Melphalan (DB01042): A Comprehensive Clinical and Pharmacological Monograph

Executive Summary

Melphalan (DrugBank ID: DB01042), a bifunctional nitrogen mustard alkylating agent, represents a cornerstone of cancer chemotherapy with a clinical legacy spanning six decades since its initial U.S. approval in 1964. Structurally a derivative of L-phenylalanine, it was rationally designed to leverage amino acid transport systems for preferential entry into malignant cells. Its primary mechanism involves the induction of extensive DNA damage, particularly inter-strand cross-links, leading to cell cycle arrest and apoptosis in both dividing and quiescent cells. This broad cytotoxicity has established melphalan as an indispensable therapeutic agent for several malignancies. Its most prominent and enduring role is in the treatment of multiple myeloma (MM), where high-dose intravenous (IV) melphalan followed by autologous stem cell transplantation (ASCT) remains the undisputed standard of care for consolidation therapy in transplant-eligible patients. It also holds approved indications for the palliative treatment of ovarian cancer and, in a highly specialized formulation, for the liver-directed treatment of uveal melanoma with hepatic metastases.

Despite its proven efficacy, the clinical use of melphalan is complicated by significant challenges. Its oral formulation is plagued by highly variable and incomplete absorption, leading to unpredictable systemic exposure and a tenuous balance between efficacy and toxicity. The principal dose-limiting toxicity across all formulations is profound and prolonged myelosuppression, which necessitates ASCT rescue at high doses and careful hematologic monitoring in all settings. Furthermore, as a direct-acting mutagen, melphalan carries an inherent risk of inducing secondary malignancies, such as myelodysplastic syndrome and acute myeloid leukemia.

The history of melphalan is marked by key innovations aimed at mitigating these challenges. The development and 2016 approval of Evomela®, a propylene glycol-free formulation utilizing Captisol® technology, addressed the poor solubility and stability of older IV preparations, thereby improving the safety and convenience of administration. In contrast, the development of its peptide-drug conjugate derivative, melflufen (Pepaxto®), provides a cautionary tale in drug development. Despite receiving accelerated approval based on promising response rates, it was ultimately withdrawn from the market after a confirmatory trial revealed a detrimental effect on overall survival, highlighting the complexities of surrogate endpoints in oncology.

Looking forward, melphalan is being conceptually repositioned from a legacy cytotoxic drug to a versatile agent with a future in modern cancer therapy. Ongoing research is intensely focused on personalizing its use through risk-adapted dosing strategies based on patient-specific factors like age, frailty, renal function, and pharmacogenomic markers. Concurrently, a deeper understanding of its immunomodulatory properties—specifically its ability to induce lymphodepletion and immunogenic cell death—has made it a rational and potent conditioning agent for use with next-generation immunotherapies, including CAR-T cells and bispecific antibodies. The future of melphalan lies not in its replacement, but in its strategic refinement and intelligent combination, ensuring its continued relevance in the evolving landscape of oncology.

Drug Identity and Physicochemical Properties

Nomenclature and Identifiers

Melphalan is a well-characterized small molecule with a comprehensive set of chemical names and identifiers used across scientific, regulatory, and clinical domains.

• Chemical Names: Its formal chemical nomenclature reflects its structure as an amino acid derivative.
• The IUPAC Name is (2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid.[1]
• The Systematic Name is 4-[bis(2-Chloroethyl)amino]-L-phenylalanine.[1]
• Common Names and Synonyms: For ease of reference, it is widely known by several common names and synonyms, including Melphalan, L-PAM (L-phenylalanine mustard), L-Sarcolysin, Phenylalanine mustard, and Alanine nitrogen mustard.[1]
• Brand Names: Melphalan has been marketed under various brand names globally. The most prominent include Alkeran®, which was the original brand name for both oral and injectable forms, and newer formulations such as Evomela® (a propylene glycol-free injection), Hepzato® (a kit for intra-arterial hepatic delivery), Ivra, and Phelinun.[1]
• Database Identifiers: The drug is cataloged in major chemical and pharmacological databases, ensuring standardized identification for research and regulatory purposes.
• DrugBank ID: DB01042 [1]
• CAS Number: 148-82-3 [1]
• PubChem CID: 460612 [1]
• Other key identifiers include UNII (Q41OR9510P), KEGG (D00369), ChEBI (CHEBI:28876), and ChEMBL (ChEMBL852).[1]

Chemical and Physical Characteristics

• Chemical Formula: C13​H18​Cl2​N2​O2​.[1]
• Molecular Weight: The average molecular weight is 305.20 g/mol, with a monoisotopic mass of 304.0745332 Da.[2]
• Structure: Melphalan is a phenylalanine derivative of nitrogen mustard. Specifically, it is the levorotatory (L) isomer of the compound.[5] This structure is a deliberate fusion of two key components: the L-phenylalanine moiety, an essential amino acid, and the bis(2-chloroethyl)amino group, a classic bifunctional alkylating "warhead".[5] The initial rationale for this design was to exploit the active transport mechanisms for amino acids, which are often upregulated in rapidly proliferating tumor cells, to achieve a degree of selective drug uptake. This structural duality is fundamental to understanding both its mechanism of action (DNA alkylation) and its pharmacology (cellular transport).
• Physical Appearance: In its pure form, melphalan is a white to buff-colored powder that is either odorless or possesses a faint odor.[6]
• Solubility and Stability: The parent compound exhibits limited solubility and stability in standard aqueous solutions, a critical physicochemical property with significant clinical ramifications.[17] It is soluble up to 20 mM in solvents like DMSO and 1eq. HCl.[4] The instability in conventional 0.9% sodium chloride solution at room temperature, where it degrades rapidly, historically limited infusion times and necessitated the use of co-solvents like propylene glycol in the original Alkeran® IV formulation.[17] This challenge was a direct impetus for the development of advanced formulations. The Captisol-enabled formulation (Evomela®) was engineered specifically to overcome these limitations, improving solubility and extending stability, thereby enhancing the drug's safety profile and clinical utility.[18] This progression from a difficult-to-handle compound to a more stable product is a clear example of how pharmaceutical science can directly address clinical needs, representing a major milestone in the drug's long lifecycle.

Clinical Pharmacology

The clinical pharmacology of melphalan is characterized by a potent, well-defined cytotoxic mechanism and a complex, highly variable pharmacokinetic profile. A thorough understanding of these two facets is essential for its safe and effective use.

