Advances in Treatment Paradigms for Multiple Myeloma · for multiple myeloma •Summarize...

Advances in Treatment Paradigms for Multiple

Myeloma

Bao Dao, PharmD, MBA, BCPS, BCOP

Hematology/Bone Marrow Transplant Clinical Pharmacist

Assistant Clinical Professor

University of California San Francisco Medical Center

Disclosure

Advisory committee member for Seattle Genetics

Learning Objectives

• Identify the mechanism of action of select new therapeutic agents for multiple myeloma

• Summarize literature regarding the use of new agents for multiple myeloma

• Explain expected outcomes to a given therapeutic modality in terms of response and toxicity

• State the place in therapy of the new therapeutic agents for multiple myeloma

• MM is the second most common hematologic malignancy• Malignancy of monoclonal plasma cells • 26,850 new cases estimated in US in 2015

o 11,240 deaths

• Mean age of affected individuals: 62 years old• MM remains an incurable malignancy

o Goal of therapy remains disease controlo Overall survival has increased 3 - 5 years to 5 - 7 years with novel agents

Multiple Myeloma (MM)

NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.

http://www.nccn.org/professional/physician_gls/pdf/myeloma

Evolution of Myeloma Therapy

19

50

’s

20

00

’s

MelphalanCorticosteroids

BortezomibLenalidomide

20

15

PanobinostatDaratumumabIxazomibElotuzumab

2

19

90

’sThalidomideAutologous Stem Cell Transplant

20

10

’s

4

CarfilzomibPomalidomide

Kyle RA, et al. Blood. 2008; 111(6):2962-72.

Current Approach to Treatment

Newly Diagnosed MM

Yes

No

TransplantCandidate?

Primary Therapyx 2-4 cycles

Primary Therapy

ASCT

MaintenanceTherapy

MaintenanceTherapy

Relapse/RefractoryTherapies



Outline

Mechanism of Action

FDA Approval Trial

Dosing/Administration

Toxicity/Monitoring

Place in therapy

• IgG human monoclonal antibody to CD38

• CD38 = transmembrane glycoprotein highly expressed on myeloma cells

◦ Low expression on other myeloid/lymphoid cells

• Complement and antibody dependent cytotoxicity

Daratumumab

Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19.

Daratumumab Trial

Phase I Patients: >2 prior MM treatment

Dose escalation (0.005 – 24 mg/kg) IV once weeklyN = 32

DOSE EXPANSIONPhase II

Schedule A8 mg/kg

Schedule B8 mg/kg

Schedule C8 mg/kg

Schedule D16 mg/kg

Schedule E16 mg/kg

N = 16 N = 8 N = 6 N = 20 N =22


Daratumumab Trial

Part 1: Dose-Escalation◦ Safety: No maximum tolerated dose was found◦ PK: 16 mg/kg was lowest tested dose consistent with target

saturation

Part 2: Dose-Expansion◦ 71% had Grade 1-2 infusion-related reaction◦ 1 patient had Grade 3 infusion-related reaction


Daratumumab Trial

Dose8 mg/kg(N = 30)

16 mg/kg(N= 42)

Population Heavily pre-treated MM patients

ORR 3 (10%) 15 (36%)

CR 0 2 (5%)

PR 3 (10%) 11 (26%)

M-protein reduction 4 (15%) 19 (46%)

Duration of response 6.9 m Not reached

PFS 2.4 m 5.6 m

OS at 12 months 77% 77%


Daratumumab

Indication≥ 3 prior lines of therapy including a PI or IMiD or who are double-refractory to a PI

and IMiD

DosingWeeks 1-8: 16 mg/kg IV weekly

Weeks 9-24: 16 mg/kg IV every 2 weeksWeeks 25+: 16 mg/kg IV every 4 weeks

Preparation

Vials: 100 mg/5mL or 400 mg/20 mL

First infusion mix in 1000 mL of NSSecond infusion and beyond mix in 500 mL of NS

Daralex® [package insert]. Horsham, PA: Janssen Biotech; 2015

Daratumumab

Pre-medicationsCorticosteroid: Methylprednisolone 100 mg IV (60 mg after 2nd infusion)

