PREVENTION AND MANAGEMENT OF ADVERSE EVENTS in RELAPSED MYELOMA

Michel Delforge

University Hospital Leuven

Belgium

Controversies in myeloma 2019

Disclosures

• consultancy and advisory boards:

▪Amgen

▪BMS

▪Celgene

▪ Janssen

▪Takeda

Some good medical reasons to prevent adverse events

• many anti-myeloma drugs are given in combination

• many anti-myeloma treatment regimens are given for prolonged periods (months or years)

• success of treatment is related to drug dosing and treatment duration

• adverse events can:▪ negatively impact the survival of patients▪ negatively interfere with the success of the current

and future treatment▪ negatively impact the quality of life of patients

• optimal myeloma treatment is a careful balance between efficacy and toxicity of a treatment regimen

ToxicityEfficacy

The patient’s perspective

Hulin et al. Leuk Res 2017;59:75

First relapse after IMiD-

based induction

Doublets

Kd / Vd

bortezomib-based triplets:

VCd, PAd, DaraVd

First relapse after

Bortezomib-based induction

(Rd)

pomalidomide-based

regimens (Pom-dex,

PVd, PCd)

daratumumab

(single agent)clinical trial

At second or subsequent relapse

adapted from Moreau P, et al. Ann Oncol 2017;00:1–11

Relapsed MM: ESMO guidelines 2017

Rd-based triplets:

DRd, ERd, KRd, IRd

Drug Class Proteasomal target reversibilityRoute of

administrationStandard dosing

caspase trypsin chymotrypsin

Bortezomib1

(PS-341)boronic acid X X reversible IV/SC days 1,4,8,11/21d

Ixazomib2

(MLN-9708)boronic acid X X reversible oral once per week

Carfilzomib3

(PR-171)epoxyketone X irreversible IV

days

1,2,8,9,15,16/28d

Oprozomib4

(ONX-0912)epoxyketone X irreversible oral daily

Marizomib5

(NPI-0052)salinospore X X X irreversible IV days 1,4,8,11/21d

Overview of proteasome inhibitors

1. Richardson et al. New Engl J Med 2003;3448:26

2. Kumar et al. Lancet Oncol 2014;15:1503

3. Siegel et al. Blood 2012;120:2817

4. Chauhan et al. Blood 2012;116:4904

5. Richardson et al. Blood 2016;127:2693

Most common grade III & IV adverse events of bortezomib

Type of side effect, % Vd (IV) Vd (SC)*

Hematological

Anemia 10 10-12

Neutropenia 14 18

Thrombocytopenia 29 9-13

Nonhematological

Peripheral neuropathy 8 5

Diarrhea 7 2-7

Constipation 2 1-2

Nausea 2 0-1

Vomiting 3 1-2

Fatigue 5 2-7

Dyspnea 5 2

Cardiac disease† NR 3

Arterial hypertension NR 3

Rash 1 NR

Adapted from Delforge & Ludwig. Blood 2017;129:2359NR, not reported; SC, subcutaneous; Vd, bortezomib plus dexamethasone.

*Twenty-one percent received bortezomib IV. †Cardiac failure and ischemic heart disease.

Grade 1 Grade 2 Grade 3 Grade 4

sensory PN

asymptomatic, loss of deeptendon reflexes or paraesthesia(including tingling), notinterfering with function

sensory alteration or paraesthesia (includingtingling), interfering withfunction but not with ADL*

sensory alteration or paraesthesia interferingwith ADL*

disabling

Motor PNasymptomatic, weakness onexamination or testing only

symptomatic weakness, interfering with functionbut not with ADL

weakness interferingwith ADL, bracing orassistance to walk (e.g.cane or walker indicated)

life-threatening,disabling (e.g. paralysis)