Mechanism of Action: The Alkylating Agent Paradigm and Beyond

Melphalan's primary antineoplastic activity stems from its classification as a cell cycle phase non-specific, bifunctional alkylating agent.[21] It is a direct-acting drug, meaning it does not require metabolic activation to become cytotoxic.[22]

• Core Mechanism of DNA Damage: The core of melphalan's action is the alkylation of cellular macromolecules, with DNA being the principal target.[22] The two chloroethyl groups of its nitrogen mustard moiety can form highly reactive carbonium ion intermediates. These intermediates then form strong, covalent bonds with nucleophilic sites on DNA bases, most notably the N7 position of guanine.[5] Because it is bifunctional, a single molecule of melphalan can react at two different sites, leading to the formation of:
• DNA mono-adducts: A single bond to a DNA base.
• DNA-protein cross-links: Covalent bonds between DNA and cellular proteins.
• Inter-strand and Intra-strand cross-links: The most critical lesions for cytotoxicity, where the two strands of the DNA helix are covalently linked together, or two bases on the same strand are linked.[1]
• Consequences of DNA Damage: These DNA lesions, particularly the inter-strand cross-links, physically prevent the separation of the DNA strands. This obstruction effectively halts fundamental cellular processes, including DNA replication and RNA transcription, which are prerequisites for cell division and survival.[1] The cell's DNA damage response pathways are activated, and if the damage is too extensive to be repaired, the cell is driven into programmed cell death, or apoptosis.
• Broad Cytotoxicity: A key feature of melphalan is its ability to exert cytotoxic effects on both rapidly dividing and resting (non-dividing) tumor cells.[1] This is crucial for its efficacy in malignancies with a low proliferative index, such as multiple myeloma, where a significant portion of the malignant plasma cells may be in a quiescent state at any given time.
• Emerging Mechanisms - Immunomodulation: Beyond its direct cytotoxic effects, a more nuanced understanding of melphalan's mechanism is emerging. It has been shown to possess significant immunomodulatory properties. High-dose melphalan can induce a specific form of apoptosis known as immunogenic cell death (ICD). This process is characterized by the translocation of calreticulin (CRT) to the cell surface and the extracellular release of damage-associated molecular patterns (DAMPs) like high-mobility group box 1 (HMGB1) protein.[26] These signals act as an "eat me" signal to dendritic cells and can prime an adaptive anti-tumor immune response, effectively turning the dying tumor into an in-situ vaccine. Furthermore, the profound lympho-depletive effect of melphalan, long considered only a toxicity, is now recognized as a therapeutic benefit in the context of adoptive cell therapy (e.g., CAR-T cells). By depleting endogenous lymphocytes, particularly suppressive regulatory T-cells (Tregs), melphalan creates homeostatic "space" and a favorable pro-inflammatory cytokine milieu that facilitates the robust engraftment and expansion of infused anti-tumor T-cells.[26] This dual ability to both kill tumor cells and favorably modulate the immune microenvironment positions melphalan as an excellent "chemo-immunotherapy" partner.

Pharmacokinetics: A Profile of High Variability

The pharmacokinetic profile of melphalan is notoriously variable, which presents a significant clinical challenge in achieving consistent therapeutic exposure while avoiding excessive toxicity. This variability is a key driver behind the evolution of its formulations and dosing strategies.

Absorption

Oral administration of melphalan is characterized by incomplete and highly erratic absorption.[5]

• The absolute bioavailability is extremely wide, ranging from as low as 25% to as high as 93%, with an average reported between 56% and 89%.[1]
• The time to first appearance of the drug in plasma can vary from 0 to 6 hours, and the time to peak concentration (Tmax​) is also inconsistent.[5]
• Critically, the co-administration of food significantly impairs absorption. Studies have shown that a high-fat meal can reduce the area under the curve (AUC), a measure of total drug exposure, by 36% to 54%.[5] This interaction mandates that oral melphalan must be taken on an empty stomach to maximize the chance of adequate absorption.[13]

This profound variability in absorption means that two patients receiving the identical oral dose can experience vastly different levels of systemic drug exposure, potentially leading to undertreatment and lack of efficacy in one, and severe toxicity in another. This liability is a primary reason why IV administration is preferred for settings like high-dose conditioning, where predictable, myeloablative exposure is paramount.

Distribution

Once in the systemic circulation, melphalan distributes rapidly into total body water.[21]

• It exhibits extensive plasma protein binding, with reported ranges of 50% to 90%.[5] The primary binding proteins are serum albumin, which accounts for approximately 40% to 60% of binding, and α1-acid glycoprotein, which accounts for about 20%.[5]
• A notable characteristic is that a significant fraction, approximately 30%, of this binding is covalent and irreversible, effectively removing that portion of the drug from further activity or clearance pathways.[5]
• The volume of distribution (Vd​) is large, reported to range from 35.5 to 185.7 L/m², indicating substantial distribution into tissues.[5]
• Penetration across the blood-brain barrier is limited. The concentration in cerebrospinal fluid (CSF) is approximately 10-fold lower than in plasma, which may limit its efficacy for central nervous system malignancies.[5]

Metabolism

Melphalan's metabolism is relatively simple and does not rely on enzymatic pathways like the cytochrome P450 system.

• The primary route of inactivation is spontaneous, non-enzymatic chemical hydrolysis in the plasma.[1]
• This process yields two main inactive metabolites: monohydroxymelphalan and dihydroxymelphalan. No other metabolites have been detected in humans.[22]

Excretion

The elimination of melphalan is biphasic and occurs through multiple routes.[21]

• The plasma elimination half-life (t1/2​) is short. Following oral administration, the terminal half-life is approximately 1.5 hours (± 0.8 hours), and following IV administration, it is even shorter at approximately 75 minutes.[1]
• This short pharmacokinetic half-life stands in stark contrast to its prolonged pharmacodynamic effect (i.e., myelosuppression that lasts for weeks). This is not a contradiction but a hallmark of its "hit-and-run" mechanism. The drug itself is cleared quickly, but the DNA damage it inflicts is irreversible and the cellular consequences, such as apoptosis of hematopoietic stem cells, unfold over a much longer period.
• Renal excretion of the unchanged drug is a recognized but highly variable pathway, with studies reporting that between 5.8% and 21.3% of an IV dose is recovered in the urine.[1] Some analyses suggest that renal clearance may be the major elimination pathway, but that its contribution is difficult to measure accurately due to the drug's rapid chemical degradation in urine within the bladder.[30]
• A significant portion of an oral dose, between 20% and 50%, is eliminated in the feces within six days.[21]

Factors Influencing Pharmacokinetic Variability

The journey of melphalan from administration to its target is influenced by several patient-specific factors, which has driven the evolution of dosing strategies from simple weight-based calculations to more sophisticated, covariate-adjusted models.

• Cellular Uptake: Melphalan does not passively diffuse into cells. It is actively transported, primarily by the L-type amino acid transporter 1 (LAT1, encoded by the SLC7A5 gene), a transporter it shares with natural amino acids like leucine and glutamine.[5] The expression level of this transporter on tumor cells can influence drug uptake and sensitivity.
• Genetic Factors: The importance of LAT1 in melphalan transport is underscored by the discovery that a single nucleotide polymorphism (SNP) in the SLC7A5 gene, rs4240803, is significantly associated with variability in melphalan pharmacokinetics.[32] This finding opens the door to future pharmacogenomically-guided dosing, where a patient's genetic profile could be used to predict their drug exposure and tailor the dose accordingly.
• Patient-Specific Covariates: Pharmacokinetic modeling has identified several key patient characteristics that significantly influence melphalan exposure. These include fat-free mass, hematocrit, and creatinine clearance.[30] The recognition that drug distribution correlates better with lean body mass than total body weight led to the now-standard practice of using adjusted ideal body weight for dose calculations in obese patients to prevent overdosing and excessive toxicity.[33] Similarly, the role of renal function in its clearance underpins the recommendation to reduce doses in patients with significant renal impairment.[33]

The following table provides a consolidated reference for the key pharmacokinetic parameters of melphalan.