Antipyretic: Acetaminophen 650 mg – 1000 mgH1-blocker: Diphenhydramine 25-50 mg

Infusion rate

First Infusion: 50 mL/hr x 1 hr, increase by 50 mL/hr every hour (max = 200 mL/hr)-1000 mL volume

Second infusion: 50 mL/hr x 1 hr increase by 50 mL/hr every hour (max = 200 mL/hr)-500 mL volume

Subsequent infusion: 100 mL/hr x 1 hr increase by 50 mL/hr every hour (max = 200 mL/hr)-500 mL volume

InteractionsSerum protein electrophoresis (SPEP)Coombs test

Daralex® [package insert]. Horsham, PA: Janssen Biotech; 2015

Prevention of infusion-related reactions◦ Post-infusion: PO steroids on 1st and 2nd day after infusion

Herpes Reactivation◦ Initiate antiviral prophylaxis 1 week prior to starting therapy and

for 3 months after stopping

Inference with Coombs test◦ Can cause false positive indirect Coombs test as daratumumab

binds to red blood cells

Toxicity/Monitoring

Place in Therapy

Guidelines Recommendations

National Comprehensive Cancer Network• Relapse/refractory MM (category 2A)• Recommendations follow FDA labeling

European Society of Medical Oncology • Not mentioned

mSMART (Mayo Clinic)• 2nd or later relapse

• After bortezomib, lenalidomide, pomalidomide

Moreau P, et al. Annals of Oncology. 2013; 24:133-7


• Save for later lines of relapse• Lenalidomide-resistant patients• More to come with combination therapy


• Humanized IgG antibody against SLAMF7

o Highly expressed on myeloma and natural killer cells

• Direct activation: Binding to SLAMF7 activates natural killer (NK)

cells, not myeloma cells

• Tagging for recognition: Elotuzumab bound to myeloma cells are

tagged for antibody-dependent cellular cytotoxicity (ADCC) from NK-

cells

Elotuzumab

Collins SM, et al. Cancer Immunol Immunother 2013; 62:1841-9.

Elotuzumab: Mechanism of Action

Myeloma Cell

NK Cell

Activation

Tagging Myeloma Cell

NK Cell

ELOQUENT-2 Trial

Inclusion Criteria

• Relapse/Refractory MM• 1-3 Previous therapies

Elotuzumab Arm (n = 321)

- Elotuzumab 10 mg/kg: Cycle 1 and 2 =

weekly then every other week

- Lenalidomide 25 mg PO daily on days 1-21

- Dexamethasone 40 mg weekly equivalent

Control Arm (n = 325)


- Dexamethasone 40 mg PO weekly

Cycles repeated every 28 days

Primary Outcomes• Progression Free Survival• Overall response rate

Secondary Outcomes• Overall Survival• Toxicity

Lonial, et al. N Engl J MEd. 2015; 373:621-31

ELOQUENT-2 ResultsElotuzumab (N = 321) Control Arm (N = 325)

Effi

cacy

Population1-3 previous therapies with CrCl >30 mL/min

30% of patients had high risk cytogenetics

ORR* 252 (79%) 213 (66%)

CR 14 (4%) 24 (7%)

Minimal Response/Stable Disease 16% 27%

PFS*19.4 months 14.9 months

Hazard ratio: 0.7 (95% CI 0.57-0.85; P<0.001)

Ad

vers

eEv

ents

Neutropenia 34% 44%

Lymphopenia 77% 49%

Infection 81% 74%

Infusion reaction 10% --

* = statistically significant Lonial, et al. N Engl J Med. 2015; 373:621-31

Elotuzumab

Indication1-3 prior therapies

Use in combo with lenalidomide/dex

Dosing

Cycle 1-2:Elotuzumab 10 mg/kg IV days 1, 8, 15, 22Lenalidomide 25 mg PO daily days 1-21

Dexamethasone 28 mg PO 3-24 hours before elotuzumab + 8 mg IV 45-90 min prior to infusion

Cycle 3 and beyond: Elotuzumab 10 mg/kg IV days 1 and 15

Lenalidomide 25 PO days 1-21Dexamethasone 28 mg PO 3-24 hours before elotuzumab + 8 mg IV 45-90 min prior to infusion

