Patient Case Introduction

The Evolving State of Relapsed/Refractory Multiple Myeloma TreatmentMMRF ONS 2016

1This material serves as an educational resource only.

Patient Case Introduction

Page Bertolotti, RN, BSN, OCNClinical Practice Nurse

Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center

Los Angeles, California



Disclosure

Page Bertolotti, RN, BSN, OCN, has disclosed the following relevant financial relationships:

– Speakers’ Bureau: Celgene Corporation and Takeda Pharmaceuticals

• Bone marrow biopsy:

− 80% plasma cells, CD38 antigen expression on flow cytometry

• Skeletal survey:

− Multiple bone lesions

• Bone marrow biopsy:

− 80% plasma cells, CD38 antigen expression on flow cytometry

• Skeletal survey:

− Multiple bone lesions

• Past medical history: MVA in 1985; melanoma in 1995 to right shin

• Past surgical history: tonsillectomy in 1980

• Family history: paternal grandmother with breast cancer, died at age 90

• Social history: recent marriage (5 months), no children, never smoked, social drinker

• Physical exam: mildly cushingoid, some nausea, still menstruating

• Past medical history: MVA in 1985; melanoma in 1995 to right shin

• Past surgical history: tonsillectomy in 1980

• Family history: paternal grandmother with breast cancer, died at age 90

• Social history: recent marriage (5 months), no children, never smoked, social drinker

• Physical exam: mildly cushingoid, some nausea, still menstruating

Total protein 12.0 (6.3–8.2)

Calcium 9.3 (8.4–10.2)

Creatinine 1.3 (0.7–1.2)

Hgb 11.6 (13–16)

IgG 7,912 (700–1,600)

Total protein 12.0 (6.3–8.2)

Calcium 9.3 (8.4–10.2)

Creatinine 1.3 (0.7–1.2)

Hgb 11.6 (13–16)

IgG 7,912 (700–1,600)

History andPhysical

DiagnosticEvaluation

Case Study

Staging: Durie-Salmon stage IIIA

53-year-old woman presents with fatigue and nausea in 2009. Elevated total protein detected on routine exam.

Labs onPresentation



Treatment Options?

Factors to consider• Age and comorbidity• Response to induction

therapy• Risk stratification• Social support and

insurance coverage• Lifestyle, goals, choices• Does the patient want a

transplant or not?

Is she eligible for an autologous stem cell

transplantation?

Treatment Plan

Acyclovir prophylaxis

Manage adverse events: peripheral neuropathy

Bone health: bisphosphonate every month

Induction therapy: Bortezomib/dexamethasone

Response was dramatic; decrease in IgG from 7,912 to 1,863 after 3 cycles



Consultation With Myeloma Specialist

Continue bz/dex for three more cycles to achieve maximum benefit of treatment and best possible remission

Patient proceeded to ASCT, December 2009, and had a small M spike of 0.1 g/dL (near CR)

Maintenance therapy prescribed 6 months post-transplant: len/dex (prophylaxis with baby aspirin and acyclovir)

Response: April 2011 (16 months post-ASCT),near CR with negative SPEP and trace IgG kappa spike

Recommendation

Relapse Post-Transplantation and Maintenance Therapy

• Elevated kappa light chain (KLC) 22 to 46 to 69• Elevated M spike 0.1 to 0.2 g/dL

Relapse 3 yrs post transplant



Relapse: Factors to Consider

• Retreatment with a prior therapy? • Second transplant?• Multidrug combination? Synergy?• New agents?• Clinical trial?

Understanding the Next Generation of Novel Agents in Multiple Myeloma

Amy Pierre, RN, MSN, ANP-BCNurse Practitioner

John Theurer Cancer Center Hackensack University Medical Center

Hackensack, New Jersey



Disclosure

Amy Pierre, RN, MSN, APN-BC, has disclosed the following relevant financial relationships:

– Speakers Bureau: Amgen/Onyx

Objectives

Define relapsed/refractory multiple myeloma

Review the approved usage, mechanism of action, safety concerns, and toxicity profile of the next-generation proteasome inhibitors, immunomodulators, and HDAC inhibitors

Understand the combination regimens commonly utilized in refractory/relapsed multiple myeloma

Discuss a patient-centered management plan to minimize the impact of treatment-related side effects



Definitions

Anderson KC et al. Leukemia. 2008;22:231.