Table 1: Key Pharmacokinetic Parameters of Melphalan

Parameter	Value / Range	Clinical Significance / Notes	Source(s)
Bioavailability (Oral)	25% - 93% (Highly variable)	Extreme variability makes oral dosing unreliable for achieving predictable exposure, especially in the curative-intent setting. Mandates IV use for high-dose conditioning.	1
Effect of Food (Oral)	AUC reduced by 36% - 54%	Oral tablets must be taken on an empty stomach (1 hour before or 2 hours after meals) to maximize absorption.	5
Tmax​ (Oral)	0 - 6 hours (Highly variable)	Reflects the erratic and unpredictable nature of oral absorption.	5
Plasma Protein Binding	50% - 90% (~30% irreversible)	High binding to albumin and α1-acid glycoprotein. Irreversible binding contributes to drug disposition.	5
Volume of Distribution (Vd​)	35.5 - 185.7 L/m²	Indicates extensive distribution into tissues beyond the plasma compartment.	5
Metabolism	Non-enzymatic chemical hydrolysis	Inactivated in plasma to monohydroxy- and dihydroxy-melphalan. Not dependent on liver enzyme systems like CYP450.	1
Elimination Half-Life (t1/2​)	IV: ~75 minutesOral: ~1.5 hours	Short plasma half-life reflects rapid clearance. This contrasts with its prolonged pharmacodynamic effect (myelosuppression) due to the "hit-and-run" mechanism of irreversible DNA damage.	1
Excretion Pathways	Renal: 5.8% - 21.3% (unchanged)Fecal: 20% - 50% (oral dose)	Elimination is complex and involves both renal and fecal routes. Renal impairment requires dose adjustment.	1

Clinical Indications and Therapeutic Use

Melphalan is a versatile chemotherapeutic agent with a well-established role in the treatment of several malignancies. Its indications range from palliative care to curative-intent, high-dose conditioning regimens, reflecting its potent cytotoxic activity.

FDA-Approved and EU-Indicated Uses

Melphalan's approved uses vary slightly between regulatory bodies in the United States (FDA) and the European Union (EMA).

Multiple Myeloma (MM)

This is the cornerstone indication for melphalan, where it is used across the treatment spectrum.[1]

• High-Dose Conditioning Treatment: In the United States and worldwide, the most common and critical use of melphalan is as a high-dose myeloablative conditioning agent administered immediately prior to autologous stem cell transplantation (ASCT).[1] This intensive therapy aims to eradicate residual myeloma cells from the bone marrow. While novel agents (e.g., proteasome inhibitors, immunomodulatory drugs) have revolutionized induction therapy, none have successfully replaced high-dose melphalan in the transplant setting. Landmark clinical trials, such as the IFM 2009 study, have repeatedly confirmed that consolidation with HDM-ASCT provides a significant survival benefit over novel agent-based therapy alone, cementing melphalan's indispensable role in the curative-intent management of transplant-eligible patients.[38]
• Palliative Treatment: Melphalan is also indicated for the palliative treatment of MM. It can be administered intravenously for patients for whom oral therapy is not appropriate, or as an oral agent, classically in combination with prednisone (the "MP" regimen).[5]

Ovarian Cancer

Melphalan is approved for the palliative treatment of non-resectable epithelial carcinoma of the ovary.[1] Its use in this setting has diminished with the advent of platinum-based chemotherapy regimens, but it remains an option.

Uveal Melanoma with Hepatic Metastases

A highly specialized indication was approved by the FDA in August 2023 for the Hepzato® Kit.[1] This is a liver-directed therapy for adults with uveal melanoma who have unresectable hepatic metastases. The indication is precisely defined for patients with metastases affecting less than 50% of the liver and either no extrahepatic disease or limited extrahepatic disease that is amenable to local treatment.[1] This therapy represents a paradigm of targeted drug delivery, using percutaneous hepatic perfusion to administer a high concentration of melphalan directly to the liver while filtering the drug from the venous return to minimize systemic toxicity.[10] It transforms a systemic drug into a potent locoregional treatment for a specific and difficult-to-treat condition.

Additional European Union Indications

The European Medicines Agency (EMA) has approved melphalan for a broader range of malignancies, including malignant lymphoma (both Hodgkin and non-Hodgkin), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), childhood neuroblastoma, and mammary adenocarcinoma.[1]

Significant Off-Label and Investigational Uses

The potent activity of melphalan has led to its investigation and use in several other clinical contexts beyond its formal approvals.

• Systemic Light-Chain (AL) Amyloidosis: Melphalan is a cornerstone agent for treating AL amyloidosis, a plasma cell dyscrasia related to multiple myeloma. The goal is to eliminate the clonal plasma cells that produce the misfolded light chains responsible for amyloid deposition.[25] It is used in two main settings:

1. Transplant-ineligible patients: Oral melphalan is combined with dexamethasone (M-Dex).[44]
2. Transplant-eligible patients: High-dose IV melphalan (typically 140-200 mg/m²) is used as a conditioning regimen before ASCT, with risk-adapted dosing based on the extent of organ damage, particularly cardiac involvement.[25]

• POEMS Syndrome: For this rare but debilitating paraneoplastic syndrome driven by a plasma cell disorder, high-dose melphalan followed by ASCT has emerged as a highly effective treatment, capable of inducing durable hematologic and clinical responses even in patients with advanced disease and poor performance status.[47] Lower-intensity regimens like oral melphalan-prednisone have also been used historically.[50]
• Allogeneic HSCT Conditioning: In the allogeneic transplant setting, melphalan is a component of many reduced-intensity conditioning (RIC) regimens. A common combination is with fludarabine (Flu-Mel), typically using a melphalan dose of 140 mg/m², to provide sufficient immunosuppression and tumor debulking for various hematologic malignancies.[1]
• Pediatric Solid Tumors: Melphalan is investigated as part of high-dose consolidation regimens with ASCT rescue for high-risk pediatric solid tumors, including neuroblastoma and Ewing's sarcoma.[1]
• Isolated Limb Perfusion (ILP): In a specialized surgical procedure, melphalan is used for regional perfusion of an isolated limb to treat locally advanced, in-transit malignant melanoma or soft-tissue sarcoma, delivering a high drug concentration to the tumor bed while sparing systemic toxicity.[19]

Dosing and Administration

Dosing for melphalan is highly dependent on the specific indication, the route of administration, patient-specific factors (renal function, body weight), and the therapeutic intent (palliative vs. myeloablative). The following table summarizes key regimens.

