et al. Blood. 2015;125:2068-2074. Palumbo A, et al. Blood. 2011;118:4519-4529.

Moving Forward: Implementing SDM in Current PracticeSDM in Current Practice

15

1 Invite pt to participate

Usually at least 2 treatment options available to pt. Inviting pt to participate informs pt that more than 1 option exists and that pt preferences and values could influence treatment decision

2 Present options Pt must receive information on available treatment options

6 Steps in Implementing SDM in Oncology

3 Provideinformation on benefits and risks

Discuss with pt pros and cons of available treatment options based on medical evidence. Verify pt understanding by asking pt to repeat information shared by provider

Kane HL, et al. CA Cancer J Clin. 2014;64:377-388. Slide credit: clinicaloptions.com

4 Assist pt in evaluatingoptions based on goals and concerns

Ask pt about personal preferences, values, issues, and concerns related to treatment options

5 Facilitate deliberation and decision making

Allow ample time for pt to think about treatmentoptions. Facilitate another visit to discuss any further pt questions or concerns

6 Steps in Implementing SDM in Oncology

further pt questions or concerns

6 Implement SDM Ensure that pt understands treatment decision and explore possible issues with implementation

Kane HL, et al. CA Cancer J Clin. 2014;64:377-388. Slide credit: clinicaloptions.com

Barrier Examples

Practice Limited time during pt encounter Time away from other pts Commitment by all multidisciplinary team members

Patient Unwilling pt Difference in goals between pt and caregiver

Barriers to Implementing SDM

Institutional Lack of policy or time commitment

Scope of Practice Laws and guidelines prohibiting autonomous

practice

Administration Inadequate support by administration

McCarter SP, et al. Sigma Theta Tau International’s 26th International Nursing Research Congress. 2015. Slide credit: clinicaloptions.com

16

Documented Challenges/Barriers to SDM

ICU nurses’ involvement in end-of-life decision making processes

– Relatives of pts wanted more involvement from nurses[1]

Roles of acute care NP

– Highly context sensitive

– Roles largely depend on laws regulating scope of practice and healthcare system policies[2]system policies[2]

Pts who have advanced cancer

– Need clarification of specific roles of nurses during different stages of treatment decision making[3]

Role of nurses in clinical decision making

– More research studies that address specific contributions

– Potentially lead to improvement of healthcare outcomes[4]

1. Lind R, et al. Nurs Ethics. 2012;19:666-676. 2. Kilpatrick K, et al. Int J Nurs Stud. 2013;50:1524-1536. 3. McCullough L, et al. Eur J Cancer Care. 2010;19:482-491. 4. Campos DC, et al. Rev Lat Am Enfermagem. 2009;17:1065-1070. Slide credit: clinicaloptions.com

SDM in MM: Conclusions

There is a shift in the dialogue related to cancer treatment decision making between pts and physicians, as well as oncology nurses

The roles of the nurse during the cancer treatment decision making process are multifaceted: advocacy, education, psychological support, adverse event management

The role of the oncology nurse during cancer treatment decisions is dynamic and continuously influenced by many factors

Nursing advocacy must be encouraged and strengthened to improve pt outcomes

Slide credit: clinicaloptions.com

SDM in MM: Conclusions

Older adults newly diagnosed with MM want to participate in treatment decision making

The wide range of treatment options and the recent addition of 5 new approvals for MM treatment make pt education essential

Pts with MM are living longer than ever and SDM is important toPts with MM are living longer than ever and SDM is important to quality, quantity of life

Oncology nurses must respect the pt’s desired role preference and all oncology practitioners must listen to the pt

Allow pts to be autonomous in making treatment decisions and provide opportunity for pts to choose the best possible treatment within the limits of the pt’s personal, social, and medical contexts

Slide credit: clinicaloptions.com

17

Go Online for More CCO Oncology Programs for Nurses!

Nursing-focused Educational Programs on cancer immunotherapy, B-cell malignancies, mantle cell lymphoma, more.

More than 1200 inPractice® pages addressing the nurse’s roles in the management of patients with cancer.

clinicaloptions.com/oncology

inPractice.com

Backup Slides

ASPIRE: Len/Dexamethasone ±Carfilzomib in RRMM—Study Design

Planned interim analysis of a randomized, open-label phase III trial

Pts with relapsed or i MM

KRdCarfilzomib Days 1, 2, 8, 9, 15, 16/cycles 1-12,

Days 1, 2, 15, 16/cycles 13-18,discontinued after cycle 18 +Lenalidomide Days 1-21 +

Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide

progressive MM, 1-3 prior treatments

with ≥ PR in ≥ 1 prior regimen,

ECOG PS 0-2, and CrCl ≥ 50 mL/min

(N = 792)

Until PD or unacceptable toxicity

Dexamethasone Days 1, 8, 15, 2228-day cycle

(n = 396)

RdLenalidomide Days 1-21 +

Dexamethasone Days 1, 8, 15, 2228-day cycle

(n = 396)

Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter. Lenalidomide: 25 mg. Dexamethasone: 40 mg.

