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Melphalan in the biologic era: A 70-year story in hematological malignancies and its legacy, evolution, and future
*Corresponding author: Biswajit Bhuyan, Department of Hematology, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha, India. biswajit.bhuyan@kims.ac.in
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Received: ,
Accepted: ,
How to cite this article: Bhuyan B, Pandit SB, Giri RK. Melphalan in the biologic era: A 70-year story in hematological malignancies and its legacy, evolution, and future. J Hematol Allied Sci. 2026;6:43-50. doi: 10.25259/JHAS_74_2025
Abstract
Melphalan, a bifunctional alkylating agent derived from nitrogen mustard, remains a cornerstone in the treatment of multiple hematological and solid malignancies – most notably multiple myeloma – and continues to serve as a key component of conditioning regimens in hematopoietic stem cell transplantation. Despite the rapid emergence of novel therapeutic classes including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and cellular therapies, melphalan remains the standard conditioning regimen for autologous stem cell transplantation due to its potent, broad-spectrum antitumor activity and predictable myeloablative properties. This review focuses on the current understanding of melphalan’s historical development, molecular mechanisms, pharmacokinetic characteristics, clinical applications across hematologic malignancies, safety considerations, and its evolving role alongside contemporary treatment modalities. We conducted systematic literature searches across major medical databases, including PubMed, Google Scholar, and the recent IMWG and Mayo Clinic Guidelines for myeloma, focusing on publications from 2000 to 2025 that provided insights into melphalan’s clinical utility, pharmacological properties, and therapeutic optimization.
Keywords
Alkylating agent
Autologous stem cell transplantation
Conditioning regimen
High-dose therapy
Multiple myeloma
Nitrogen mustard
Pharmacokinetics
INTRODUCTION
The story of melphalan begins in 1953 with its synthesis as a nitrogen mustard derivative incorporating L-phenylalanine to enhance tumor selectivity.[1] Since its introduction, melphalan has been employed in the management of a broad spectrum of malignancies, including ovarian and breast cancers, neuroblastoma, lymphomas, and most prominently, multiple myeloma (MM). Early uses of melphalan in myeloma and lymphoma showed encouraging initial results, although mostly the oral formulations were used at low doses.[2-4] MM accounts for about 10% of all hematological malignancies and about 1% of all malignancies.[5] Despite the extensive armamentarium of drugs, it remains an incurable disease. Initial use of high-dose melphalan without stem cell support was accompanied by a high incidence of mortality and grade 3–4 myelosuppression in all patients.[6] The later discovery of stem cell rescue following high-dose melphalan shortened the duration of myelosuppression as well as complications of melphalan, changing the landscape of the disease. High-dose melphalan (200 mg/m2) with stem cell support was associated with improved rates of overall survival (OS) and progression-free survival (PFS) in various studies performed subsequently. It became the standard of care in all transplant-eligible MM patients. Later, high-dose melphalan was incorporated into conditioning regimens for autologous BMT for lymphoma, neuroblastoma, and allogenic BMT.[7] This review article provides an overview of the early development of the drug, clinical indications, pharmacokinetics, key clinical data, trials, and drug interactions.
METHODS
We conducted an extensive systematic literature review utilizing multiple medical databases, including PubMed, Google Scholar, Web of Science, and Cochrane Library. The search strategy included publications from January 2000 to January 2025 to capture both foundational studies and recent advances. Primary search terms included “melphalan,” “high-dose melphalan,” “multiple myeloma,” “stem cell transplantation,” “conditioning regimen,” “pharmacokinetics,” “solid malignancies,” and with appropriate Boolean operators. Our inclusion criteria included randomized controlled trials, extensive observational cohort studies, pharmacokinetic analyses, systematic reviews, meta-analyses, and current clinical practice guidelines. Exclusion criteria included case reports with fewer than 10 patients, non-English publications without accessible translation, and publications lacking methodological details sufficient for quality assessment.
