An overview of onco-pharmacy in multiple myeloma

Tamilarasan

Clinical Pharmacist. Kauvery Hospital, Tennur, Trichy, Tamil Nadu

Background

Multiple Myeloma is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in overabundance of monoclonal para protein, destruction of bone and displacement of other hematopoietic cell lines.

Drug choices for Multiple Myeloma

Proteasome Inhibitors
Immunomodulatory agents
Monoclonal antibodies
Alkylating agents & Anthracyclines
Corticosteroids

1. Proteasome Inhibitors

Drugs

Bortezomib
Carfilzomib
Ixazomib

Mechanism of action

Inhibition of proteasome activity

↓

Induction of apoptosis by activating caspase-8 and caspase-9

↓

Upregulation NOXA & down-regulation of adhesion molecules

↓

Cell apoptosis

Drug	Route of administration	Dose	Side effect	Remarks
Bortezomib	IV or SC	1.3 mg/m² on days 1, 4, 8, 11 every 21 days	Peripheral neuropathy, fatigue, nausea, diarrhea, thrombocytopenia	Antiviral prophylaxis given for herpes zoster. May be given weekly for patients with peripheral neuropathy.
Carfilzomib	IV	10-min infusion twice weekly on 2 consecutive days for 3 weeks in a 4-week cycle – 20 mg/m² Cycle 1: Days 8, 9, 15, 16; and all future cycles	Fatigue, nausea, diarrhea, thrombocytopenia	Higher cardiac risk in patients with pre-existing heart conditions. Antiviral prophylaxis given for herpes zoster.
Ixazomib	Oral	4 mg on days 1, 8, 15 of a 28-day cycle	Thrombocytopenia, neutropenia, diarrhea, constipation, nausea	3 mg dose recommended for patients with liver/kidney impairment. Antiviral prophylaxis given for herpes zoster.

2. Immunomodulatory agents

Thalidomide
Lenalidomide
Pomalidomide

Mechanism of action

Interaction with bone marrow microenvironment with down-regulation of adhesion molecules

↓

Targeting the cereblon and downstream targets

↓

Regulation of pro and anti-inflammatory cytokines

↓

Regulation of T cell and NK cells activity

⇓

Anti-angiogenesis stimulated

↓

Induction of apoptosis by activating caspase 8 and 9

Drug	Route of administration	Dose	Side effect	Remarks
Thalidomide	Oral	200 mg daily (rarely above 100 mg due to tolerance)	Embryo-fetal toxicity, venous and arterial thromboembolism, peripheral neuropathy	Causes irreversible peripheral neuropathy
Lenalidomide	Oral	25 mg on days 1–21 of a 28-day cycle; 10 mg continuous for maintenance	Embryo-fetal toxicity, low WBC and platelet counts, thromboembolism	Given with dexamethasone; requires anti-thrombotic prophylaxis
Pomalidomide	Oral	4 mg on days 1–21 of a 28-day cycle	Embryo-fetal toxicity, low WBC and platelet counts, thromboembolism	Given with dexamethasone; requires anti-thrombotic prophylaxis

Drug Dilution

S. No	Drug	Dilution	Administration
1	Bortezomib	For IV: 1 mg/ml of 0.9% NaCl; For SC: 1.3 ml of 0.9% NaCl	Administer over 5–10 min
2	Carfilzomib	Reconstitute with 5 ml sterile water + dilute in 50–100 ml of dextrose or 0.9% NaCl	Administer over 10–30 min
3	Daratumab	Dilute with 500 ml of 0.9% NaCl	Administer over initial 3–6 hours
4	Elotuzumab	Dilute with 250–1000 ml of NaCl or dextrose	Administer over 1–4 hours depending on dose
5	Isatuximab	Dilute with 250 ml of NaCl	Administer over initial 3–4 hours
6	Cyclophosphamide	Dilute with 100–250 ml of NaCl or dextrose	Administer over 30–60 min

Combination of drugs

Most widely used combination of the drugs are

VRD
KRD
Daratumumab based

VRD: Proteasome Inhibitors (Bortezomib)+Immunomodulatory agents (Lenalidomide) + Dexamethasone.

KRD: Proteasome Inhibitors (Carfilzomib)+Immunomodulatory agents (Lenalidomide)+Dexamethasone.

Daratumumab based

D-VRD – Daratumumab + Bortezomib + Lenalidomide + Dexamethasone.
D-RD – Daratumumab + Lenalidomide + Dexamethasone.
D-KD – Daratumumab + Carfilzomib + Dexamethasone

Dose adjustment

Renal

Lenalidomise

Crcl > 60ml – No adjustment
Crcl = 30 – 60ml – 5mg PO qDay
Crcl < 30ml – 2.5mg PO qDay

Pomalidomide – End stage on dialysis – 3 mg/day
Bortezomib – No dose adjustment needed
Carfilzomib – No dose adjustment needed. Monitor for worsening renal function
Ixazomib – Crcl < 30ml – 3mg per day

Hepatic

Carfilzomib – Bilirubin > 1 to 3 – reduce dose to 25%
Ixazomib – Bilirubin > 1.5 – Decrease dose to 3 mg

Hematologic

Need to monitor for neutropenia, thrombocytopenia, anemia
If the blood count drops, reduce the dose of Proteasome Inhibitors and Immunomodulatory agents

Why antiviral administer for MM patient

MM increase the risk of herpez zoster due to disease related immunosuppression and treatment related immunosuppression.

Disease related: MM impair B-cell and T-cell function. It may cause Hypogammaglobinemia.

Treatment related: Bortezomib imparing T-Cell and reactivation of herpes zoster.

Supportive Care

Infection Management

Antiviral – Acyclovir or valacyclovir routinely prescribed
Antibacterial – Levofloxacin in early MM treatment in selected patient
IVIG – For patient with recuurent infection and documented hypogammaglobulinemia

Anemia Management

Erythropoiesis stimulating agent used.
Blood transfusion

Thrombosis Management

Immunomodulatory agents administer with steroid increase the venous thromboembolism.
Aspirin, LMWH are used to manage

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An overview of onco-pharmacy in multiple myeloma