• Previously treated myeloma patients who, after a period of being off-therapy, require salvage therapy

Relapsed Myeloma

• Disease that is nonresponsive while on therapy or progresses within 60 days of the last therapy

Refractory Myeloma

• Refractory disease in patients who have never achieved a minor response or better that then either becomes nonresponsive while on salvage therapy or progress within 60 days of last therapy

Relapsed and Refractory Myeloma

Disease Phases of Multiple Myeloma

Figure 2, page 7

Kurtin SE. Relapsed or relapsed/refractory multiple myeloma. J Adv Pract Oncol. 2013;4(Suppl 1):5-14.



Treatment Selection for Relapsed/Refractory Myeloma

Lonial S. Hematology Am Soc Hematol Educ Program. 2010;303.

• How deep was the patient’s response to prior therapy?

• How long was the duration of response to the previous therapy?

• How aggressive is the disease?

• Is the patient eligible for a clinical trial?

Disease Characteristics

• What is the patient’s performance status?

• Does the patient have pre-existing toxicities from either myeloma or previous treatment regimens?

• What are the patient’s comorbidities?

• Is the patient transplant eligible?

• Is the patient eligible for a clinical trial?

Patient Characteristics

Newly Approved Agents for the Relapsed/Refractory Setting

• Carfilzomib• Ixazomib

Proteasome Inhibitors

• Pomalidomide

Immunomodulator

• Panobinostat

HDAC Inhibitor



Carfilzomib

• Second-generation proteasome inhibitor (IV) Drug Class

• 2012Approval Date

• In combination with dexamethasone or with lenalidomide + dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy

• As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy

FDA-Approved Indication

• Irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome

• Has antiproliferative and pro-apoptotic activities in tumor cells

• Delays tumor growth in myeloma

Mechanism of Action

Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; 2016.

Carfilzomib: ASPIRE Trial • The international, randomized, phase 3 superiority trial evaluating carfilzomib

with lenalidomide and low-dose dexamethasone (KRd) vs lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory MM who had received one to three lines of therapy.

• Primary end point: progression-free survival (PFS)

KRD (N=396) PFS = 26.3months

ORR = 87% ≥CR = 32%

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

RD (N=396) PFS = 17.6months

ORR = 67% ≥CR = 9%

N=792PFS increased by 9 months with KRd;

higher ORR, deeper response, and longer median duration of response with KRd



Carfilzomib: ENDEAVOR Trial • The phase 3, randomized, multicenter, superiority study comparing

carfilzomib and dexamethasone (Kd) to bortezomib and dexamethasone (Vd) in patients with relapsed or refractory MM

• Primary end point: PFS

KD (N=464) PFS = 18.7months

ORR = 77% ≥CR = 13%

Doubled the PFS with Kd;Higher ORR, deeper response, and longer

median duration of response with Kd;PFS benefit was extended whether prior

treatment with a PI or not

VD (N=465) PFS = 9.4months

ORR = 63% ≥CR = 6%

N=929

Dimopoulos MA et al. Lancet Oncol. 2016;17:27.

Carfilzomib/Lenalidomide/ Dexamethasone (KRd)

KRd

Cycles 1–12Carfilzomib 27 mg/m2 IV Days 1, 2, 8, 9, 15, 16 (20 mg/m2 Days 1, 2, Cycle 1 only, to assess tolerability to carfilzomib)

Cycles 13–18Carfilzomib 27 mg/m2 IV Days 1, 2, 15, 16

Cycles 19+Carfilzomib discontinued after Cycle 18

Lenalidomide 25 mg: Days 1 to 21

Dexamethasone 40 mg: Days 1, 8, 15, 22

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



Carfilzomib Monotherapy (K)Carfilzomib/Dexamethasone (Kd)

Dimopoulos MA et al. Lancet Oncol. 2016;17:27.