Common Toxicity Criteria (CTC) for peripheral neuropathy

* ADL: Activities of Daily Living

serious for trials

serious for patients

Clinical presentation of PN induced bythalidomide and bortezomib

Thalidomide Bortezomib

Localization extremities: “glove and stocking” yes yes

symmetrical yes yes

Sensory symptoms paraesthesia ++ ++

numbness ++ +

hyperaesthesia + ++

neuropathic pain + ++

proprioceptive failure + +

Motor symptoms decreased muscle strength -/+ -/+

Autonomic symtoms hypotension, impotence, bradycardia

+ +

Argyriou AA, et al. Blood 2008;112:1593Cata JP, et al. J Pain 2007;8:296

Delforge et al. Lancet Oncol, 2010;11:1086

Chaudry V, et al. Neurology 2002;59:1872Mileshkin L, Prince HM. Leuk Lymphoma 2006;47:2276

Dose modifications for bortezomib-inducedperipheral neuropathy

Grade 1 Grade 2 Grade 3 Grade 4

symptom asymptomatic, loss of deep tendon reflexes or paraesthesia (including tingling), not interfering with function

sensory alteration or paraesthesia (includingtingling), interfering with function but not with ADL*

sensory alteration or paraesthesia interfering with ADL*

disabling

intervention continue to monitor thepatient with clinicalexamination. Considerreducing the dose ifsymptoms worden

reduce dose to 1.0 mg/sqm twice weekly orchange treatment schedule to 1.3 mg/sqmonce weekly

withhold treatment untilsymptoms or toxicity have resolved. When toxicityresolves to grade 1 or lower: re-initiatetreatment at 0,7 mg/sqm

permanent treatmentdiscontinuation

* ADL: Activities of Daily Living 1.Velcade, Summary of Product Characteristics2.Delforge et al. Lancet Oncol, 2010;11:108

▪ Pharmacological treatment• medication: only to alleviate symptoms

✓ anticonvulsants: gabapentin, pregabalin

✓ opioids: fentanyl, tramadol, morphine,

✓ serotonin/norepinephrine-reuptake inhibitors

▪ Topical treatment: mostly of limited use• lidocaine patch

• 0.5% menthol in calamine cream

▪ others▪ physical exercise (especially when patient is on steroids)

▪ mineralocorticoids in case of hypotension

▪ caution with high doses of Vit C or Vit B

Intervention for treatment-related PN

Colvin LA, et al. JCO 2008;18:4519-20Wolf et al. Eur J Cancer 2008; 44: 1507-15Delforge et al. Lancet Oncol, 2010;11:1086

.

DVd vs Vd: Safety

CP-73725 Mateos et al. ASH 2018 #3270

• discontinuation due to treatment-related adverse events was similar for DVd (10%) and Vd (9%)

• with longer follow-up, second primary malignancies were reported in 6% of DVd patients and 2% of Vd patients

Most common adverse events of ixazomib

Moreau et al. New Engl J Med 2016; 374: 1621

Most common grade III & IV adverse events of carfilzomib

Type of side effect, % Kd KRd

Hematological

Anemia 14 18

Neutropenia NR 30

Thrombocytopenia 9 17

Nonhematological

Peripheral neuropathy 1 3

Diarrhea 3 4

Constipation 1 <1

Nausea 1 NR

Vomiting 1 NR

Fatigue 5 8

Dyspnea 5 3

Cardiac disease† 6 7

Arterial hypertension 9 4

Rash NR NR

Adapted from Delforge & Ludwig. Blood 2017;129:2359NR, not reported; Kd, carfilzomib plus dexamethasone; KRd, carfilzomib plus lenalidomide

plus dexamethasone. †Cardiac failure and ischemic heart disease.

ASPIRE ENDEAVOR FOCUS

Carfilzomib (KRd)Control

(Rd)Carfilzomib (Kd)

Control (Vd)

Carfilzomib (K)

Control (BSC)

n 392 389 463 456 157 153

Carfilzomib dose, mg/m2 20/27 20/56 20/27

Treatment-emergent cardiac adverse events of interest, any grade

Cardiac failure* 25 (6.4) 16 (4.1) 38 (8.2) 13 (2.9) 12 (7.6) 7 (4.6)

Hypertension* 62 (15.8) 32 (8.2) 120 (25.9) 44 (9.6) 25 (15.9) 9 (5.9)

Dyspnea 89 (22.7) 70 (18.0) 143 (30.9) 78 (17.1) 25 (15.9) 19 (12.4)