(days 1, 15)Dexamethasone 40 mg PO on days 8 ad 22

PreparationVials: 300 mg and 400 mg

Further dilute with 230 mL of NS or D5W

Empliciti® [package insert]. Princeton, NJ: Bristol-Myer Squibb; 2015

Elotuzumab

Pre-medications

Corticosteroid: Dexamethasone 28 mg PO given 3-24 hours before elotuzumab + dexamethasone 8 mg 45-90 minutes prior to infusion

Antipyretic: Acetaminophen 650 mg – 1000 mgH1-blocker: Diphenhydramine 25-50 mg

H2-blocker: Ranitidine 50 mg IV or 150 mg PO

Infusion rate

First Infusion: 0.5 mL/min x 30 mins, then double rate every 30 mins as tolerated (max: 2 mL/min)Second infusion: 1 mL/min x 30 mins, then 2 mL/min as tolerated (max 2 mL/min)Subsequent infusion: Initiate at 2 mL/min and continue to completion

Interactions Serum protein electrophoresis (SPEP)

Empliciti® [package insert]. Princeton, NJ: Bristol-Myer Squibb; 2015

Toxicity/Monitoring

Infusion reactions◦ Rechallenge when symptoms resolve

Infections◦ Higher Zoster reactivation◦ Anti-viral prophylaxis◦ Monitor CBC

Hepatotoxicity◦ Monitor liver function tests periodically

Elotuzumab: Place in Therapy


National Comprehensive Cancer Network• Relapsed/refractory MM (category 1)• Recommendations follow FDA labeling


mSMART (Mayo Clinic)• 1st relapse

• Indolent relapse or frail patients

• Good choice for front-line relapse therapy




• MM cells have high protein turnover and accumulation

• Proteasomes = main pathway for degradation of intracellular protein • Clearance of misfolded and unfolded proteins

• Reversible PI inhibitor• Cell-cycle arrest

• Apoptosis

• Disruption of microenvironment

Ixazomib

Ocio EM. et al. Leukemia. 2013; 1:1-18

TOURMALINE

Inclusion Criteria

• Relapse/Refractory MM• 1-3 Previous therapies

Ixazomib Arm (n = 360)

- Ixazomib 4 mg PO on days 1, 8, 15


- Dexamethasone 40 mg on days 1, 8, 15, 22


- Placebo PO on days 1, 8, 15


- Dexamethasone 40 mg on days 1, 8, 15, 22


Primary Outcomes• Progression Free Survival


Moreau P, et al. N Engl J Med. 2016; 374:1621-34

RESULTS: TOURMALINE

Ixazomib (N = 360) Control Arm (N = 362)

PopulationMM who received 1-3 previous therapies with CrCl >30 mL/min


ORR* 282 (78%) 259 (72%)

CR* 42 (12%) 24 (7%)

VGPR 131 (36%) 117 (32%)

PR 240 (67%) 235 (65%)


Hazard ratio: 0.74 (95% CI 0.59-0.94; P=0.01)

Median time to response 1.1 months 1.9 months

Median treatment cycles 17 (1-34) 15 (1-34)

* = statistically significantMoreau P, et al. N Engl J Med. 2016; 374:1621-34

TOURMALINE: Toxicity

Ixazomib (N = 360) Control Arm (N = 362)

Neutropenia 118 (33%) 111 (31%)

Thrombocytopenia 112 (31%) 57 (16%)

Anemia 103 (29%) 98 (27%)

Diarrhea 164 (45%) 139 (39%)

Nausea 104 (29%) 79 (22%)

Rash 131 (36%) 82 (23%)

Peripheral NeuropathyAll grades: 97 (27%)

Grade 3: 9 (2%)All grades: 78 (22%)

Grade 3: 6 (2%)

Thromboembolism 29 (8%) 38 (11%)