HISTORY AND DEVELOPMENT
The development of melphalan represents a significant chapter in the evolution of cancer chemotherapy. Its origins trace back to 1953 when researchers Bergel and Stock synthesized the compound by incorporating L-phenylalanine into a nitrogen mustard backbone, hypothesizing that the amino acid moiety would enhance selective uptake by tumor cells.[1] The first documented therapeutic use of melphalan in humans occurred in 1958, when Blokhin et al. administered the drug to six patients with MM and other malignancies. Three patients achieved significant regression in tumor burden, marking one of the earliest demonstrations of chemotherapeutic responsiveness in this otherwise fatal malignancy.[2] Throughout the 1960s and 1970s, melphalan gained widespread use as part of conventional, low-dose oral regimens – most notably melphalan plus prednisone (MP). Despite its modest response rates and high relapse rates, low-dose melphalan in combination with prednisolone became the global standard of care for MM for nearly four decades.[8] However, high-dose melphalan without stem cell support was associated with very high mortality rates and Grade 3–4 myelosuppression as reported by Selby et al.[6] The most transformative shift in melphalan’s history occurred when McElwain and Powles, and Barlogie et al. reported their landmark experience using high-dose intravenous melphalan followed by autologous bone marrow infusion, demonstrating markedly shortened myelosuppression and proving that melphalan dose-intensity could be safely escalated with stem-cell rescue.[9,10] In the 1990s, the French IFM group conducted pivotal studies that established 200 mg/m2 as the standard conditioning dose, while also demonstrating that melphalan alone provided comparable efficacy to MP total body irradiation (TBI) while offering a superior toxicity profile.[11] Melphalan has maintained its relevance through successful integration with novel therapeutic classes. The sequential application of induction therapy with quadruplet therapy consisting of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies (Dara-RVD) followed by consolidation with melphalan-based transplant has been the standard of care in newly diagnosed myeloma.[12] A timeline of the development of myeloma is summarized in Table 1.
| Year | Milestone | Significance |
|---|---|---|
| 1953 | Initial synthesis | Nitrogen mustard derivative with L-phenylalanine |
| 1960s | Early clinical use | Established activity in multiple myeloma |
| 1983 | High-dose protocol (McElwain) | Introduced ASCT concept |
| 1990s | Randomized trials | Established superiority over conventional therapy |
| 2000s | Formulation improvements | Propylene glycol-free development |
| 2010s | Novel agent intration | Combined with proteasome inhibitors and IMiDs |
ASCT: Autologous stem cell transplantation, IMiDs: Immunomodulatory drugs
MECHANISM OF ACTION
Melphalan is a bifunctional alkylating agent of the nitrogen mustard class that exerts its cytotoxicity through covalent interaction with DNA. Cytotoxic activity begins with intramolecular cyclization of the chloroethyl moieties, generating highly reactive aziridinium ions that readily alkylate nucleophilic sites. DNA is the principal target, with preferential attack at the N7 position of guanine, producing interstrand and intrastrand cross-links, as well as DNA–protein adducts.[13] These lesions collectively disrupt replication and transcription, overwhelming cellular repair mechanisms. Beyond direct DNA damage, melphalan also induces oxidative stress by depleting intracellular glutathione, facilitating accumulation of reactive oxygen species that promote lipid peroxidation, protein modification, and additional DNA injury – effects particularly pronounced in malignant cells with impaired redox homeostasis. The mechanism of action of melphalan is depicted in Figure 1.
![Mechanism of action of melphalan, adopted from Poczta et al.[13]](/content/129/2026/6/1/img/JHAS-6-043-g001.png)
- Mechanism of action of melphalan, adopted from Poczta et al.[13]
PHARMACOKINETICS AND PHARMACODYNAMICS
The pharmacokinetic profile of melphalan exhibits marked interindividual variability. Following intravenous administration, the drug shows biphasic elimination with an initial rapid distribution phase and a slower terminal phase. The volume of distribution (0.5–0.7 L/kg) indicates extensive tissue penetration, while plasma protein binding – primarily to albumin – is concentration-dependent and ranges from 60% to 90%, leaving only a small unbound, pharmacologically active fraction. The elimination half-life typically ranges from 60 to 90 min, although significant variability is common. Renal excretion accounts for roughly 10–15% of unchanged melphalan, with the remainder eliminated as inactive hydrolysis products; thus, impaired renal function can reduce clearance and increase systemic exposure. Oral melphalan displays even greater variability due to incomplete and erratic gastrointestinal (GI) absorption.[14] Bioavailability ranges widely from 25% to 89%, and high-fat meals significantly reduce both the extent and rate of absorption, necessitating fasting administration. Because of this unpredictability, oral formulations are used mainly in palliative settings, while intravenous dosing is preferred when consistent exposure is required. Recent advances include propylene glycol-free IV formulations that offer improved stability and may reduce solvent-related toxicity. The pharmacokinetic properties of oral and IV melphalan are summarized in Table 2.