Ischemic heart disease† 23 (5.9) 18 (4.6) 13 (2.8) 9 (2.0) 3 (1.9) 0

Treatment-emergent cardiac adverse events of interest, grade ≥ 3

Cardiac failure* 15 (3.8) 7 (1.8) 22 (4.8) 8 (1.8) 9 (5.7) 5 (3.3)

Hypertension* 22 (5.6) 8 (2.1) 44 (9.5) 12 (2.6) 6 (3.8) 0

Dyspnea 12 (3.1) 8 (2.1) 26 (5.6) 10 (2.2) 3 (1.9) 0

Ischemic heart disease† 13 (3.3) 8 (2.1) 8 (1.7) 7 (1.5) 1 (0.6) 0

Incidence of cardiovascular adverse events with carfilzomib

*Standardized MedDRA Query, narrow scope. †Standardized MedDRA Query, broad scope. All values are n (%) unless indicated

otherwise.

BSC, best supportive care; CV, cardiovascular; d, dexamethasone; K, carfilzomib; MedDRA, Medical Dictionary for Regulatory

Activities;

R, lenalidomide; V, bortezomib.

Chari A, et al. Blood Adv. 2018;2:1633

Monitoring:

• Patients at risk should1:

• be treated with caution and remain under close follow-up

• have a comprehensive medical assessment prior to starting treatment with carfilzomib

• Assessment should optimise the patient’s status, with particular attention to blood pressure and fluid management1

Risk factors for cardiovascular complications with carfilzomib

Fluid management:• Hydration is recommended before carfilzomib administration1

• Reduction of fluid volume in patients with increased cardiac risk should be considered1,4,5

• Diuretics could be considered to optimise fluid balance5

Increased age: ≥75 years of

age

Pre‐existing cardiac failure (NYHA Class III

and IV) and other cardiac diseases

Recent myocardial infarction

(within prior 4 months)

Conduction abnormalities and

arrhythmias uncontrolled by

medications

Angina uncontrolled

by medications

1. Kyprolis® (carfilzomib) SmPC, Amgen; 2. Rosenthal A, et al. Blood Cancer J 2016;6:e3844; 3. Zamorano JL, et al. Eur Heart J 2016;37:2768–2801; 4. Mikhael J. Clin Lymphoma Myeloma Leuk. 2016;16(5):241-5;

5. Koulaouzidis G, et al. Heart Failure Clin 2017;13:289–95.NYHA: New York Heart Association.

Infusion-related reactions with MoAbs

• IRR percentages derived from clinical trials:▪ daratumumab (n = 1166):

• any grade IRRs: 40% of patients during the first infusion, 2% with the second infusion,• grade 3 in < 1% of patients; grade 4 in 0.2% of patients• most common symptoms: nasal congestion, cough, throat irritation, chills, nausea, vomiting and

diarrhea

▪ elotuzumab (n = 554)• any grade IRR: 10% of which 70% during the first infusion• all IRR < grade 3• most common symptoms: chills, fever, hypertension

• Prophylactic measures:▪ daratumumab:

• steroids (dexamethasone 20 mg or methylprednisolone 100 mg IV (60 mg from second infusion)• antihistaminic• paracetamol• post-infusion: 20 mg prednisolone on days 2 and 3

▪ elotuzumab:• dexamethasone: 28 mg oral and 8 mg IV• H1 and H2 blocker• paracetamol

Daratumumab EU SPC, elotuzumab SPC

Additional prophylactic measures

• For daratumumab: patients with a history of obstructive pulmonary disease1

▪ close observation

▪ the use of post-infusion medications including short- and long-acting bronchodilators, and inhaled corticosteroids should be considered

▪ following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medications may be discontinued at the discretion of the physician