Table 2: Comprehensive Dosing Regimens for Melphalan by Indication

Indication	Formulation / Brand	Dosing Regimen	Administration Notes	Key Dose Adjustments	Source(s)
Multiple Myeloma - High-Dose Conditioning	IV (Evomela®, generics)	Standard (Mel200): 100 mg/m²/day IV over 30 min for 2 days (Day -3, -2) prior to ASCT.Reduced (Mel140): 140 mg/m² IV as a single dose (Day -1) or split over 2 days.	Prophylactic antiemetics required. Infuse via central line.	Obesity: Use adjusted ideal body weight if >130% IBW.Renal Impairment/Frail: Use Mel140.	33
Multiple Myeloma - Palliative	IV (Ivra®, generics)	16 mg/m² IV over 15-20 min every 2 weeks for 4 doses, then every 4 weeks.		Renal Impairment: Consider 50% dose reduction if BUN ≥30 mg/dL.Myelosuppression: Dose reduce or hold based on blood counts.	33
	Oral (Alkeran®, generics)	Highly variable. e.g., 6 mg daily for 2-3 weeks; OR 0.2 mg/kg/day for 5 days every 4-6 weeks. Maintenance: 1-3 mg daily.	Must be taken on an empty stomach.	Myelosuppression: Adjust based on nadir counts.	33
Ovarian Cancer - Palliative	Oral (Alkeran®, generics)	0.2 mg/kg/day for 5 days; repeat course every 4-5 weeks.	Must be taken on an empty stomach.	Myelosuppression: Dose based on hematologic tolerance.	33
Uveal Melanoma - Hepatic Metastases	Intra-arterial (Hepzato® Kit)	3 mg/kg (based on ideal body weight) via hepatic artery every 6-8 weeks for up to 6 infusions. Max dose 220 mg.	Specialized procedure requiring percutaneous hepatic perfusion with filtration.	Patient Weight: Must be >35 kg.Myelosuppression: Reduce to 2 mg/kg for subsequent cycles if severe toxicity occurs.	10
AL Amyloidosis (Off-Label)	IV (Evomela®, generics)	Conditioning for ASCT: 140-200 mg/m² as a single dose, risk-adapted based on organ function.		Cardiac/Organ Dysfunction: Dose reduction to 140 mg/m² or lower is common.	25
	Oral (generics)	M-Dex regimen: e.g., 10 mg/m² daily for 4 days with dexamethasone, every 28 days.	Take on an empty stomach.	Age >75 years: Consider 50% dose reduction.	44

Safety Profile and Risk Management

The clinical utility of melphalan is intrinsically linked to its significant toxicity profile. The non-specific DNA alkylating mechanism that makes it a potent anticancer agent also accounts for its effects on healthy, rapidly dividing tissues and its long-term carcinogenic potential. Rigorous monitoring and proactive management are paramount.

Boxed Warnings and Contraindications

The U.S. Food and Drug Administration (FDA) mandates several boxed warnings for melphalan, highlighting its most severe and life-threatening risks.[25]

• Severe Bone Marrow Suppression: This is the primary and most consistent dose-limiting toxicity. Melphalan induces profound myelosuppression, leading to neutropenia, thrombocytopenia, and anemia. This can result in life-threatening complications, including severe infections and bleeding. Intravenous formulations have been shown to cause more severe myelosuppression than oral formulations. At myeloablative doses used for conditioning, this effect is expected and absolute, requiring rescue with hematopoietic stem cells. Continuous and frequent monitoring of complete blood counts is mandatory for all patients.[35]
• Hypersensitivity: Serious, acute hypersensitivity reactions, including life-threatening anaphylaxis, have occurred in approximately 2% of patients receiving the IV formulation. Symptoms can include urticaria, edema, rash, tachycardia, and hypotension. Treatment must be discontinued immediately if a serious reaction occurs.[25] A known cross-sensitivity exists with the related alkylating agent chlorambucil, which can manifest as a rash.[21]
• Leukemogenicity / Secondary Malignancies: Melphalan is a potent mutagen and a confirmed human carcinogen. It produces chromosomal aberrations in vitro and in vivo. Prolonged use is associated with a significantly increased risk of developing therapy-related secondary malignancies, most commonly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).[1] The risk-benefit ratio must be carefully considered, particularly in younger patients with a longer life expectancy.

The primary contraindication for melphalan is a history of a serious allergic reaction (hypersensitivity) to the drug or any of its excipients.[21]

Adverse Effects

The adverse effect profile of melphalan is extensive and is a direct, predictable consequence of its mechanism of action on rapidly proliferating cells.

• Most Common and Hematologic Toxicity: Myelosuppression is the most common and severe adverse effect, occurring in virtually all patients at conditioning doses and frequently at palliative doses. This manifests as decreased neutrophil, white blood cell, lymphocyte, and platelet counts, as well as anemia.[1] The clinical consequences are a high risk of bacterial, fungal, and viral infections, including febrile neutropenia, and an increased risk of bleeding and bruising.
• Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, and stomatitis/mucositis are extremely common, particularly with high-dose IV regimens.[1] Mucositis can be severe, causing significant pain, inability to eat or drink, and requiring nutritional support and potent analgesics. Prophylactic antiemetics are standard practice.
• Less Common but Severe Organ Toxicities:
• Pulmonary Toxicity: Interstitial pneumonitis and irreversible pulmonary fibrosis have been reported, primarily with prolonged use. These conditions can be fatal.[1]
• Hepatotoxicity: Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a serious and potentially fatal complication associated with high-dose conditioning regimens. Other hepatic effects include hepatitis, jaundice, and elevated liver function tests.[5]
• Cardiac Toxicity: Cardiac arrest has been reported in rare cases. High-dose infusions can cause a transient increase in heart rate.[1]
• Renal Toxicity: Melphalan can be nephrotoxic, and this risk is exacerbated by co-administration with other nephrotoxic drugs, such as cyclosporine.[5]
• Reproductive Toxicity: Melphalan causes gonadal suppression. In many patients, this is irreversible, leading to permanent infertility due to azoospermia in males and amenorrhea in premenopausal females.[15]
• Dermatologic and Local Toxicity: Alopecia (hair loss) is common with high doses. Rash and itching can also occur.[1] IV melphalan is a tissue irritant with vesicant properties. If extravasation (leakage from the vein) occurs, it can cause severe, delayed-onset pain and tissue necrosis.[15]

Drug-Drug and Drug-Food Interactions

Managing potential interactions is critical to ensure patient safety and therapeutic efficacy.

Table 3: Clinically Significant Drug-Drug Interactions with Management Recommendations

Interacting Drug/Class	Potential Effect	Clinical Significance/Severity	Management Recommendation	Source(s)
Cyclosporine	Increased risk of severe nephrotoxicity.	Major	Monitor renal function closely. Consider alternative immunosuppressants if possible.	21
Nalidixic Acid	Increased risk of fatal hemorrhagic enterocolitis (reported in children).	Major	Concurrent use is contraindicated/avoided.	10
Live Vaccines (BCG, MMR, Varicella, Nasal Flu, etc.)	Risk of disseminated, life-threatening infection due to immunosuppression.	Major	Avoid use during and for a period after melphalan therapy. Vaccinate prior to treatment if possible.	14
Cimetidine (and other H2-receptor antagonists)	Decreased absorption and bioavailability of oral melphalan.	Moderate	Monitor for reduced melphalan activity. Consider alternative agents (e.g., PPIs) or using IV melphalan if H2 blockade is necessary.	21
Cisplatin	Potentiated renal toxicity.	Moderate	Monitor renal function closely when used in sequence or combination.	21
Other Myelosuppressive Agents (e.g., Bendamustine, other chemotherapy)	Additive bone marrow suppression.	Major/Moderate	Monitor blood counts vigilantly. Dose adjustments of one or both agents may be required.	33
Amphotericin B	Increased risk of renal toxicity, bronchospasm, and hypotension.	Moderate	Use with caution. Monitor renal function and vital signs closely.	33