3 4 5 6 71 2 10 11 12 13 148 9 17 18 19 20 2115 16 22 23 24 25 26 27 28

3 4 5 6 71 2 10 11 12 13 148 9 17 18 19 20 2115 16 22 23 24 25 26 27 28

Carfilzomib20 mg/m2

Carfilzomib56 mg/m2

Carfilzomib56 mg/m2

Week

1Week

1Week

2Week

2Week

3Week

3Week

4Week

4Dexamethasone,

20 mgDexamethasone,

20 mgDexamethasone,

20 mgDexamethasone,

20 mg

CYCLE 1

CYCLES 2-on, until disease progression or unacceptable toxicity

3 4 5 6 71 2 10 11 12 13 148 9 17 18 19 20 2115 16 22 23 24 25 26 27 28

Carfilzomib56 mg/m2

Carfilzomib56 mg/m2

Carfilzomib56 mg/m2

Week

1Week

1Week

2Week

2Week

3Week

3Week

4Week

4Dexamethasone,

20 mgDexamethasone,

20 mgDexamethasone,

20 mgDexamethasone,

20 mg

NO CARFILZOMIB DOSING

NO CARFILZOMIB DOSING

Carfilzomib: Administration Precautions

• Hydration– Adequate hydration is required prior to all dosing in

Cycle 1– Monitor for fluid overload

• Premedications– Premedicate with dexamethasone

• Thromboprophylaxis

• Infection prophylaxis– Antiviral

• Maximum BSA Dosing of 2.2 m2




Carfilzomib: Adverse Reactions Occurring in ≥20%

• Hematologic: anemia, neutropenia, thrombocytopenia

• GI: diarrhea, nausea• General: fatigue, pyrexia, insomnia, infusion

reactions• Infections: URI• F/E/N: hypokalemia• Musculoskeletal: muscle spasms• Respiratory: cough, dyspnea• Cardiac: hypertension


Carfilzomib: Nursing Implications

• Patient education regarding:– Infusion reactions: premedicate, hydration– Venous embolus: cough, chest pain, swelling or pain

in the legs– Thrombocytopenia: bleeding, bruising– GI: antidiarrheals, antiemetics– Zoster reactivation: painful rash– Cardiac: dyspnea, peripheral edema, chest pain,

maintain normal blood pressure– Infection precautions– Risk of TLS: hydration, may need uric acid–lowering

agent



Ixazomib

Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; 2015.

• Second-generation oral proteasome inhibitor Drug Class


• In combination with dexamethasone and lenalidomide for the treatment of patients with multiple myeloma who have received at least one prior therapy


• Reversibly and preferentially binds and inhibits the 20S proteasome

• Induces apoptosis of multiple myeloma cell lines

• The combination of ixazomib and lenalidomide demonstrates synergistic cytotoxic effects

Mechanism of Action

Ixazomib: TOURMALINE-MM1 Trial

Moreau P et al. Blood. 2015;126: Abstract 727.

• An international, randomized, double-blind, placebo-controlled clinical trial evaluating ixazomib, lenalidomide, and dexamethasone (IRD) compared to placebo with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma who received 1–3 prior lines of therapy.

• Primary end point: PFS

IRD (N=360) PFS = 20.6months

ORR = 78% ≥CR = 12%

40% decrease in risk of progression;PFS extended to patients with high-risk

cytogenetics (overcomes high risk)

Placebo RD (N=362)

PFS = 14.7months

ORR = 72% ≥CR = 7%

N=722



Ixazomib/Lenalidomide/Dexamethasone

Starting dose is 4 mg oral capsule

Dosing Schedule for Ixazomib Taken With Lenalidomide and Dexamethasone

28-Day Cycle (a 4-week cycle)

Week 1 Week 2 Week 3 Week 4

Day 1Days2–7 Day 8

Days9–14 Day 15

Days 16–21 Day 22

Days 23–28

Ixazomib

Lenalidomide Daily Daily Daily

Dexamethasone

Moreau P et al. Blood. 2015;126: Abstract 727.Ixazomib [package insert]. Cambridge, MA: Takeda Pharmaceuticals Inc; 2015.

For moderate hepatic impairment or severe renal impairment, reduce starting dose to 3 mg.

Ixazomib: Administration Precautions

• Take ixazomib at approximately the same day each week

• Take 1 hour before food or 2 hours after food• Ixazomib and dexamethasone should not be

taken at the same time• Antiviral prophylaxis is required• Thromboprophylaxis in combination with

lenalidomide• Avoid concomitant administration with strong

CYP3A inducers




Ixazomib: Adverse Reactions Occurring ≥20%

• Diarrhea• Constipation• Thrombocytopenia• Peripheral neuropathy• Nausea/vomiting• Back pain• Peripheral edema


Ixazomib: Nursing Implications

• Patient education regarding:– Thrombocytopenia: bruising, bleeding– Take antiemetics and antidiarrheals– Monitor for neuropathy: tingling, numbness,

pain, burning in feet or hands, or weakness in extremities

– Swelling or weight gain– Development of a rash– Antiviral prophylaxis– Thromboprophylaxis with lenalidomide



Pomalidomide

Pomalidomide [package insert]. Summit, NJ: Celgene Corporation; 2015.

• Immunomodulator (oral)Drug Class


• In combination with dexamethasone for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy


• Inhibits proliferation, induces apoptosis and antiangiogenic activity in tumor cells and models

• Enhances T-cell– and natural killer cell–mediated immunity, inhibits the production of pro-inflammatory cytokines

• Works synergistically with dexamethasone to overcome lenalidomide resistance

Mechanism of Action

Pomalidomide Phase 3 Trial

San Miguel J et al. Lancet Oncol. 2013;14:1055.