| Parameter | Intravenous Melphalan | Oral Melphalan |
|---|---|---|
| Bioavailability | 100% | 25–89% (highly variable) |
| Protein binding | 60–90% | 60–90% |
| Half-life | 60–90 min | 60–90 min |
| Metabolism | Spontaneous hydrolysis | Spontaneous hydrolysis |
| Elimination | Renal (10–15% unchanged) | Renal (10–15% unchanged) |
CLINICAL INDICATIONS
Melphalan finds application across several clinical scenarios in hematologic and solid malignancies, with the most established role in the management of MM and hematopoietic stem cell transplantation conditioning. Initial studies on low-dose melphalan in combination with steroids (dexamethasone/prednisolone) showed promising but short-term results.[15,16] In MM, high-dose melphalan with autologous stem cell transplantation (ASCT) represents the standard of care for eligible patients. The typical regimen employs melphalan 200 mg/m2 administered over 1 or 2 days, followed by reinfusion of previously collected autologous hematopoietic stem cells.[11] This approach consistently produces higher complete response rates, longer PFS, significant gain in quality-adjusted survival, and, in some studies, OS advantage compared to conventional chemotherapy.[17-19] For patients unsuitable for full-dose conditioning due to advanced age, comorbidities, or renal impairment, a reduced dose of 140 mg/m2 provides a balance of efficacy and tolerability.[20-22] The optimal dosing strategy of melphalan should be individualized based on a comprehensive assessment of physiological reserve, organ function, and disease characteristics.[23] In relapsed refractory Hodgkin and Non-Hodgkin lymphomas, melphalan-containing regimens {BCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan [BEAM], Carboplatin, Etoposide, Melphalan [CEM], Cyclophosphamide, BCNU (Carmustine), VP-16 (Etoposide) [CBV]} have demonstrated efficacy in disease control and facilitation of hematopoietic recovery.[24,25] Melphalan also contributes to reduced-intensity conditioning regimens for allogeneic transplantation, typically combined with other agents such as fludarabine.[26] Applications of oral melphalan continue in specific palliative contexts, particularly for patients with symptomatic MM who are not candidates for more intensive approaches.[15,16] The primary clinical applications and standard dosing of melphalan are summarized in Table 3.
| Indication | Dose | Evidence level |
|---|---|---|
| MM – ASCT conditioning | 200 mg/m2 IV | Multiple RCTs |
| MM – reduced dose | 140 mg/m2 IV | Guideline recommendation |
| Lymphoma conditioning | 140 mg/m2 IV | Guideline recommendation |
| MM – oral palliative | 0.15–0.25 mg/kg/day | Historical standard |
MM: Multiple myeloma, ASCT: Autologous stem cell transplantation, RCT: Randomized controlled trial, IV: Intravenous
DOSAGE AND ADMINISTRATION
For high-dose conditioning before ASCT in MM, the standard dose is 200 mg/m2, typically administered as a single dose or divided over 2 consecutive days. Administration occurs through intravenous infusion over 30–45 min, with appropriate premedication to minimize nausea and vomiting. Stem cell infusion typically follows after 24–48 h to allow clearance of the circulating drug and minimize stem cell damage. Dose modification to 140 mg/m2 is recommended for patients over 70 years of age, those with moderate to severe renal impairment (creatinine clearance below 60 mL/min), or individuals with significant comorbidities compromising physiological reserve.[20,21] For obese patients, the current guidelines recommend calculating body surface area using actual body weight, though some centers employ adjusted or ideal body weight approaches to avoid excessive dosing.