• For all monoclonal antibodies: increased risk of herpes zoster and other infections▪ anti-viral prophylaxis should be considered for the prevention of herpes zoster virus

reactivation

1. Daratumumab EU SmPC, https://www.ema.europa.eu [Accessed 28 Sept. 2018].

Immunomodulatory drugs

Lenalidomide

15-25 mg/d

N

NH

O O

O

NH2

Structurally similar, but functionally different both

qualitatively and quantitatively

N

N

O

O

O

O

Thalidomide

100-200 mg/d

Pomalidomide

1-4 mg/d

N

O

O

NH

O

O

N H2

DRd vs Rd: Safety

CP-73725

• no new safety signals were picked up with longer follow-upBahlis et al. ASH 2018 #1996

Major side effects of pomalidomide-dexapooled analysis of MM-002, MM-003 and MM-010

• pooled analysis of 1088 patients

• ≥ 2 prior treatments

• grade 3 or 4 infections occurred in 34% of patients

• 14% of patients with infection had pneumoniaMoreau et al. Eur J Haematol 2017;99:199

G-CSF, granulocyte colony-stimulating factor; LoDEX, low-dose dexamethasone; POM, pomalidomide; wk, week; VTE, venous thromboembolism.

Dimopoulos MA, et al. Leukemia. 2014; 28:1573

Considerations to prevent hematologicaltoxicities with Pom-dex

Adjust based on age

> 75: 20 mg/wk≤ 75: 40 mg/wk

4 mg/day, regardless of comorbidity

Consider using in Cycles 1–3 to

prevent neutropenia

Consider using in Cycles 1–3 to reduce the risk

of infection

Consider for all patients to

reduce the risk of VTE

LoDEX G-CSF AntibioticsThrombo-

prophylaxisPOM

ProphylaxisStarting dose

Candidate for POM + LoDEX therapy

Pomalidomide-based combinations• Pom-cyclo-dexamethasone (PCd)1

▪ n = 100

▪ prophylaxis:

o trimethoprim-sulfametoxazole: 3 x 800 mg/w

o valacyclovir: 2 x 500 mg/d

o amoxicilline: 2 x 1 g/d

▪ grade III/IV neutropenia: 51%

▪ grade III/IV infections: 6%

• Dara-pom-dex (DPd)2

▪ n = 112

▪ grade III/IV neutropenia: 62%

• Isa-pom-dex (IPd)3

▪ n = 45

▪ grade III/IV neutropenia: 84%

▪ grade III/IV lymphopenia: 73% 1. Garderet et al. Blood 2018;132:2555

2. Siegel et al. ASH 2018; abstract 32713. Mikhael et al. Blood 2019; prepublished online march 12

Elotuzumab-based combinationsElo-Rd

Elo-Pom-dex

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

any grade grade 3/4 any grade grade 3/4

Elotuzumab (n = 60) Control group (n = 55)

Dimpoulos et al. New Engl J Med 2018;379:1811

Uncertainties about future drugs for relapsed MM

Main toxicities Any Grade Grade 3/4

Hematologic

Thrombocytopenia 73% 59%

Neutropenia 32% 23%

Non-hematologic

Nausea 73% 8%

Diarrhea 43% 5%

Fatigue 63% 15%

Vomiting 44% 4%

Vogl DT, et al. J Clin Oncol 2018;36(9):859FDA warning; 21 march 2019

Interim results from phase III BELLINI trial

venetoclax selinexor

Future immunotherapies for MM

• GSK2857916 or belantamab mafodotin

• antibody-drug conjugate against BCMA

• phase I study in 35 patients

• common adverse events

▪ thrombocytopenia (grade III/IV in 35%)

▪ eye toxicity

o corneal events in 69% (mostly grade I/II)

o blurred vision in 51%

o photophobia in 29%

Trudel et al. Blood Cancer J 2019; 9:37 Raje et al. New Engl J Med 2019;380:1726

conjugated monoclonal antibodies CAR-T cells

Conclusions• treatment practices in relapsed multiple myeloma are rapidly

changing

• single-agent short-term exposure has been gradually replaced by long-term multi-drug treatment regimens

• the success of treatment is largely dependent on optimal drug dose delivery and treatment duration

• the quality of life of MM patients is largely dependent on theabsence of disabling or dangerous adverse events

• more active drug combinations and advanced immunotherapies are associated with more profound immune suppression and can induce more adverse events

• awareness and prevention of adverse events are cornerstones of successful myeloma management