• Phase 3 multicenter, randomized trial evaluating pomalidomide with low-dose dex therapy (PD) vs high-dose dex (D) in adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy

• Primary end point = PFS

PD (N=302) PFS = 4.0months

ORR = 31% PR = 26%

55% reduced risk of progression or death with PD; Significant OS

advantage

D (N=153) PFS = 1.9months

ORR = 10% PR = 9%

N=455



Pomalidomide/Dexamethasone

San Miguel J et al. Lancet Oncol. 2013;14:1055.

Sunday Monday Tuesday Wednesday Thursday Friday Saturday

STA

RT

C

YC

LE

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Off Off Off Off Off Off

STA

RT

N

EX

T

CY

CL

E

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide4 mg

Pomalidomide: Administration Precautions

BLACK BOX WARNING:– Embryo-Fetal Toxicity: Contraindicated in

pregnancy. Must comply with contraception and pregnancy testing.

– Only available through REMS program (restricted distribution program)

– Venous and Arterial Thromboembolism: DVT, PE, MI, and stroke occur in patients treated with pomalidomide. Thromboprophylaxis is recommended and choice of regimen should be based on assessment of the patient’s underlying risk factors.




Pomalidomide: Administration Precautions

• Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements (female pregnancy testing and male contraception)

• Women of reproductive potential must have negative pregnancy testing and use contraception methods before initiating pomalidomide

• Take with water at least 2 hours before or 2 hours after a meal, at approximately the same time each day

• Thromboprophylaxis• Monitor blood counts


Pomalidomide: Adverse Reactions Occurring in ≥30%

• Fatigue and asthenia• Neutropenia• Anemia• GI distress: constipation, nausea, diarrhea• Dyspnea• Upper respiratory tract infections• Back pain• Pyrexia




Pomalidomide: Nursing Implications

• Patient education regarding:– Embryo-fetal toxicity: compliance regarding

pregnancy testing and contraception, no blood donation, no sperm donation

– Risk of embolus: provide thromboprophylaxis– Cytopenias: fever, infection, bruising/bleeding,

fatigue– Have supportive GI medications at home– Skin rash: antihistamines and topical

corticosteroids

Panobinostat

Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

• Nonselective histone deacetylase inhibitor (oral)Drug Class

• 2015: accelerated approval based on PFSApproval Date

• In combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent


• Inhibition of histone deacetylase activity results in cell cycle arrest and apoptosis of some transformed cells and cytotoxicity

• Helps to turn on tumor suppressor genes

Mechanism of Action



Panobinostat: PANORAMA-1 Trial

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

• A multicenter, randomized, placebo-controlled, double-blind phase 3 trial of panobinostat, bortezomib, and dexamethasone (FVD) vs placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens

• Primary end point = PFS

FVD (N=387) PFS = 12months

ORR = 60.7%

CR/nCR = 27.6%

83% improvement with FVD and maintained across all subgroups; maybe more so

with prior V and IMiD; CR nearly doubled with clinically meaningful median

duration of response

Placebo VD (N=381)

PFS = 8.1months

ORR = 54.6%

CR/nCR = 15.7%

N=768

Panobinostat/Bortezomib/Dexamethasone

San Miguel JF et al. Lancet Oncol. 2014;15:1195.Panobinostat [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

Starting dosage is Panobinostat 20 mgMedication Key Panobinostat 20 mg oral Bortezomib 1.3 mg/m2 by injection Dexamethasone 20 mg oral

CYCLES 1–8 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

Week 1

Week 2

Week 3 REST

Consider continuing treatment for an additional eight cycles for patients with clinical benefit, unless they have unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks).

CYCLES 9–16 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

Week 1

Week 2

Week 3 REST

For mild hepatic impairment, reduce starting dose to 15 mg.For moderate hepatic impairment, reduce starting dose to 10 mg.

F V D

F V D

F V D

D

D

F

F

V D

V D

F D

F D

F V D

F V D

D

D

F

F

F

F



Panobinostat: Administration Precautions


BLACK BOX WARNING:– Diarrhea: Severe diarrhea occurred in 25% of

patients. Monitor for symptoms, institute antidiarrheal treatment, and interrupt panobinostat and then reduce dose or discontinue.

– Cardiac: Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.