Stewart AK, et al. N Engl J Med. 2015;372:142-152. Slide credit: clinicaloptions.com

18

ASPIRE: PFS

KRd Rd(n = 396) (n = 396)

Median PFS, mos 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83)P value (one sided) < .0001

1.0

0.8

0.6

0.4

rtio

n S

urv

ivin

gu

t P

rog

ress

ion

0.2

0

Pro

po

rW

ith

ou

KRdRd

0 6 12 18 24 30 36 42 48Mos Since Randomization

Stewart AK, et al. N Engl J Med. 2015;372:142-152.

Risk Group by FISH

KRd (n = 396) Rd (n = 396) HR P Value

n Median PFS, Mos n Median PFS, Mos

High 48 23.1 52 13.9 0.70 .083

Standard 147 29.6 170 19.5 0.66 .004

Slide credit: clinicaloptions.com

ASPIRE: Adverse Events

Select AEs (All Grades), %[1] KRd (n = 392)

Rd (n = 389)

Nonhematologic AEs occurring in ≥25% of pts Diarrhea 42.3 33.7 Fatigue 32.9 30.6 Cough 28.8 17.2 Pyrexia 28.6 20.8

Upper respiratory tract infection 28.6 19.3

Hypokalemia 27.6 13.4

Implications[2]

Monitor blood counts

Monitor for infection

Cardiac

– EKG for pts with cardiac history, ECHO baselineyp

Muscle spasms 26.5 21.1Hematologic AEs occurring in ≥ 25% of pts Anemia 42.6 39.8 Neutropenia 37.8 33.7 Thrombocytopenia 29.1 22.6

Other AEs of Interest Dyspnea 19.4 14.9 Peripheral neuropathy 17.1 17.0 Hypertension 14.3 6.9 Acute renal failure 8.4 7.2 Cardiac failure 6.4 4.1 Ischemic heart disease 5.9 4.6

– Diuretics, inhalers, minimize fluids, longer infusion time (30 mins)

Advise pts on

– Shortness of breath (dyspnea)

– Fatigue

– Cytopenias

– Infection prevention

– VTE prophylaxis1. Stewart AK, et al. N Engl J Med. 2015;372:142-152.2. Carfilzomib [package insert]. 2016. Slide credit: clinicaloptions.com

PANORAMA1: Bortezomib/Dex ±Panobinostat in RRMM—Study Design

Randomized, multicenter, placebo-controlled, double-blind phase III trial

Pts with

Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2

Stratified by prior lines of therapy and prior bortezomib

Panobinostat 20 mg Days 1 3 5 of Wks 1 2 4 5

Phase I: Eight 3-wk cycles Phase II: Four 6-wk cycles

Pts with symptomatic

RRMM after 1-3 prior treatments

(bortezomib-refractory excluded)(N = 768)

g yBortezomib

1.3 mg/m2 IV Days 1, 4 of Wks 1, 2Dexamethasone

20 mg Days 1, 2, 4, 5 of Wks 1, 2(n = 387)

Placebo Days 1, 3, 5 of Wks 1,2

Bortezomib 1.3 mg/m2 IV Days 1, 4 of Wks 1, 2

Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2

(n = 381)

San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

20 mg Days 1, 3, 5 of Wks 1, 2, 4, 5Bortezomib

1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5Dexamethasone

20 mg Days 1, 2 of Wks 1, 2, 4, 5

Placebo Days 1,3,5 of Wks 1, 2, 4, 5

Bortezomib 1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5

Dexamethasone 20 mg Day 1 of Wks 1, 2, 4, 5

≥ SD

≥ SD

Slide credit: clinicaloptions.com

19

PANORAMA1: PFS

Significant improvement in PFS with addition of panobinostat to bortezomib and dexamethasone

100

80

Panobinostat, bortezomib, and dexamethasonePlacebo, bortezomib, and dexamethasone

San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

80

60

40

20

0

PF

S (

%)

Mos0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

, ,

HR: 0.63 (95% CI: 0.52-0.76; P < .0001)

Slide credit: clinicaloptions.com

PANORAMA 1: Safety

Select AEs (≥ 10% Incidence and ≥ 5% Greater Incidence With Pan), %

Pan + Bort/Dex (n = 381) Pbo + Bort/Dex (n = 377)

All Grades Grade 3/4 All Grades Grade 3/4

Arrhythmia 12 3 5 2

Diarrhea 68 25 42 8

Nausea 36 6 21 1

Vomiting 26 7 13 1

Fatigue 60 25 42 12

Cardiac

GI

Evaluate and treat diarrhea, fatigue. Watch for myelosuppression, PN with bortezomib

Richardson P, et al. ASCO 2014. Abstract 8510^. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

Peripheral edema 29 2 19 <1

Pyrexia 26 1 15 2

Weight loss 12 2 5 1

Decreased appetite 28 3 12 1

Thrombocytopenia 97 67 83 31

Anemia 62 18 52 19

Neutropenia 75 34 36 11

Leukopenia 81 23 48 8

Lymphopenia 82 53 74 40

Other

Heme

Slide credit: clinicaloptions.com

GI events, fatigue, and prolonged QT-C interval are major concerns

Panobinostat + Bortezomib/dex: Dose and Schedule

Novel Agents in MM Cycles 1-8 (28-Day Cycles)

Wk 1 Wk 2

D 1

D 2

D 3

D 4

D 5

D 6

D 7

D 1

D 2

D 3

D 4

D 5

D 6

D 7

Panobinostat20 mg PO

Bortezomib co ce s

Alternate dosing can be confusing

Bortezomib1.3 mg/m2

Dexamethasone20 mg PO

Panobinostat PI. 2015.