Moreau P et al. N Engl J Med. 2016; 374:1621-34

Ixazomib

Indication>1 prior therapies

Combo with lenalidomide/dex

Dosing4 mg once weekly on days 1, 8, and 15 every 28 days

CrCl <30 or hemodialysis: 3 mg

AdministrationTake 1 hour before eating or 2 hours after eating

Missed dose: Make up dose if next dose >72 hours away

Preparations4 mg capsules3 mg capsules

2.3 mg capsules

Ninlaro® [package insert]. Cambridge, MA: Millennium; 2015

Toxicity

Thrombocytopenia◦ Nadir = 14-21 days (transient/cyclical) ◦ Routine CBC

Peripheral neuropathy

Generalized rash◦ Steroid creams, topical antihistamine, or dose reductions

Diarrheao Routine CBC

Ixazomib: Place in Therapy


National Comprehensive Cancer Network• Frontline therapy (category 2A)

• Transplant and non-transplant candidates• Relapsed/refractory MM (category 1)

European Society of Medical Oncology Not mentioned

mSMART (Mayo Clinic)

• 1st relapse• Indolent relapse or frail patients

• 2nd relapse • After bortezomib, carfilzomib, lenalidomide,

pomalidomide

• Desire oral regimen• Potential for maintenance therapy




• Histone deacetylase (HDAC) is unregulated in MM cells

• Hypoacetylation of histones gene silencing

• Panobinostat = potent inhibitor pan-HDAC inhibitoro Cell cycle arrest and apoptosis

o Aggresome pathway inhibition

• Minimal activity as single-agent

Panobinostat

Richardson PG, et al. Expert Rev Clin Pharmacol. 2016; 1:35-48.

PANORAMA1

Inclusion Criteria

• Relapse/Refractory MM

• 1-3 Previous therapies

Panobinostat Arm (n = 387)Pano 20 mg PO TIW on weeks 1 and 2

Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11

Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, 12


Placebo PO TIW on weeks 1 and 2

Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11

Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, 12


Primary Outcomes• Progression Free Survival


Bortezomib 1.3 mg/m2 IV weeklyDex 20 mg on twice weekly

+/-

Panobinostat PO TIW two weeks on and one week off

6 week cycles

Cycles 1-8 Cycles 9-12

San-Miguel JF, et al. Lancet Oncol. 2014; 15:1195-206.

RESULTS: PANORAMA1

Panobinostat (N = 387) Control Arm (N = 381)

Population1-3 previous therapies with CrCl >60 mL/min


ORR* 235 (60.7%) 208 (54.6%)

CR 42 (11%) 22 (6%)

PR 128 (33%) 148 (39%)


Hazard ratio: 0.63 (95% CI 0.52-0.76; P<0.0001)

Median time to response 1.5 months 2 months

Median duration of treatment

5 months 6.1 months

* = statistically significant


PANORAMA1 Toxicity

Panobinostat (N = 360) Control Arm (N = 362)

NeutropeniaAll grades: 285 (75%)Grade 3-4: 131 (34%)

All grades: 134 (36%)Grade 3-4: 43 (11%)

ThrombocytopeniaAll grades: 371 (98%)Grade 3-4: 256 (67%)

All grades: 314 (84%)Grade 3-4: 118 (31%)

Anemia 235 (62%) 197 (52%)

Diarrhea 164 (68%) 157 (42%)

Nausea 138 (36%) 78 (21%)

Peripheral NeuropathyAll grades: 97 (27%)

Grade 3: 9 (2%)All grades: 78 (22%)

Grade 3: 6 (2%)


Panobinostat

Indication>2 prior therapies

Combo with bortezomib/dex

Dosing

Cycle 1-8:21 days

Panobinostat 20 mg on days 1, 3, 5, 8, 10, 12Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11

Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12

Cycle >9:42 days

Cycle 1-8:Panobinostat 20 mg on days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33

Bortezomib 1.3 mg/m2 on days 1, 8, 22, 29Dexamethasone 20 mg on days 1, 2, 8 ,9, 22, 23, 29, 30

AdministrationMay be taken +/- food

Avoid star fruit, pomegranate and grapefruit

Preparations 20 mg, 15 mg, and 10 mg capsules

Farydak® [package insert]. East Hanover, NK: Novartis; 2015

Monitoring parameters o CBC, LFTs, EKG

Thrombocytopeniao Non-cumulativeo Bleeding risk

Peripheral neuropathyo Symptomatic treatment

Diarrheao Rx antidiarrheals

Monitoring

Arrhythmias/QTc prolongationo Drug interactions

Nausea/vomitingo Drug interactions

Drug interactionso CYP3A4 inducers - AVOIDo CYP3A4 inhibitors – Dose reduce panobinostat to 10 mg o Avoid use with CYP2D6 substrates

Monitoring

Panobinostat: Place in Therapy


National Comprehensive Cancer Network• Relapse/refractory MM (category 1)• Recommendations follow FDA labeling• Mentions high rates of toxicity


mSMART (Mayo Clinic)• >2 relapse

• After bortezomib, lenalidomide, pomalidomide

• Reasonable option for relapseo Careful vigilance for toxicity




How Does it Stack Up?