Panobinostat: Administration Precautions

• Avoid star fruit, pomegranates, and grapefruit • If dose is missed, can take up to 12 hours after the

specified dose time• Ensure antidiarrheals are at home• Obtain baseline ECG and monitor throughout therapy

– Do not initiate panobinostat if QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities

• Obtain serum electrolytes prior to therapy and weekly or more often if needed

• Monitor liver function tests and complete blood counts




Panobinostat: Adverse Reactions ≥20%

• Diarrhea (68%): severe in 25%• Fatigue• Nausea/vomiting• Peripheral edema• Low appetite• Pyrexia• Myelosuppression

– Thrombocytopenia 67%– Severe neutropenia 34%

• Electrolyte abnormalities


Panobinostat: Nursing Implications

• Patient education regarding:– Diarrhea: at first abdominal cramping, loose stool, or

diarrhea, take antidiarrheals, monitor electrolytes– Antiemetics– Cardiac: chest pain, fast/slow heart rate, palpitations,

lightheadedness, dizziness, shortness of breath, edema, monitor EKG

– Bleeding: dark stools, blood in urine, bruising– Diet: avoid start fruit, pomegranate, grapefruit; if

appetite low, eat small frequent meals– Cytopenias: bleeding, bruising, infections, fatigue,

short of breath

.



Summary

• Myeloma is a disease characterized by phases of remission and relapse

• Choice of treatment at relapse is based on patient-specific and disease-specific factors

• Treatment goals are to address symptoms, prevent further organ damage, achieve a complete remission, and prolong overall survival

• Understanding the mechanism of action, safety data, and potential toxicities of relapsed/refractory regimens helps minimize the impact of treatment-related side effects

• Patient education can improve early detection of treatment-related adverse events

Patient Case Continuation

Page Bertolotti, RN, BSN, OCNClinical Practice Nurse

Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center

Los Angeles, California



Goals of therapy

• Individualize care: benefit outweigh risk?• What does the patient want?

– This young woman wanted to maintain as much functional status and quality of life as possible

– Less trips to the Center and avoid long commute

– Spa dates and wine tasting with friends– Lifestyle choice- oral therapy and avoid

steroids

Gather the Multidisciplinary Team!

• Other physicians– Orthopedic surgeon– Nephrologist– Radiation oncologist– Cardiologist– Psychiatrist– Dentist

• Nurse practitioners• Physician assistants

• Oncology nurses• Pharmacists• Pain team• Social workers• Counselors• Dietitians• Physical therapy• Home healthcare



Relapse Post-Transplantation and Maintenance Therapy

• Discontinue len/dex and start pomalidomide and weekly dexamethasone

Treatment with first relapse

• Moderate response to pom/dex with reduction in KLC• Intolerance to steroid with weight gain despite several dose reductions

Response to treatment

Second Relapse

• In the fall of 2013, her kappa free light chain started to rise• Lifestyle was no longer as significant as before

Second relapse

• January 2014, she was switched to carfilzomib and dexamethasone

Treatment choice

• Good response with reduction in KLC, M spike• In December 2015, her serum M-spike increased consistent with

progressive disease.

Response to treatment



Case Study Continued

• December 2015: elevated M spike on carfilzomib

• Patient chose to continue carfilzomib and dose was escalated to 56 mg/m2

– Fear of “moving on and burning through new options”

– Developed clenching jaw due to prochlorperazine pre-med, changed to dronabinol. Ondansetron was ineffective.

• March 2016: Time to move on to another therapy

Immunotherapy

Charise Gleason, MSN, NP-C, AOCNPChief Advanced Practice Provider

Department of Hematology and Medical Oncology Adjunct Faculty

The Winship Cancer Institute at Emory University Atlanta, Georgia



Disclosure

Charise Gleason, MSN, NP-C, AOCNP, has disclosed no relevant financial relationships.

Relapse Workup

• Diagnostic workup demonstrates:– Skeletal survey with no new lesions– Bone marrow biopsy with 60% plasma cells

and now with deletion 17p– SPEP with M spike of 3.92 g/dL– UPEP of 0– FKLC 870.4 mg/L– Hgb 8.8 mg/dL

• Goals of therapy:– Rapid control– Maintain quality of life



Cytogenetics

• These are the genes of the plasma cells (not the patient)

• May indicate more about the biology of the disease

• Most can be found at diagnosis, but others may be “acquired” later

• Could well be the most “prognostic” tool in myeloma, as it may separate “high-risk”myeloma from standard risk

Disease Trajectory: Relapsed/Refractory Disease

Figure 2, page 7

Kurtin SE. Relapsed or relapsed/refractory multiple myeloma. J Adv Pract Oncol. 2013;4(Suppl 1):5-14.



Are the Goals Different?