Drug-Food Interactions:

The only clinically significant drug-food interaction pertains to the oral formulation. Food, particularly high-fat meals, drastically and variably reduces the absorption of melphalan tablets.5 Therefore, it is a strict requirement that

oral melphalan be administered on an empty stomach, defined as at least 1 hour before or 2 hours after a meal or snack.[13] There are no known food interactions with the intravenous formulations.[59]

Use in Specific Populations and Patient Counseling

• Pregnancy and Lactation: Melphalan is classified as a teratogen, mutagen, and carcinogen and can cause severe fetal harm. Its use during pregnancy is contraindicated. Females of reproductive potential must have a negative pregnancy test before starting therapy and must use highly effective contraception during treatment and for at least 6 months after the final dose. Males with female partners of childbearing potential must use effective contraception during treatment and for at least 3 months after the final dose.[1] Due to the potential for secretion into breast milk and risk to the infant, breastfeeding is not recommended during therapy.[21]
• Fertility: The high risk of permanent infertility is a critical counseling point for all patients of reproductive age. Patients should be informed about this risk before initiating therapy and counseled on fertility preservation options, such as sperm banking for males and oocyte or embryo cryopreservation for females.[14]

Regulatory History and Formulations

The regulatory and developmental history of melphalan is a story of longevity, incremental innovation, and a notable cautionary tale, reflecting broader trends in oncology drug development.

Timeline of Approval and Market Evolution

Melphalan's journey began over half a century ago. It was first approved for medical use in the United States in 1964, making it one of the foundational agents of the modern chemotherapy era.[1] Its enduring efficacy, particularly in multiple myeloma, has secured its place on the World Health Organization's List of Essential Medicines.[1] The original product, marketed under the brand name

Alkeran®, was available as both a 2 mg oral tablet and an injectable powder for intravenous (IV) reconstitution.[1] However, the early IV formulation was pharmaceutically challenging due to the inherent poor solubility and chemical instability of the melphalan molecule in aqueous solution. This necessitated the use of a specialized solvent/diluent system containing propylene glycol, a co-solvent associated with its own toxicities, including renal dysfunction and cardiac arrhythmias.[18]

Formulation Advancements: The Case of Evomela®

For over 50 years, clinicians managed the limitations of the original IV formulation. A significant advancement came on March 10, 2016, with the FDA approval of Evomela®, the first new formulation of melphalan since its initial approval.[18]

• Technology: Evomela is a propylene glycol-free formulation that leverages Captisol® technology. Captisol is a chemically modified cyclodextrin that encapsulates the melphalan molecule, dramatically improving its solubility and stability in standard 0.9% sodium chloride solution.[18]
• Clinical Advantage: This innovation conferred several key clinical benefits. By eliminating the need for propylene glycol, it removed the risk of co-solvent-related toxicities. Furthermore, the enhanced stability (stable for 4 hours at room temperature in an infusion bag, plus 1 hour after initial reconstitution) provides greater flexibility and safety for hospital pharmacies preparing the drug and for clinical staff administering it.[18] The approval of Evomela was based on a Phase 2 study demonstrating its bioequivalence to the standard Alkeran formulation.[18] This development is a prime example of how modern pharmaceutical science can add significant value by reformulating an old, effective drug to improve its safety and ease of use.

The Melflufen (Pepaxto®) Story: A Case Study in Accelerated Approval

The story of melphalan flufenamide, or melflufen, is a recent and highly instructive chapter in regulatory science.

• Concept and Design: Melflufen (marketed as Pepaxto®) is a peptide-drug conjugate. It was designed to enhance the therapeutic index of melphalan by covalently linking it to a peptide, making the molecule more lipophilic. The theory was that this would facilitate rapid uptake into myeloma cells, where intracellular peptidases would cleave the conjugate, releasing a high concentration of the active melphalan payload directly inside the target cell.[62]
• Accelerated Approval: Based on promising overall response rates (ORR) of 23.7% in a heavily pretreated subgroup of patients in the single-arm Phase 2 HORIZON trial, the FDA granted melflufen accelerated approval on February 26, 2021. This pathway is intended to speed the availability of drugs for serious conditions with unmet needs, based on a surrogate endpoint reasonably likely to predict clinical benefit.[63]
• Confirmatory Trial and Withdrawal: The required confirmatory study was the Phase 3 OCEAN trial, which randomized patients to melflufen-dexamethasone versus pomalidomide-dexamethasone. While the trial successfully met its primary endpoint of improved progression-free survival (PFS) for melflufen, the analysis of the key secondary endpoint, overall survival (OS), revealed a concerning trend toward a higher risk of death in the melflufen arm (Hazard Ratio 1.104).[63] This detrimental OS signal, despite a positive PFS result, triggered an FDA clinical hold and intense regulatory scrutiny. After an FDA advisory committee voted overwhelmingly against the drug's favorable risk-benefit profile, the manufacturer voluntarily withdrew Pepaxto from the US market in October 2021. The FDA formally revoked the approval in February 2024, stating that the drug had not been shown to be safe or effective under its conditions of use.[63] This case has become a landmark example of the potential perils of the accelerated approval pathway and has fueled debate about the suitability of PFS as a primary endpoint for approval when it diverges from overall survival.

Generic Availability

Melphalan is available as a generic medication.[1] Generic versions of both the

2 mg oral tablets and the 50 mg injectable vial for reconstitution are available in the United States and other markets.[14] For example, Fresenius Kabi launched a generic version of Melphalan Hydrochloride for Injection in the US in 2018.[71] While some older generic formulations have been discontinued, the availability of generics provides a lower-cost alternative to branded products for this essential medicine.[72]

Clinical Evidence and Future Perspectives

The clinical role of melphalan, while rooted in decades of use, continues to be refined and re-evaluated in the context of a rapidly evolving therapeutic landscape. A review of key clinical trials and ongoing research illuminates its enduring importance and future potential.