Cycles 9-16 (28-Day Cycles)

Wk 1 Wk 2

D 1

D 2

D 3

D 4

D 5

D 6

D 7

D 1

D 2

D 3

D 4

D 5

D 6

D 7

Panobinostat

Bortezomib

Dexamethasone

Slide credit: clinicaloptions.com

20

TOURMALINE-MM1: Rd ± Ixazomib— PFS

Phase III trial (N = 722) in R/R MM and 1-3 prior Tx

Addition of ixazomib to Rd resulted in 35% improvement in PFS vs Rd alone100

80

Median PFS:IRd: 20.6 mosPlacebo-Rd: 14.7 mos

FS

(%

)

PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed

Moreau P, et al. ASH 2015. Abstract 727. Slide credit: clinicaloptions.com

60

40

20

0

Log-rank P = .012HR (95% CI): 0.742 (0.587-0.939)Number of events: IRD 129; placebo-Rd 157

0 2 4 6 8 10 12 14 16 18 20 22 24Mos From Randomization

Pro

bab

ilit

y o

f P

F

TOURMALINE-MM1: Response

CharacteristicIxazomib + Rd

(n = 360)Placebo + Rd

(n = 362)P Value

ORR, % CR VGPR PR

78.311.736.466.7

71.56.6

32.364.9

.035

.019

Moreau P, et al. ASH 2015. Abstract 727.

Median time to response, mos 1.1 1.9

Median DoR, mos 20.5 15.0

Median TTP, mos 21.4 15.7 .007*

*HR: 0.712.

Slide credit: clinicaloptions.com

TOURMALINE-MM1: Safety

AE, %Ixazomib + Rd (n = 361) Placebo + Rd (n = 359)

Any Grade Grade 3/4 Any Grade Grade 3/4

AEs attributed to ixazomib and/or lenalidomide

Diarrhea Constipation Nausea Vomiting Rash

4535292336

6< 1215

3926221223

3< 10

< 12

Moreau P, et al. ASH 2015. Abstract 727.

Rash Back pain Upper respiratory infection Thrombocytopenia

36242331

5< 1< 119

23171916

2309

AEs attributed to ixazomib

Peripheral neuropathy Peripheral edema

2728

21

2220

00

AEs attributed to lenalidomide

Thromboembolism Neutropenia

833

< 323

1131

< 424

Slide credit: clinicaloptions.com

21

Ixazomib + Rd: Dose and Schedule

28-Day Cycles

Wk 1 Wk 2 Wk 3 Wk 4

Day 1Days 2-7

Day 8

Days 9-14

Day 15

Days 16-21

Day22

Days 23-28

Ixazomib 4 mg PO

Ixazomib [package insert]. 2015. Slide credit: clinicaloptions.com

Ixazomib implications:

Dose reduce for hepatic impairment

Nausea, rash, and thrombocytopenia can occur

HSV prophylaxis

Rapidly absorbed

Lenalidomide 20 mg PO

QD QD QD

Dexamethasone40 mg PO

ELOQUENT-2: Safety

AE, %Elotuzumab + Len/Dex

(n = 318)Len/Dex(n = 317)

Hematologic (grade ≥ 3) Anemia Neutropenia

1526

1633

Nonhematologic (grade ≥ 3) Fatigue 9 8

Infusion reactions experienced by 10% of pts; most were grade 1/2 and occurred during first treatment cycle

Dimopoulos MA, et al. ASH 2015. Abstract 28. Slide credit: clinicaloptions.com

Fatigue Diarrhea Pyrexia

953

853

GI disorders (any grade) 81 68

Respiratory disorders (any grade) 63 53

Renal/urinary (any grade) 25 18

Peripheral neuropathy (any grade) 15 9

SIRIUS: Study Design

Open-label, international, multicenter, 2-stage study

Pts with MM who had recei ed ≥ 3 prior lines of

Daratumumab 8 mg/kg q4w

(n = 18)

Stage 1 Response assessment Stage 2

Enrollment of additional pts at 16 mg/kg dose

(outcomes reported for all pts at 16 mg/mg dose)

Primary objective:ORR

Secondary objectives: PFS, OS, duration of response, time to response, clinical benefit rate

Lonial S, et al. ASCO 2015. Abstract LBA8512.

received ≥ 3 prior lines of therapy or were

refractory to a PI and an IMiD

(N = 53)

(n 18)

Daratumumab 16 mg/kgqw x 8 then q2w x 16,

then q4w thereafter(n = 16)

Daratumumab 16 mg/kgqw x 8 then q2w x 16,

then q4w thereafter(n = 90)

Slide credit: clinicaloptions.com