Target the tumor

Target the tumor

Restoration of function

MRD, clonal control

Prevention/Microenvironment

Refractoryrelapse

Relapsed Disease

Newly diagnosed

Premalignant

Continuing Evolution of Multiple Myeloma Treatment: New Classes and Targets

PLD, peglylated liposomal doxorubicin; IMiD, immunomodulatory drug; HDAC, histone deacetylase; KSP, kinesin spindle protein, SINE, selective inhibitor of nuclear export

Novel Therapies and Immunotherapy

Chemotherapy

Monoclonal antibody

Proteasome inhibitor

IMiD HDAC inhibitor

Adoptive T cell therapy

Vaccines

Checkpoint inhibitors

20122003 2006 2007 2013 2015 2016+

PLD

Carfilzomib

Bortezomib

Thalidomide

Lenalidomide

Pomalidomide

Panobinostat Isatuximab

CAR-T

Atezolizumab

Nivolumab

Vaccines

Ixazomib

Daratumumab

Elotuzumab



Monoclonal Antibody Therapy

What is it?

• It is an injection of antibodies that can directly bind to the surface of a myeloma cell

How does it work against

myeloma?

• Antibodies bind to myeloma cells then kill them using different mechanisms

Excitement of Monoclonal Antibodies

• Novel mechanism of action− Additive or synergistic effects with

current anti-MM drugs• Generally well tolerated− Toxicity profile non-overlapping

with approved anti-MM drugs• Can be combined with other

immune therapies• May be ideally suited to eliminate

MRD• May be beneficial in all patient

groups (SMM, ND, RR, MRD)• Many targets possible − MM cell− Microenvironment− Immune signals

Advantages

• Infusion reactions can limit therapy in some

• No biomarkers for response to predict who may most benefit

• Few long-term survivors

Disadvantages



Elotuzumab

Lonial S et al. N Engl J Med. 2015;373:621.Dimopoulos MA et al. Blood. 2015;126: Abstract 28.NK, natural killer; ADCC, antibody-dependent cellular cytotoxicity

Anti-SLAMF7 mAb

SLAMF7 expressed on both MM cells and NK cells

Tags MM cells for ADCC via NK cells and activates NK cells via EAT-2 for MM cell destruction independent of ADCC

Activity in combination with lenalidomide led to ELOQUENT trial

Best Confirmed Response, n (%)

All Pts(n=28)

Pts w/o Prior Len

(n=22)

ORR (≥PR) 23 (82) 21 (95)

VGPR 8 (29) 7 (32)

PR 14 (50) 13 (59)

SD 3 (11) 1 (5)

PD 2 (7) 0

Lonial S et al. J Clin Oncol. 2012; 30:1953.

Phase 1/2 Elotuzumab + Len/Dex: Efficacy



Study Design

Stratification in phase II: prior therapies (1 vs 2 or 3 lines), prior thalidomide or thalidomide analogs.Len/dex: lenalidomide + low-dose dexamethasone.

↓Assessments were performed once per cycle. *Progression defined by IMWG Criteria. Lonial S et al. J Clin Oncol. 2012; 30:1953.

PROGRESSION

daily dose daily dose daily dose daily dose daily dose daily dose

Elotuzumab 10 mg/kg IV+ Len/dex

n=36

Elotuzumab 20 mg/kg IV+ Len/dex

n=37

1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 28

Elotuzumab

Dosing

Lenalidomide

DexamethasoneCycle day

Phase 1n=28

Phase 2n=73

RANDOMIZE

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 CYCLE N

*

Most Common Treatment-Emerging Grade 3/4 Adverse Events Before and

After 18 Months of Treatment

Grade 3/4 AEs,* n (%)

OnsetElotuzumab + Len/dex

10 mg/kgElotuzumab + Len/dex

20 mg/kg≤18 months

n=39>18 months

n=20≤18 months

n=59>18 months

n=31Neutropenia 8 (21) 1 (5) 13 (22) 1 (3)Thrombocytopenia 8 (21) 1 (5) 10 (17) 0Lymphopenia 10 (26) 1 (5) 5 (9) 0Anemia 5 (13) 1 (5) 7 (12) 0Hyperglycemia 2 (5) 0 7 (12) 0Fatigue 3 (8) 1 (5) 5 (9) 0Diarrhea 4 (10) 2 (10) 3 (5) 0Leukopenia 3 (8) 1 (5) 4 (7) 0Hypokalemia 3 (8) 1 (5) 3 (5) 1 (3)Pneumonia 3 (8) 0 3 (5) 2 (7)

*In ≥5% of patients across elotuzumab 10 and 20 mg/kg.