Review of Key Clinical Trials

• Establishing High-Dose Melphalan as the Standard of Care: Early landmark trials in the 1980s and 1990s established high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) as the superior treatment for transplant-eligible multiple myeloma (MM) compared to conventional chemotherapy. These studies consistently demonstrated higher complete response rates and improved overall survival, solidifying HDM-ASCT as the standard of care for consolidation.[30] Doses of 140 mg/m² to 200 mg/m² were found to have significant clinical activity in MM, as well as in other diseases like relapsed ovarian cancer and neuroblastoma.[31]
• The IFM 2009 Study: Reaffirming the Role of HDM in the Novel Agent Era: One of the most pivotal modern trials for melphalan was the IFM/DFCI 2009 study. This trial addressed the critical question of whether HDM-ASCT was still necessary after induction with highly effective novel agents. It randomized newly diagnosed, transplant-eligible MM patients to receive induction with RVD (lenalidomide, bortezomib, dexamethasone) either alone or followed by consolidation with a single HDM-ASCT. The results were definitive: the arm that included HDM-ASCT demonstrated a significantly longer progression-free survival (PFS).[38] This trial powerfully reaffirmed the central role of high-dose melphalan consolidation, showing that it provides a level of cytoreduction that even the best novel agent combinations cannot match.
• Genomic Impact of HDM (IFM 2009 Sub-study): A sophisticated sub-analysis of paired diagnosis and relapse samples from the IFM 2009 study provided a crucial, albeit complex, insight into melphalan's biological legacy. The analysis revealed that patients who received HDM had a significantly higher mutational burden in their myeloma cells at the time of relapse compared to those treated with RVD alone.[38] This finding is a direct molecular confirmation of melphalan's DNA-damaging and mutagenic effects on surviving tumor cells. Intriguingly, this increased genomic complexity did not translate to a worse overall survival in the trial. One hypothesis is that the new mutations created by melphalan may also generate novel tumor antigens (neoantigens), potentially making the relapsed tumor more visible to the immune system and susceptible to subsequent therapies.[38] This highlights a critical duality: melphalan's mutagenicity is a driver of resistance but may also be a source of immunogenicity.
• Risk-Adapted Dosing Trials: Recognizing that the standard 200 mg/m² dose (Mel200) may be too toxic for all patients, research has focused on risk-adapted dosing. A recent large retrospective analysis of 233 MM patients compared outcomes for those receiving Mel200 versus a reduced dose of 140 mg/m² (Mel140). The study found that patients receiving Mel140 were, as expected, older and more frail. However, there was no significant difference in PFS or overall survival between the two groups. Importantly, the rates of achieving minimal residual disease (MRD) negativity were comparable. These findings provide strong evidence supporting Mel140 as a safe and equally effective alternative for older or less fit patients, advancing the push toward personalized conditioning regimens.[54]
• Efficacy in Extramedullary Myeloma: The role of HDM-ASCT in patients with extramedullary disease (EMM), a high-risk feature, has been a clinical question. A recent single-center retrospective review of 246 patients (70 with EMM, 176 without) found that HDM-ASCT was equally effective in both cohorts. There were no statistically significant differences in PFS or OS at one year post-transplant, suggesting that HDM-ASCT should remain the standard consolidation approach for eligible patients, regardless of extramedullary involvement.[75]

Ongoing Research and Clinical Trials

The current clinical trial landscape for melphalan is vibrant and focused on two main strategies: optimizing its use through novel combinations and refining its administration.

• Novel Conditioning Combinations: A multitude of clinical trials are actively investigating the addition of other agents to the melphalan conditioning backbone, with the goal of deepening the pre-transplant response and improving long-term outcomes. These combinations span a wide range of drug classes:
• Proteasome Inhibitors: Carfilzomib [76], Ixazomib [76], Oprozomib.[76]
• Immunomodulatory Drugs (IMiDs): Lenalidomide [76], Thalidomide.[76]
• Other Cytotoxic Agents: Bendamustine [76], Busulfan [52], Topotecan [76], Treosulfan.[52]
• Targeted and Immunomodulatory Agents: The histone deacetylase inhibitor Panobinostat [76], the nuclear export inhibitor Selinexor [76], the anti-IL-6 antibody Siltuximab [52], and the cytokine Interleukin-7.[78]
• Optimizing Administration and Personalizing Dose: Research is also focused on refining how melphalan itself is delivered. A notable Phase I/II trial (NCT03417284) is directly comparing different infusion durations of the Evomela formulation (a standard 30-60 minute infusion versus a prolonged 8-9 hour infusion) to study the pharmacokinetic and pharmacodynamic relationship and determine an optimal schedule.[79] This, along with other trials incorporating intensive pharmacokinetic sampling, reflects a broader movement toward exposure-response analysis and the development of truly personalized, pharmacokinetically-guided dosing strategies.[32]

Future Directions and Expert Recommendations

Melphalan is poised to remain a central agent in the management of multiple myeloma and other diseases, with its future defined by optimization, personalization, and strategic combination.

• The Enduring Role in ASCT: Despite the revolutionary success of novel immunotherapies like CAR-T cells and bispecific antibodies, HDM-ASCT is not on the verge of obsolescence. It remains a cornerstone therapy for transplant-eligible MM, valued for its proven efficacy, deep responses, broad accessibility, and relative cost-effectiveness. The future clinical challenge is not about replacing HDM-ASCT, but about determining its optimal sequencing and integration with these new modalities.
• Personalized Conditioning Regimens: The "one-size-fits-all" approach of Mel200 is obsolete. The future of conditioning therapy is personalized and risk-adapted. Clinical practice is already shifting to use factors like age, frailty, performance status, renal function, and body composition to select between Mel200 and Mel140.[54] The next frontier will be the integration of real-time therapeutic drug monitoring and pharmacogenomic markers, such as polymorphisms in the SLC7A5 transporter gene, to prospectively tailor the melphalan dose for each individual patient, maximizing efficacy while minimizing toxicity.[32]
• Melphalan as an Immunomodulatory Partner: Perhaps the most compelling future direction for melphalan is harnessing its immunomodulatory properties. Its potent lymphodepletive effects and its ability to induce immunogenic cell death make it an ideal "stage-setting" or conditioning agent for subsequent immunotherapies.[26] Future treatment paradigms will likely involve carefully designed and sequenced combinations of HDM followed by CAR-T cell therapy, bispecific antibodies, or checkpoint inhibitors. In this context, melphalan's role is transformed: its "toxicities" (lymphodepletion) become part of its desired therapeutic mechanism, creating a favorable immune microenvironment for the immunotherapy to thrive.
• Managing the Mutagenic Legacy: The confirmation that HDM increases the mutational load at relapse is a critical finding with long-term implications.[38] This "mutagenic signature" carries the dual potential to drive therapy resistance or to create therapeutically targetable neoantigens. Future research must focus on understanding this balance, developing strategies to mitigate the risk of oncogenic evolution, and designing therapies that can specifically exploit the unique genomic landscape of a post-melphalan relapse.

Conclusion

Melphalan is a paradigm of a legacy drug that has not only maintained its clinical relevance but is actively being redefined for the modern era of oncology. From its origins as a rationally designed alkylating agent, it has become the non-negotiable standard of care for myeloablative conditioning in multiple myeloma, a testament to its profound and durable cytotoxic efficacy. The clinical journey of melphalan has been one of continuous learning and adaptation, marked by a growing understanding of its complex and variable pharmacokinetics, which has driven innovations in formulation (Evomela®) and the development of sophisticated, patient-tailored dosing strategies.

The safety profile of melphalan is formidable and a direct consequence of its potent mechanism, demanding vigilant management of its myelosuppressive, gastrointestinal, and long-term carcinogenic risks. The cautionary tale of its derivative, melflufen, serves as a crucial reminder of the primacy of overall survival as the ultimate arbiter of clinical benefit in regulatory science.

Looking ahead, the role of melphalan is set to expand beyond that of a simple cytotoxic agent. The recognition of its potent immunomodulatory effects—its ability to induce immunogenic cell death and create a permissive environment through lymphodepletion—positions it as an ideal partner for the next generation of immunotherapies. The future of melphalan will be defined by this synergy, as well as by the ongoing pursuit of personalized medicine through risk-adapted dosing, pharmacokinetic monitoring, and pharmacogenomics. Melphalan is not a relic of the past; it is a dynamic and essential tool whose full potential is still being unlocked through scientific inquiry and innovative clinical application.

