Dosing & Uses
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 20mg/vial
Multiple Myeloma
Indicated in combination with dexamethasone for relapsed or refractory multiple myeloma (RRMM) in adults who have received ≥4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody
Each cycle is 28 days
Melphalan flufenamide 40 mg IV on Day 1, PLUS
Dexamethasone 40 mg PO/IV on Days 1, 8, 15, and 22 (reduce dose to 20 mg in patients aged ≥75 yr)
Continue until disease progression or until unacceptable toxicity
Dosage Modifications
Dose reductions for adverse reactions
- Administered IV on Day 1 of each 28-day cycle
- First dose reduction: Reduce to 30 mg
- Second dose reduction: Reduce to 20 mg
- Unable to tolerate 20-mg dose: Permanently discontinue
Myelosuppression
- Platelet count <50 x 109/L or absolute neutrophil count (ANC) <1 x 109/L on intended dosing day
- Withhold and monitor platelet count weekly until ≥50 x 109/L and ANC weekly until ≥1 x 109/L
- Resume at same dose if delay ≤2 weeks or at 1 dose level lower if delay >2 weeks
- Grade 4 hematological adverse reaction on an intended dosing day in 2 consecutive cycles: Resume at 1 dose level lower
Nonhematologic adverse reactions
- Grade 2: Consider withholding until resolved to Grade ≤1 or baseline; consider resuming at 1 dose level
- Grade 3 or 4: Withhold until resolved to Grade ≤1 or baseline; resume at 1 dose level as clinically appropriate
Renal impairment
- Mild (CrCl 45-89 mL/min): No dosage adjustment necessary
- Moderate-to-severe (CrCl 15-44 mL/min): Not studied
Hepatic impairment
- Mild (total bilirubin [TB] ≤1.5x ULN and any AST): No dosage adjustment necessary
- Moderate-to-severe (TB >1.5x ULN and any AST): Effects on pharmacokinetics is unknown
Dosing Considerations
Monitoring parameters
- Verify pregnancy status in females of reproductive potential before initiation
- Complete blood cell count, including neutrophils: Baseline, during treatment (more frequently during first 2 months), and as clinically indicated
Limitation of use
- Not indicated or recommended for use as conditioning regimen for transplantation outside of controlled clinical trials
Safety and efficacy not established
No overall differences in safety were observed compared with younger patients
Clinical studies in patients with RRMM did not include enough patients aged >65 yr to determine differences in treatment response
Adverse Effects
>10%
All grades
- Leukocytes decreased (99%)
- Platelets decreased (99%)
- Lymphocytes decreased (97%)
- Neutrophils decreased (95%)
- Hemoglobin decreased (84%)
- Creatinine increased (68%)
- Fatigue (55%)
- Nausea (32%)
- Diarrhea (27%)
- Pyrexia (24%)
- Respiratory tract infection (24%)
- Cough (17%)
- Constipation (15%)
- Peripheral edema (14%)
- Decreased appetite (14%)
- Hypokalemia (14%)
- Headache (13%)
- Bone pain (13%)
- Pain in extremity (13%)
- Vomiting (13%)
- Pneumonia (13%)
- Back pain (12%)
- Dizziness (11%)
- Dyspnea (11%)
- Insomnia (11%)
Grade 3 or 4
- Lymphocytes decreased (95%)
- Leukocytes decreased (88%)
- Neutrophils decreased (82%)
- Platelets decreased (80%)
- Hemoglobin decreased (50%)
- Pneumonia (11%)
1-10%
All grades
- Dyspnea exertional (10%)
- Hypocalcemia (10%)
- Arthralgia (10%)
- Hypersensitivity reaction (7%)
- Febrile neutropenia (6%)
- Sepsis (3.8%)
Grade 3 or 4
- Fatigue (6%)
- Respiratory tract infection (5%)
- Hemorrhages (3.8%)
- Pyrexia (1.9%)
- Peripheral edema (1.3%)
- Dyspnea (1.3%)
- Hypokalemia (1.3%)
- Bone pain (1.9%)
- Pain in extremity (1.9%)
- Creatinine increased (1%)
<1%
Grade 3 or 4 H4
- Decreased appetite (0.6%)
- Hypocalcemia (0.6%)
- Back pain (0.6%)
- Insomnia (0.6%)
- Nausea (0.6%)
- Constipation (0.6%)
Warnings
Contraindications
History of serious hypersensitivity reaction to melphalan flufenamide or melphalan
Cautions
Can cause fetal harm
Anemia reported; monitor red blood cells (RBCs); treat anemia as clinically indicated and as per standard guidelines; may require modifying or delaying the dose to allow RBCs to recover
Fatal infections occurred in clinical trials; respiratory tract infection occurred in 24%, pneumonia in 13%, and sepsis in 3.8% of patients; consider antimicrobials as clinically appropriate
Secondary malignancies (eg, myelodysplastic syndrome, acute leukemia) occurred; monitor long term for development of secondary malignancies
Thrombocytopenia
- Thrombocytopenia reported
- Grade 3 or 4 thrombocytopenia occurred in 43% of patients during first cycle; median onset time from first dose is 15 days
- Monitor platelets; do not administer if platelet count <50 x 109/L
Neutropenia
- Neutropenia and febrile neutropenia reported
- Grade 3 or 4 neutropenia occurred in 50% during first cycle; median onset time from first dose is 15 days
- Monitor neutrophil counts; do not administer if ANC <1 x 109/L
- Consider leukocyte growth factor as clinically appropriate
Increased risk of mortality at higher doses than recommended
- Increased mortality observed in dogs administered a single melphalan flufenamide IV dose (17.5 mg/kg) or an equimolar dose of melphalan