[27] Oral melphalan dosing follows different principles, with typical MM regimens employing 6–10 mg/m2 daily for 4–7 days repeated every 4–6 weeks, often combined with prednisone/dexamethasone.[8,15,28] Administration should occur on an empty stomach as food, particularly high-fat meals, significantly reduces bioavailability.[29] Renal impairment significantly influences melphalan pharmacokinetics, necessitating dose reduction proportional to the degree of dysfunction. For creatinine clearance between 30 and 60 mL/min, a 25–50% dose reduction is recommended, while severe impairment below 30 mL/min warrants avoidance or extreme caution with aggressive supportive measures.[30] Hemodialysis does not significantly remove melphalan due to extensive protein binding and tissue distribution. Special administration considerations include the use of cryotherapy for mucositis prophylaxis, wherein patients hold ice chips in the mouth during and for 30–60 min following melphalan infusion. This technique reduces oral mucosal drug exposure through vasoconstriction and has demonstrated a significant reduction in mucositis severity in randomized studies.[31]
WARNINGS AND PRECAUTIONS
With high-dose conditioning, profound neutropenia and thrombocytopenia occur uniformly, necessitating stem cell support for hematologic recovery. The period of severe cytopenias typically spans 7–14 days, during which vigilant monitoring for infectious complications and bleeding manifestations is essential. Prophylactic antimicrobials, growth factor support, and transfusion protocols constitute standard supportive care measures during this vulnerable period.[32] GI toxicities, particularly mucositis and diarrhea, frequently limit melphalan dosing. Oral mucositis affects the majority of patients receiving high-dose therapy, presenting as erythema, ulceration, and pain that can compromise nutrition and quality of life.[33,34] Diarrhea occurs through similar mechanisms affecting the intestinal mucosa, requiring symptomatic management and vigilance for dehydration or electrolyte disturbances.[32] Hepatotoxicity manifests primarily as transaminase elevations, which occur in 20–40% of patients receiving high-dose melphalan. These abnormalities typically follow a predictable time course, peaking around day +7 to +10 post-transplantation and resolving spontaneously in most cases. Rare instances of veno-occlusive disease (sinusoidal obstruction syndrome) have been reported, particularly with very high doses or in combination with other hepatotoxic agents, necessitating monitoring for characteristic signs including weight gain, hepatomegaly, and hyperbilirubinemia.[35] The potential for secondary malignancies represents a concerning long-term complication of melphalan therapy. Myelodysplastic syndrome and acute myeloid leukemia occur with increased incidence following high-dose melphalan, with cumulative risk estimates of 3–7% at 7–10 years post-treatment. Sperm banking and oocyte or embryo cryopreservation should be offered to appropriate candidates before treatment initiation.[36] The recent availability of propylene glycol-free formulations may reduce local toxicity risk. Extravasation during intravenous administration can cause significant local tissue damage, including pain, erythema, and potential tissue necrosis. Precautions include secure venous access verification before administration and prompt intervention with topical measures and possible consultation for severe cases.[37] Women of childbearing potential require effective contraception during and after therapy, as melphalan poses significant fetal risk with potential for teratogenic effects.