Regimen PFS (months) ORR CR

Carfilzomib, Lenalidomide, Dexamethasone (KRd)

26.4 87.1% 17.7%

Daratumumab 5.6 36% 5%

Elotuzumab (ERd) 19.4 79% 4%

Ixazomib (IRd) 20.6 78% 12%

Panobinostat (PVd) 11.99 60.7% 11%

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


Lonial, et al. N Engl J MEd. 2015; 373:621-31.

Moreau P et al. N Engl J Med. 2016; 374:1621-34.


Future Directions

Daratumumab

-CASTOR: Dara-Bortezomib-Dex

-POLLUX: Dara-Lenalidomide-Dex

Ixazomib

-Maintenance therapy after

transplant


chemotherapy induction

Elotuzumab

-Induction therapy with bortezomib,

dexamethasone


transplant

Panobinostat

-Panobinostat-carfilzomib-dex for

relapsed MM

-Panobinostat-bortezomib-

lenalidomide-dex for induction

therapy

Role of the Pharmacist

Monitoring for toxicityo Infusion reactionso Pharmacological treatment of toxicities

Proper administrationo Pre-medicationso Complicated scheduleso Interactions

Patient counseling

Supportive care

Which of the new agents for multiple myeloma is FDA approved to be used as monotherapy?

A. ElotuzumabB. DaratumumabC. IxazomibD. PanobinostatE. Pomolidomide

Assessment Question #1

Patient KS is scheduled to receive her first dose of elotuzumab at your infusion center. KS’s hematologist asked what is the proper steroid dosing prior to elotuzumab. Which is the correct steroid schedule prior to elotuzumab?

A. Dexamethasone 32 mg PO 3 hours before infusion + 8 mg IV 45-90 minutes before infusion

B. Methylprednisolone 80 mg IV 45-90 before infusion C. Dexamethasone 28 mg PO 3-24 hours before infusion + 8 mg IV 45-90

minutes before infusion D. Dexamethasone 40 mg IV 30 minutes before infusion


Anti-viral prophylaxis would be recommended with which following myeloma therapy?

A. ElotuzumabB. DaratumumabC. IxazomibD. PanobinostatE. A and D F. All the above


1) National Comprehensive Cancer Network. Multiple Myeloma (Version 3.2016). http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed July 26, 2016.

2) Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008; 111(6):2962-72.

3) Lokhorst HM, Plesner T, Lauback JP et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015; 373(13):1207-19.

4) Daralex® [package insert]. Horsham, PA: Janssen Biotech; 2015

5) Moreau P, San Miguel J Ludwig H, et al. Multiple Myeloma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. Ann Oncol. 201324(6):vi133-7.

6) Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myleoma via CS1 ligation: evidence for augmented NK cell functioncomplementing ADCC. Cancer Immunol Immunother. 2013; 62(12):1841-9.

7) Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373(7):621-31

8) Empliciti® [package insert]. Princeton, NJ: Bristol-Myer Squibb; 2015

9) Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma WorkingGroup (IMWG). Leukemia. 2014;28(3):525-42.

10) Moreau P, Masszi T, Grzasko, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 37417):1621-34

11) Ninlaro® [package insert]. Cambridge, MA: Millennium; 2015

12) Richardson PG, Harvey RD, Lauback JP, et al. Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol. 2016; 9(1):35-48.

13) San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients withrelapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014; 15(11):1195-206.

14) Farydak® [package insert]. East Hanover, NK: Novartis; 2015

15) Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372:142-152.

References

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Advances in Treatment Paradigms for Multiple Myeloma · for multiple myeloma •Summarize...

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