• Across dosages, 51 patients received therapy for over 18 months• Most treatment-emergent AEs occurred within 18 months of therapy



Best Response From the Phase 2 Cohort

Phase 2Elotuzumab

10 mg/kg

Phase 2Elotuzumab

20 mg/kg Total

Patients, n 36 37 73

ORR (≥PR), n (%)(95% CI)*

33 (92)(78–98)

28 (76)(59–88)

61 (84)(73–91)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 18 (50) 14 (38) 32 (44)

PR, n (%) 10 (28) 10 (27) 20 (27)

<PR, n (%) 3 (8) 9 (24) 12 (16)

*By Clopper-Pearson method.

Richardson PG et al. Lancet Haematol. 2015;2:e516.

ELOQUENT-2 Study Design Open-label, international, randomized, multicenter phase 3 trial (168 global sites)

Lonial S et al. N Engl J Med. 2015;373:621.

Elo + Len/dex (E-Rd) schedule (n=321)Elo (10 mg/kg IV): Cycle 1 and 2: weekly;

Cycles 3+: every other weekLen (25 mg PO): days 1–21

Dex: weekly equivalent, 40 mg

Len/dex (Rd) schedule (n=325)Len (25 mg PO): days 1–21;

Dex: 40 mg PO days 1, 8, 15, 22

Key inclusion criteria

• RRMM• 1–3 prior lines of

therapy• Prior len exposure

permitted in 10% of study population (patients not refractory to len)

Assessment• Tumor response:

every 4 weeks until progressive disease

• Survival: every 12 weeks after disease progression

• End points:– Co-primary: PFS and overall response rate (ORR)– Other: OS (data not yet mature); duration of response, quality of life, safety

• All patients received premedication to mitigate infusion reactions prior to elotuzumabadministration

Repeat every 28 days



ELOQUENT-2: Key AEs Reported in ≥30% of Patients

Adverse event, n (%)

E-Ld (n=318) Ld (n=317)

Any Grade Grade 3/4

Any Grade Grade 3/4

Common non-hematologic adverse events

Fatigue 149 (47) 27 (8) 123 (39) 26 (8)

Pyrexia 119 (37) 8 (3) 78 (25) 9 (3)

Diarrhea 149 (47) 16 (5) 114 (36) 13 (4)

Constipation 113 (36) 4 (1) 86 (27) 1 (<1)

Muscle spasms 95 (30) 1 (<1) 84 (26) 3 (1)

Cough 100 (31) 1 (<1) 57 (18) 0

Common hematologic toxicities

Lymphocytopenia 316 (99) 244 (77) 311 (98) 154 (49)

Neutropenia 260 (82) 107 (34) 281 (89) 138 (44)

Infections 259 (81) 89 (28) 236 (74) 77 (24)

• Exposure-adjusted infection rate was 197 (incidence rate per 100 person-years of exposure) in both arms

• There was no detriment to overall health-related quality of life with the addition of Elo to Ld

ELOQUENT-2: Infusion Reactions

• Infusion reactions occurred in 10% of patients• 70% of infusion reactions occurred with the first dose• No Grade 4 or 5 infusion reactions • Elotuzumab infusion was interrupted in 15 (5%) patients due to an infusion

reaction (median interruption duration 25 minutes)• 2 (1%) patients discontinued the study due to an infusion reaction

Events, n (%)E-Ld (n=318)

Grade 1/2

Grade 3

Grade 4/5

Infusion reaction 29 (9) 4 (1) 0

Pyrexia 10 (3) 0 0

Chills 4 (1) 0 0

Hypertension 3 (1) 1(<1) 0

Lonial S et al. N Engl J Med. 2015;373:621.



Daratumumab

1. Lokhorst HM et al. N Engl J Med. 2015;373:1207.2. Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print].

3. Plesner T et al. Blood. 2015;126: Abstract 507. 4. Voorhees PM et al. Blood. 2015;126: Abstract 1829.

mAb, monoclonal antibody; PI, proteasome inhibitor; IMiD, immunomodulatory drug

Anti-CD38 mAb

Active as single agent and in combination with lenalidomide1-3

First mAb approved for the treatment of MM patients who have received at least three prior lines of therapy (including a PI and an IMiD) or who are double refractory to a PI and an IMiD

Infusion reactions main side effect4

Potential impact on both standard- and high-risk disease

Daratumumab

The most clinically advanced of the anti-CD38 monoclonal antibodies

A phase 2 study in patients who had already received multiple lines of therapy showed:

• The majority of patients had reduction in their paraprotein levels compared to their baseline levels

• Between 21% and 29% overall response rates were observed even in patients who were refractory to:− Carfilzomib− Pomalidomide− Bortezomib + lenalidomide− Or all 4 agents

Lonial S et al. Lancet. 2016; Jan 6 [Epub ahead of print].