- Limited clinical experience at dosages higher than recommended
- Safety and efficacy not established for use as a conditioning regimen in patients receiving transplant
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, fetal harm may occur
There are no available data on use in pregnant females to evaluate for a drug-associated risk
Advise pregnant females of the potential risk to a fetus
Verify pregnancy status in females of reproductive potential before initiation
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 6 months after last dose
- Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months after last dose
Infertility
- Females: May cause amenorrhea in premenopausal women and result in infertility
- Males: Based on animal data, male fertility may be impaired; alkylating drugs can also cause irreversible testicular suppression
Animal data
- Animal reproductive or developmental toxicity studies were not conducted
- Melphalan flufenamide is genotoxic and was toxic to actively dividing cells in animal studies and may potentially cause teratogenicity and embryofetal lethality
Lactation
No data are available on drug presence or its metabolites in human breast milk, or effects on breastfed children, or milk production
Advise women not to breastfeed during treatment and for 1 week after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Peptide conjugated alkylating drug
May passively distribute into cells and thereafter enzymatically hydrolyze to melphalan
Crosslinking of DNA is involved in antitumor activity of melphalan flufenamide
In cellular assays, melphalan flufenamide inhibited proliferation, induced apoptosis of hematopoietic and solid tumor cells, and showed synergistic cytotoxicity with dexamethasone in melphalan-resistant and nonresistant multiple myeloma cell lines
Absorption
Peak plasma time
- Melphalan flufenamide: During 30-min infusion
- Active metabolites: 4-15 min after 40-mg infusion ended
Peak plasma concentration
- 40-mg single dose: 432 ng/mL
- Steady-state: 419 ng/mL
AUC
- 40-mg single dose: 3,143 mcg⋅hr/ mL
- Steady-state: 2,933 mcg⋅hr/mL
Distribution
Vd: 35 L (melphalan flufenamide); 76 L (melphalan)
Metabolism
Melphalan flufenamide: Metabolized in tissues to desethyl-melphalan flufenamide and melphalan
Melphalan: Metabolized primarily by spontaneous hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan
Elimination
Half-life
- Melphalan flufenamide: 2.1 min
- Melphalan: 70 min
Clearance
- Melphalan flufenamide: 692 L/hr
- Melphalan: 23 L/hr
Administration
IV Compatibilities
D5W
0.9% NaCl
IV Preparation
Determine dose, total volume of reconstituted solution required, and number of vials needed
Remove vial(s) from refrigerator and place at room temperature for at least 30 min
Shake vial(s) vigorously or vortex to disintegrate lyophilized powder cake into loose powder
Following steps must be completed within 30 min
-
Reconstitution
- Reconstitute each vial with 40 mL of room temperature (20-25ºC/68-77ºF) D5W to obtain a final concentration of 0.5 mg/mL
- Shake vial(s) vigorously until solution is clear; allow vials to stand to dissipate any air bubbles to confirm a clear solution
-
Dilution
- Withdraw and discard 80 mL from a cold (2-8ºC [36-46ºF]) 250-mL infusion bag of 0.9% NaCl
- Withdraw required volume of reconstituted solution and transfer into an IV bag containing 0.9% NaCl to obtain a final concentration of 0.1-0.16 mg/mL; discard any product remaining in vial(s)
- Gently invert bag to mix solution; NOT shake
- Visually inspect solution (clear/colorless to pale yellow) and discard if solution is discolored or particles are present
- Must begin infusion within 60 min of initial reconstitution; if not immediately used, refrigerate at 2-8C (36-46F), within 30 min after initial reconstitution, for up to 6 hr
- Degrades in solution, especially at room temperature; do not exceed storage timelines for diluted solution
Premedication
Consider a serotonin-3 (5-HT3) receptor antagonist or other antiemetics before and during treatment
IV Administration
Visually inspect diluted solution; do not use if visibly opaque particles, discoloration, or foreign particles are observed
Infuse over 30 min via central venous access device (eg, ediport, peripherally inserted central catheter, tunneled central venous catheter)
If infusion bag was stored in a refrigerator, allow to reach to room temperature (20-25ºC [68-77ºF]); start infusion within 30 min of removing diluted solution from refrigerator
Once completed, flush central catheter per individual institutional guidelines
Storage
Unopened vials
- Refrigerate at 2-8ºC (36-46ºF) and protect from light
- Retain in original carton until use
Diluted solutions
- Must begin infusion of diluted solution within 60 min of initial reconstitution
- If not immediately used, refrigerate at 2-8ºC (36-46ºF), within 30 min after initial reconstitution, for up to 6 hr
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Patient Handout
Formulary
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