ADVERSE EFFECTS
With high-dose melphalan, severe myelosuppression and hematologic toxicities dominate the acute safety profile, affecting all lineages. The time to neutrophil recovery is approximately 10–14 days, with platelet recovery typically lagging by several additional days, but this timeline can vary depending on multiple patient- and treatment-related factors.[38] Anemia universally develops, though typically less precipitously than other cytopenias, with red blood cell transfusions providing supportive management. An adequate stem cell dose (>2.0–5.0 × 106 CD34 + cells/kg) is critical as it ensures rapid and reliable neutrophil and platelet count, minimizing infectious complications and reducing hospital stay.[39] GI toxicities significantly impact patient comfort and quality of life during treatment. Oral mucositis presents in approximately 70–90% of patients receiving high-dose melphalan, with 30–50% experiencing severe (Grade 3–4) manifestations characterized by ulceration, bleeding, 60–80% of the patients having diarrhea, and 20–40% having grade 2 or higher diarrhea, necessitating aggressive fluid and electrolyte replacement. Despite antiemetic prophylaxis, grade 2 nausea and vomiting still develop in transplant patients, though severe refractory emesis affects only 10–20% with appropriate preventive strategies. Worse GI toxicities are associated with more extended hospital stay, greater use of antibiotics, electrolyte repletion, and imaging studies. Plasma cell neoplasm, poor renal function, female sex, and older age are risk factors for severe GI toxicity, which facilitate a risk-adapted approach to prophylaxis and management of toxicity.[40,34] Prophylaxis of melphalan-induced GI toxicity begins with cryotherapy for mucositis and combination antiemetics, while amifostine and novel agents like uproleselan, an E-selectin, are used to reduce mucosal injury. For established complications, treatment escalates to antimotility agents, opioids, advanced therapies like palifermin or octreotide, and supportive care with total parenteral nutrition (TPN) and antibiotics.[41-43] The syndrome of sinusoidal obstruction syndrome (venoocclusive disease) occurs rarely with melphalan monotherapy. Still, it represents a serious complication characterized by tender hepatomegaly, weight gain, and jaundice, requiring specialized management approaches.[34] Skin rash occurs less frequently, in approximately 10–20% of patients, and may represent either direct toxicity or hypersensitivity reaction. Nail changes, including Beau’s lines and pigmentary alterations, may develop weeks to months following treatment as transient manifestations. Other notable adverse effects include fatigue, which nearly universally affects patients during the recovery phase and may persist for months following treatment. Anorexia and taste alterations frequently accompany the acute treatment period, potentially contributing to nutritional compromise. Table 4 summarizes the approach and management of GI toxicities of melphalan.
| GI Toxicity |
Treatment/Management |
|---|---|
| Oral mucositis |
Ice chips peri-melphalan infusion (cryotherapy) For severe cases: Palifermin (recombinant human keratinocyte growth factor) |
| Nausea and vomiting |
First-line: 5-HT3 receptor antagonists (ondansetron, palonosetron)±steroids Add-on: NK1 receptor antagonists (aprepitant, netupitant) Olanzapine |
| Diarrhea | Cytoprotection: Amifostine Severe/Secretory: Octreotide Antimotility agents (loperamide, diphenoxylate/atropine) Oral budesonide L-Glutamine. |
| Grade 3–4 mucositis/diarrhea or ischemic colitis |
Supportive Care: Bowel rest, Ryle’s tube aspiration, TPN Specific Agents: Palifermin, uproleselan (E-selectin antagonist) |
| Severe pain from mucositis |
Opioid analgesia |
| Infection | Broad-spectrum antibiotics and targeted therapies. |
| Diagnostic tests | Indication/target pathogens |
| Stool PCR | Clostridium difficile |
| Multiplex nucleic acid-based GI pathogen panel |
Comprehensive detection: C. difficile, EPEC, Shigella, Norovirus, Giardia, Astrovirus |
| Abdominal CT scan/colonoscopy |
For severe pain, peritoneal signs, suspected infections: typhlitis, cholecystitis |
CT: Computed tomography, GI: Gastrointestinal, PCR: Polymerase chain reaction, TPN: Total parenteral nutrition, EPEC: Enteropathogenic Escherichia coli
DRUG INTERACTIONS
Subsequent administration of myelosuppressive agents should be delayed until adequate hematologic recovery from melphalan effects. The oral bioavailability of melphalan is significantly reduced by concomitant food intake, particularly high-fat meals, necessitating administration on an empty stomach. Live vaccines are contraindicated during and following melphalan therapy due to the potential for uncontrolled replication in immunocompromised hosts.[44] Nalidixic acid has been associated with increased risk of hemorrhagic colitis, though the clinical significance remains uncertain.[45] The propylene glycol component in conventional intravenous melphalan formulations may contribute to additional interactions, particularly with medications that inhibit alcohol dehydrogenase or themselves contain glycol derivatives. The newer propylene glycol-free formulation eliminates this potential interaction source.[46]