Works cited

1. Melphalan - Wikipedia, accessed July 11, 2025, https://en.wikipedia.org/wiki/Melphalan
2. Melphalan free base | CAS#148-82-3 | alkylating nitrogen mustard | MedKoo, accessed July 11, 2025, https://www.medkoo.com/products/20740
3. CAS Number 148-82-3 | Melphalan - Spectrum Chemical, accessed July 11, 2025, https://www.spectrumchemical.com/cas/148-82-3
4. Melphalan | Additional Apoptosis-related Compounds - R&D Systems, accessed July 11, 2025, https://www.rndsystems.com/products/melphalan_4619
5. Melphalan: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/drugs/DB01042
6. Melphalan | C13H18Cl2N2O2 | CID 460612 - PubChem, accessed July 11, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Melphalan
7. Melphalan - OEHHA - CA.gov, accessed July 11, 2025, https://oehha.ca.gov/chemicals/melphalan
8. Melphalan (Alanine Nitrogen Mustard, Alkeran, NSC 8806, NSC 241286, L-Phenylalanine Mustard, CAS Number: 148-82-3) | Cayman Chemical, accessed July 11, 2025, https://www.caymanchem.com/product/16665/melphalan
9. Busulfan, Melphalan, Topotecan Hydrochloride, and a Stem Cell Transplant in Treating Patients With Newly Diagnosed or Relapsed Solid Tumor | ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/study/NCT00638898
10. Melphalan (intra-arterial route, intravenous route) - Mayo Clinic, accessed July 11, 2025, https://www.mayoclinic.org/drugs-supplements/melphalan-intra-arterial-route-intravenous-route/description/drg-20071590
11. en.wikipedia.org, accessed July 11, 2025, https://en.wikipedia.org/wiki/Melphalan#:~:text=Melphalan%2C%20sold%20under%20the%20brand,mammary%20adenocarcinoma%3B%20and%20uveal%20melanoma.
12. Melphalan - brand name list from Drugs.com, accessed July 11, 2025, https://www.drugs.com/ingredient/melphalan.html
13. Melphalan Tablets: Uses & Side Effects - Cleveland Clinic, accessed July 11, 2025, https://my.clevelandclinic.org/health/drugs/20961-melphalan-tablets
14. Melphalan (Alkeran): Uses, Side Effects, Dosage & Reviews - GoodRx, accessed July 11, 2025, https://www.goodrx.com/melphalan/what-is
15. Melphalan for Children and Adolescents - Together by St. Jude™, accessed July 11, 2025, https://together.stjude.org/en-us/treatment-tests-procedures/medicines-list/melphalan.html
16. Melphalan | CAS 148-82-3 | SCBT - Santa Cruz Biotechnology, accessed July 11, 2025, https://www.scbt.com/p/melphalan-148-82-3
17. A Phase I and Pharmacokinetic Study of Melphalan Using a 24-hour Continuous Infusion in Patients with Advanced Malignancies - AACR Journals, accessed July 11, 2025, https://aacrjournals.org/clincancerres/article/6/1/57/287756/A-Phase-I-and-Pharmacokinetic-Study-of-Melphalan
18. Evomela (melphalan) FDA Approval History - Drugs.com, accessed July 11, 2025, https://www.drugs.com/history/evomela.html
19. Stability of Melphalan in 0.9 % Sodium Chloride Solutions Prepared in Polyvinyl Chloride Bags for Intravenous Injection - PMC - PubMed Central, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4561048/
20. New Melphalan Formulation Becomes FDA Approved in Myeloma - Targeted Oncology, accessed July 11, 2025, https://www.targetedonc.com/view/new-melphalan-formulation-fda-approved-in-myeloma
21. melphalan - Cancer Care Ontario, accessed July 11, 2025, https://www.cancercareontario.ca/en/drugformulary/drugs/monograph/43801
22. MELPHALAN - Pharmaceuticals - NCBI Bookshelf, accessed July 11, 2025, https://www.ncbi.nlm.nih.gov/books/NBK304320/
23. pmc.ncbi.nlm.nih.gov, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5367467/#:~:text=Melphalan%20exerts%20its%20cytotoxicity%20by,RNA%2C%20proteins%2C%20and%20lipids.&text=Melphalan%20has%20been%20used%20in,%2C%20sarcoma%2C%20and%20ovarian%20cancer.
24. Melphalan (Alkeran) for Multiple Myeloma, accessed July 11, 2025, https://www.myeloma.org/treatment/multiple-myeloma-medications/melphalan-alkeran
25. Melphalan | Drug Lookup | Pediatric Care Online - AAP Publications, accessed July 11, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5320/Melphalan
26. Immunostimulatory Effects of Melphalan and Usefulness in Adoptive Cell Therapy with Antitumor CD4+ T Cells - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/27910767/
27. Plasma Pharmacokinetics of High-Dose Oral Melphalan in Patients Treated with Trialkylator Chemotherapy and Autologous Bone Marrow Reinfusion1 - AACR Journals, accessed July 11, 2025, https://aacrjournals.org/cancerres/article-pdf/49/5/1318/2438274/cr0490051318.pdf
28. ORAL CHEMOTHERAPY EDUCATION, accessed July 11, 2025, http://oralchemoedsheets.com/sheets/Melphalan_Patient_Education.pdf
29. Melphalan-Oral (Alkeran®, Melphalan Oral, L-pam) | OncoLink, accessed July 11, 2025, https://www.oncolink.org/cancer-treatment/oncolink-rx/melphalan-oral-alkeran-r-melphalan-oral-l-pam
30. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy - PMC - PubMed Central, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2856049/
31. High-dose intravenous melphalan: a review - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/7602368/
32. Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/28160288/
33. Evomela, Hepzato (melphalan) dosing, indications, interactions, adverse effects, and more, accessed July 11, 2025, https://reference.medscape.com/drug/evomela-hepzato-melphalan-342105
34. Variation in melphalan dosing in myeloma patients undergoing high-dose chemotherapy and autotransplantation | Journal of Clinical Oncology - ASCO Publications, accessed July 11, 2025, https://ascopubs.org/doi/10.1200/jco.2008.26.15_suppl.7047
35. EVOMELA (melphalan) for injection - accessdata.fda.gov, accessed July 11, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207155s001lbl.pdf
36. Evomela (melphalan): Uses, Side Effects, Dosage & Reviews - GoodRx, accessed July 11, 2025, https://www.goodrx.com/evomela/what-is
37. Evaluate Safety and Efficacy of High-dose Melphalan HCL for Injection in MM Patients With Auto-HSC Transplantation | ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/study/NCT06425276
38. High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma | Blood | American Society of Hematology, accessed July 11, 2025, https://ashpublications.org/blood/article/141/14/1724/493962/High-dose-melphalan-treatment-significantly
39. Melphalan Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 11, 2025, https://www.drugs.com/dosage/melphalan.html
40. Melphalan - National Cancer Institute, accessed July 11, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/melphalan
41. Melphalan Hydrochloride - NCI, accessed July 11, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/melphalan-hydrochloride