Overall Response Rate:DARA + LEN/DEX

19%

28%

9%

25%

0

10

20

30

40

50

60

70

80

90

100

16 mg/kgO

RR

, %

sCR CR VGPR PR

ORR = 81%

34%CR or

63%VGPR or

better

• Clinical benefit rate (ORR + minimal response) = 88% N = 32

Plesner T et al. Blood. 2015;126: Abstract 507.

34%CR or better

63%VGPR

or better

100

75

50

25

0

-25

-50

-75

-100-90

Re

lativ

e C

ha

nge

In P

ara

pro

tein

Fro

m B

ase

line

(%

)

N=32

Urine M-proteinSerum M-protein

28%

33%

4%5%

0

10

20

30

40

50

60

70

80

16 mg/kg

OR

R, %

PR VGPR

Overall Response Rate:DARA + POM-D

• ORR in double-refractory patients = 67%• Clinical benefit rate (ORR + minimal response) = 74%

43%VGPR

or better

9%CR or better

N = 75

Chari A et al. Blood. 2015;126: Abstract 508.

ORR = 71%75

50

25

0

-25

-50

-75Re

lativ

e C

ha

nge

In P

ara

pro

tein

Fro

m B

ase

line

(%

)

N=75

Urine M-proteinSerum M-proteinFree light chain

-100



The Practical Part: Infusion Reactions

Be prepared: • Start infusions early• Pre-med everyone → additional meds likely to be needed

Lonial S et al. N Engl J Med. 2015;373:621. Lokhorst HM et al. N Engl J Med. 2015;373:1207.

Martin TG et al. Blood. 2014;124. Abstract 83.

• Anti-CD38 mAb− Sinus/nasal congestion− Throat irritation− Cough, dyspnea, wheezing− Rare: anaphylaxis, severe HTN,

CP, arrhythmias• Elotuzumab− Fever, chills− Hypertension− Less: bradycardia, hypotension

Common Symptoms

• Recognize early and stop infusion (37% dara, 5% elo)

• Give additional premedications• Restart at ½ the rate

(discontinue if Gr 4 or recurs)

Treatment

The Practical Part:Response and Blood Typing

• mAb may be detectable on SPEP/IFE

• Can obscure CR assessment

Assessing Response

• VZV prophylaxis

Infection

• Anti-CD38 may interfere with blood bank tests− CD38 on reagent RBCs

• Positive DAT• Positive antibody screen• Approaches to resolve anti-CD38

interference*Send type and screen BEFORE first dose-DARA

− Genotype/phenotype recipient’s RBCs− DTT-treating reagent RBCs (+/-

available, give Kell- cells)− Neutralize anti-CD38 in plasma

(anti-idiotype, sCD38)

Blood Banking

1. Chapuy CI et al. Transfusion. 2015;55:1545.2. Oostendorp M et al. Transfusion. 2015;55:1555.

IgG k MMIgG k agent

ELP G A M K L1



Current Clinical Trials of Monoclonal Antibodies in MMmAb Target Combination Patient Types Phase Elotuzumab SLAMF7 Len/dex New, relapsed 3

Daratumumab CD38 Len/dexBz/dex New, relapsed 3

Tabalumab BAFF Relapsed/refractory 2

Isatuximab CD38Len/dexPom/dexCyBorD

Relapsed/refractory 1

Indatuximab* CD138 Len/dex Relapsed/refractory 1/2

Milatuzumab CD74 Relapsed/refractory 1/2

MOR03087 CD38 Relapsed/refractory 1/2

Pembrolizumab PD-1 Pom/dexLen/dex Relapsed/refractory 1/2

Nivolumab PD-1Elo/pom/dex Relapsed/refractory 3

IpilimumabLirilumab Relapsed/refractory 1

Atezolizumab PD-L1 Rev Relapsed/refractory 1

Lirilumab KIR ElotuzumabUrelumab Relapsed/refractory 1

Urelumab CD137 ElotuzumabLirilumab Relapsed/refractory 1

*Immunotoxin conjugate

Case Continued…Treatment History

• Bortezomib/dex• ASCT followed by three additional cycles

of bortezomib/dex• Maintenance len/dex• Pomalidomide/dex• Carfilzomib/dex



Next Treatment

• Daratumumab/pom/dex– Prospective study on pom and del 17p1

• Expectations of treatment– Effective– Potential AEs– Reportable signs and symptoms

• Outcomes• Quality of life

1. Leleu X et al. Blood. 2015;125:1411.

Concerns for Patients Multiply Relapsed

• New mutations• Older• Frailty• Comorbidities• Residual treatment effects• Less response



Supportive Care

• Remember we treat the patient, not the disease…– Bone disease– Fatigue and anemia– Infections– Overall quality of life

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