CLINICAL DATA
The efficacy and safety of melphalan have been established through decades of clinical investigation across multiple study designs and patient populations. The foundational evidence for high-dose melphalan in MM derives from randomized trials conducted in the 1990s and early 2000s. The French IFM 90 trial demonstrated superior response rates, event-free survival, and OS with high-dose therapy compared to conventional chemotherapy, establishing transplantation as standard care for eligible patients.[11] Subsequent studies, including the MRC myeloma VII trial, confirmed these findings, solidifying the role of dose-intensive approaches.[18] Fermand et al. conducted a randomized trial comparing early ASCT with ASCT deferred until relapse. OS was comparable between the two groups; however, early transplantation was preferred because it reduced the total duration of chemotherapy and was associated with improved quality of life.[19] The IFM 95 trial addressed the question of optimal conditioning regimen by randomizing patients to melphalan 200 mg/m2 versus melphalan 140 mg/m2 plus TBI. This study demonstrated equivalent efficacy between the approaches but superior tolerability with melphalan alone, establishing single-agent high-dose melphalan as the preferred conditioning regimen.[11] In the era of novel agents, the role of transplantation has been re-examined in multiple randomized trials. The IFM 2009 study compared transplantation versus no transplantation following induction with lenalidomide, bortezomib, and dexamethasone, demonstrating significantly prolonged PFS with the transplant approach.[47] Similarly, the determination trial conducted in the United States confirmed PFS advantage with early transplantation, though OS differences were not statistically significant in initial analyses.[48] The EMN02/HO95 trial demonstrated that upfront ASCT significantly improved PFS compared with bortezomib-based chemotherapy, with additional benefit seen for patients undergoing tandem (double) ASCT. OS was also favorably impacted, particularly in the high-risk cytogenetic subgroup.[49] In systemic AL amyloidosis, dose-adjusted melphalan with stem cell support produces hematologic and organ responses in selected patients. However, careful patient selection is crucial given the unique vulnerability of amyloid-involved organs. The E4A97 multicenter trial evaluated high-dose melphalan followed by ASCT in AL amyloidosis, showing meaningful hematologic and organ responses in selected patients despite notable treatment-related mortality.[50] The key trial results are summarized in Table 5.
| Trial | Regimen | PFS | OS |
|---|---|---|---|
| IFM 95 | Mel200 versus Mel140+TBI | Equivalent | Equivalent |
| MRC myeloma VII |
HDT with ASCT versus conventional chemotherapy |
Significantly improved |
Significantly improved (54.1 vs. 42.3 months) |
| MAG (Myélome- Autogreffe) randomized trial (Fermand et al.) |
HDT with ASCT versus conventional chemotherapy |
Significant gain in quality- adjusted survival |
|
| Determination | RVD±ASCT | 67 versus 46 months |
Similar |
| EMN02/HO95 | Single versus Tandem |
Better in high-risk |
Better in high-risk |
| E4A97 (AL amyloidosis) |
Single | 64% response rates PFS: Not reached |
Not reached |
MRC: Medical Research Council; RVD: lenalidomide (R), bortezomib (V), and dexamethasone (D), ASCT: Autologous stem cell transplantation, HDT: High-dose therapy, PFS: Progression-free survival, OS: Overall survival, TBI: Total body irradiation, IFM: Intergroupe Francophone du Myélome, MAG: Myélome-Autogreffe, EMN : European Myeloma Network
CONCLUSION
Melphalan maintains its fundamental position in the therapeutic armamentarium for MM and other hematologic malignancies more than six decades after its initial development. Its enduring clinical utility stems from potent and broad antitumor activity, a predictable toxicity profile that is manageable mainly with contemporary supportive care, and established efficacy within multimodal treatment approaches. The future therapy will likely involve continued refinement of new melphalan derivatives expected to have a better toxicity profile. Personalized dosing strategies incorporating pharmacokinetic monitoring and patient-specific factors hold promise for optimizing the therapeutic index, maximizing efficacy while minimizing toxicity. The successful integration of melphalan with emerging immunotherapeutic approaches represents another promising direction, potentially leveraging synergistic mechanisms of action. Advances in supportive care, including more effective mucositis prevention and management strategies, may further enhance the tolerability of melphalan-based regimens.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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