42. Melphalan | AL amyloidosis Treatment Guide | Myeloma UK, accessed July 11, 2025, https://www.myeloma.org.uk/wp-content/uploads/2023/04/Myeloma-UK-AL-amyloidosis-Melphalan-Treatment-Guide.pdf
43. AL amyloidosis Melphalan Treatment Guide - Myeloma UK, accessed July 11, 2025, https://www.myeloma.org.uk/library/al-amyloidosis-melphalan-treatment-guide/
44. 1466-AL amyloidosis melphalan and dexamethasone oral SUPERSEDED - eviQ, accessed July 11, 2025, https://www.eviq.org.au/haematology-and-bmt/multiple-myeloma/1466-al-amyloidosis-melphalan-and-dexamethasone-or
45. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis | Blood | American Society of Hematology, accessed July 11, 2025, https://ashpublications.org/blood/article/110/2/787/23015/Treatment-with-oral-melphalan-plus-dexamethasone
46. Low-dose continuous oral melphalan for the treatment of primary systemic (AL) amyloidosis - Boston University, accessed July 11, 2025, https://www.bu.edu/amyloid/files/pdf/sanchorawala-com.pdf
47. pmc.ncbi.nlm.nih.gov, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3974956/#:~:text=With%20respect%20to%20clinical%20response,25%2C%2026%2C%2027%5D.
48. Advanced POEMS syndrome treated with high-dose melphalan ..., accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3974956/
49. POEMS syndrome | Myeloma UK, accessed July 11, 2025, https://www.myeloma.org.uk/wp-content/uploads/2023/04/Myeloma-UK-POEMS-syndrome-Infosheet.pdf
50. Long term melphalan-prednisolone chemotherapy for POEMS syndrome - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/9328260/
51. Update on the POEMS syndrome - BLOOD RESEARCH, accessed July 11, 2025, https://www.bloodresearch.or.kr/journal/view.html?uid=2528&vmd=Full&
52. Myeloma Recruiting Phase 2 Trials for Melphalan (DB01042) | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/indications/DBCOND0028342/clinical_trials/DB01042?phase=2&status=recruiting
53. 813-Autologous conditioning high dose melphalan 140 mg/m ... - eviQ, accessed July 11, 2025, https://www.eviq.org.au/haematology-and-bmt/blood-and-marrow-transplant/autologous/813-autologous-conditioning-high-dose-melphalan-14
54. Melphalan 140 mg/m2 is Safe and Effective for Frail and Older Multiple Myeloma Patients With Comparable Rates of Minimal Residual Disease Negativity - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/40090795/
55. Melphalan Disease Interactions - Drugs.com, accessed July 11, 2025, https://www.drugs.com/disease-interactions/melphalan.html?professional=1
56. Melphalan (Alkeran®) - Health Online, accessed July 11, 2025, https://healthonline.washington.edu/sites/default/files/record_pdfs/Melphalan-Alkeran-SCCA.pdf
57. Melphalan Interactions Checker - Drugs.com, accessed July 11, 2025, https://www.drugs.com/drug-interactions/melphalan.html
58. Melphalan (oral route) - Mayo Clinic, accessed July 11, 2025, https://www.mayoclinic.org/drugs-supplements/melphalan-oral-route/description/drg-20064651
59. Melphalan: High-Dose (Alkeran® ) - UPMC Hillman Cancer Center, accessed July 11, 2025, https://hillman.upmc.com/patients/community-support/education/chemotherapy-drugs/melphalan-high-dose-for-sct
60. Melphalan HCl Intravenous: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed July 11, 2025, https://www.webmd.com/drugs/2/drug-4439/melphalan-hcl-intravenous/details
61. en.wikipedia.org, accessed July 11, 2025, https://en.wikipedia.org/wiki/Melphalan#:~:text=Melphalan%20was%20approved%20for%20medical,available%20as%20a%20generic%20medication.
62. Mechanism of action - Oncopeptides, accessed July 11, 2025, https://oncopeptides.com/en/science/melflufen/mechanism-of-action/
63. The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8866737/
64. WITHDRAWN: FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma, accessed July 11, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple
65. FDA Approved Pepaxto for Relapsed or Refractory Multiple Myeloma, accessed July 11, 2025, https://jhoponline.com/issue-archive/2021-issues/april-2021-vol-10-no-2/fda-approved-pepaxto-for-relapsed-or-refractory-multiple-myeloma
66. Melphalan Flufenamide for R/R MM Pulled from US Market Over Efficacy Concerns, accessed July 11, 2025, https://www.targetedonc.com/view/melphalan-flufenamide-for-r-r-mm-pulled-from-us-market-over-efficacy-concerns
67. FDA Revokes Melphalan Flufenamide Approval, Citing Efficacy/Safety Concerns, accessed July 11, 2025, https://www.targetedonc.com/view/fda-revokes-melphalan-flufenamide-approval-citing-efficacy-safety-concerns
68. Buy Alkeran (melphalan) Online - Blink Health, accessed July 11, 2025, https://www.blinkhealth.com/alkeran
69. Melphalan Hcl Prices - U.S. & International | PharmacyChecker.com, accessed July 11, 2025, https://www.pharmacychecker.com/melphalan+hcl/
70. Melphalan Medicare Coverage and Co-Pay Details - GoodRx, accessed July 11, 2025, https://www.goodrx.com/melphalan/medicare-coverage
71. Generic melphalan available in US - MDEdge, accessed July 11, 2025, https://www.mdedge.com/hematologytimes/article/185009/multiple-myeloma/generic-melphalan-available-us
72. Generic Alkeran Availability - Drugs.com, accessed July 11, 2025, https://www.drugs.com/availability/generic-alkeran.html
73. FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4337224/
74. High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma - PMC, accessed July 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10273091/
75. Real world outcomes of high dose melphalan conditioning prior to autologous stem cell transplant in extramedullary multiple myeloma vs. multiple myeloma without extramedullary involvement: A single center experience. - ASCO Publications, accessed July 11, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7550
76. Myelomas Completed Phase 1 / 2 Trials for Melphalan (DB01042) | DrugBank Online, accessed July 11, 2025, https://go.drugbank.com/indications/DBCOND0070163/clinical_trials/DB01042?phase=1%2C2&status=completed
77. Carfilzomib and Melphalan Before Stem Cell Transplant in Treating Patients With Multiple Myeloma | ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/study/NCT01842308
78. Melphalan Recruiting Phase 1 Trials for Multiple Myeloma (MM) Treatment - DrugBank, accessed July 11, 2025, https://go.drugbank.com/drugs/DB01042/clinical_trials?conditions=DBCOND0040908&phase=1&purpose=treatment&status=recruiting
79. Melphalan Hydrochloride in Treating Participants With Newly-Diagnosed Multiple Myeloma Undergoing Donor Stem Cell Transplantation | ClinicalTrials.gov, accessed July 11, 2025, https://clinicaltrials.gov/study/NCT03417284
80. Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies-Current Research and Clinical Approaches - PubMed, accessed July 11, 2025, https://pubmed.ncbi.nlm.nih.gov/33922721/