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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
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.
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
NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.
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
Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19.
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
Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19.
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%
Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19.
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
NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.
• 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.
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)
- Lenalidomide 25 mg PO daily on days 1-21
- 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
Guidelines Recommendations
National Comprehensive Cancer Network• Relapsed/refractory MM (category 1)• Recommendations follow FDA labeling
European Society of Medical Oncology • Not mentioned
mSMART (Mayo Clinic)• 1st relapse
• Indolent relapse or frail patients
• Good choice for front-line relapse therapy
Moreau P, et al. Annals of Oncology. 2013; 24:133-7
NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.
• 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
- Lenalidomide 25 mg PO daily on days 1-21
- Dexamethasone 40 mg on days 1, 8, 15, 22
Control Arm (n = 362)
- Placebo PO on days 1, 8, 15
- Lenalidomide 25 mg PO daily on days 1-21
- Dexamethasone 40 mg on days 1, 8, 15, 22
Cycles repeated every 28 days
Primary Outcomes• Progression Free Survival
Secondary Outcomes• Overall Survival• Toxicity
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
20% of patients had high risk cytogenetics
ORR* 282 (78%) 259 (72%)
CR* 42 (12%) 24 (7%)
VGPR 131 (36%) 117 (32%)
PR 240 (67%) 235 (65%)
PFS*20.6 months 14.7 months
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
Guidelines Recommendations
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
Moreau P, et al. Annals of Oncology. 2013; 24:133-7
NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.
• 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
Control Arm (n = 381)
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
Cycles repeated every 21 days
Primary Outcomes• Progression Free Survival
Secondary Outcomes• Overall Survival• Toxicity
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
5% of patients had high risk cytogenetics
ORR* 235 (60.7%) 208 (54.6%)
CR 42 (11%) 22 (6%)
PR 128 (33%) 148 (39%)
PFS*11.99 months 8.08 months
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
San-Miguel JF, et al. Lancet Oncol. 2014; 15:1195-206.
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%)
San-Miguel JF, et al. Lancet Oncol. 2014; 15:1195-206.
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
Guidelines Recommendations
National Comprehensive Cancer Network• Relapse/refractory MM (category 1)• Recommendations follow FDA labeling• Mentions high rates of toxicity
European Society of Medical Oncology • Not mentioned
mSMART (Mayo Clinic)• >2 relapse
• After bortezomib, lenalidomide, pomalidomide
• Reasonable option for relapseo Careful vigilance for toxicity
Moreau P, et al. Annals of Oncology. 2013; 24:133-7
NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma.
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.
Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19.
Lonial, et al. N Engl J MEd. 2015; 373:621-31.
Moreau P et al. N Engl J Med. 2016; 374:1621-34.
San-Miguel JF, et al. Lancet Oncol. 2014; 15:1195-206.
Future Directions
Daratumumab
-CASTOR: Dara-Bortezomib-Dex
-POLLUX: Dara-Lenalidomide-Dex
Ixazomib
-Maintenance therapy after
transplant
-Maintenance therapy after
chemotherapy induction
Elotuzumab
-Induction therapy with bortezomib,
dexamethasone
-Maintenance therapy after
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
Assessment Question #2
Anti-viral prophylaxis would be recommended with which following myeloma therapy?
A. ElotuzumabB. DaratumumabC. IxazomibD. PanobinostatE. A and D F. All the above
Assessment Question #3
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