1. Introduction
Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by the clonal proliferation of malignant plasma cells within the bone marrow, leading to the production of monoclonal immunoglobulins [ 1 , 2 , 3 ]. Genetic alterations, metabolic dysregulation, and complex interactions with the bone marrow microenvironment contribute to disease progression and to a wide spectrum of clinical manifestations, including bone lesions, hypercalcemia, anemia, immune dysfunction, and renal impairment [ 4 ]. According to data from the Global Cancer Observatory (GLOBOCAN), more than 187,000 new cases of MM were diagnosed worldwide in 2022 [ 5 ].
Over the past two decades, the therapeutic landscape of MM has undergone profound transformation, resulting in substantial improvements in patient outcomes. Five-year overall survival (OS) has increased from approximately 30% in the 1990s to over 60% in recent years [ 6 ]. These advances are largely attributable to the introduction of several novel therapeutic classes, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies, antibody–drug conjugates (ADCs), T-cell-redirecting bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies [ 7 ]. Combination regimens incorporating these agents, often administered as triplets or quadruplets, now represent the standard of care in both newly diagnosed and relapsed disease settings [ 8 , 9 ].
Despite these advances, MM remains an incurable disease characterized by recurrent relapses and the progressive development of drug resistance [ 10 ]. Patients who become refractory to multiple therapeutic classes, particularly those with triple-class refractory disease (i.e., refractory to PIs, IMiDs, and anti-CD38 monoclonal antibodies), represent a difficult-to-treat population with limited therapeutic options and poor prognosis [ 11 , 12 , 13 , 14 ]. This unmet clinical need has driven the development of novel therapeutic strategies targeting previously unexploited biological vulnerabilities of MM cells. These include selective inhibitors of nuclear export (SINE), such as selinexor; BCL2 inhibitors, such as venetoclax; cereblon E3 ligase modulators (CELMoDs); antibody–drug conjugates targeting B-cell maturation antigen (BCMA), such as belantamab mafodotin; and peptide–drug conjugates, such as melflufen, designed to enhance the intracellular delivery of cytotoxic agents [ 15 , 16 , 17 , 18 , 19 ] ( Figure 1 ). However, the clinical trajectory of melflufen raises a broader question: how should therapies with discordant efficacy signals be interpreted in the era of rapidly evolving treatment landscapes? In this review, we critically reassess the clinical and biological trajectory of melflufen and discuss whether the mechanistic principles underlying enzyme-targeted drug delivery may still retain translational relevance despite the negative clinical outcomes observed in OCEAN.
2. Mechanism of Action of Melflufen
Melphalan, first synthesized in 1953, exerts its cytotoxic activity by alkylating DNA and inducing interstrand cross-links, thereby inhibiting DNA and RNA synthesis and ultimately triggering apoptosis [ 20 ]. It has been used in the treatment of MM since the late 1950s and remains a key component of high-dose conditioning regimens for autologous stem cell transplantation (ASCT) [ 21 ]. Building on the well-established clinical activity of melphalan, melflufen was developed as a peptidase-potentiated alkylating agent designed to enhance intracellular drug delivery and improve tumor selectivity [ 22 ].
Melflufen is a highly lipophilic peptide–drug conjugate composed of a melphalan-derived alkylating moiety linked to a peptide carrier (p-L-fluorophenylalanine ethyl ester), which facilitates rapid passive diffusion across cellular membranes [ 23 , 24 ] ( Figure 2 ). Once inside the cell, melflufen undergoes rapid enzymatic hydrolysis mediated by intracellular peptidases and esterases, leading to the release of hydrophilic alkylating metabolites, including melphalan and desethyl-melflufen [ 22 , 25 ]. Because these metabolites exhibit limited membrane permeability, they become trapped within the cell, resulting in the intracellular accumulation of cytotoxic alkylating compounds [ 22 , 26 ].
The preferential activation of melflufen within malignant plasma cells is largely driven by aminopeptidases, a family of proteolytic enzymes that catalyze the hydrolysis of N-terminal amino acids from peptides [ 20 ]. Aminopeptidases play a key role in protein turnover and are frequently overexpressed in malignant cells, including MM. Elevated expression of several aminopeptidases such as aminopeptidase N (ANPEP/CD13), LAP3, and DPP7 has been associated with disease progression and poor prognosis, suggesting that these enzymes may represent a therapeutic vulnerability [ 27 , 28 ]. Following intracellular activation, melflufen-derived metabolites induce extensive DNA damage, including cross-links affecting both nuclear and mitochondrial DNA, ultimately leading to apoptosis. In addition, melflufen disrupts mitochondrial membrane potential, further contributing to tumor cell death [ 25 , 29 , 30 ]. Importantly, preclinical studies indicate that the cytotoxic activity of melflufen is largely independent of TP53 mutational status, a feature associated with poor prognosis and resistance to therapy in MM [ 25 , 26 , 31 ]. Moreover, melflufen appears less susceptible to multidrug resistance mechanisms mediated by multidrug resistance protein 1 (MDR1/ABCB1), which contribute to resistance to several anti-myeloma agents [ 32 , 33 , 34 ].
Taken together, these properties allow melflufen to achieve enhanced intracellular retention of alkylating metabolites following aminopeptidase-mediated activation. This pharmacologic strategy was developed to increase intracellular delivery of alkylating agents in MM cells while exploiting tumor-associated peptidase activity [ 35 ].
3. Preclinical Development
Preclinical studies demonstrated that melflufen exhibits potent cytotoxic activity in MM cell lines as well as in primary patient-derived myeloma cells. Compared with melphalan, melflufen achieves significantly higher intracellular accumulation of alkylating metabolites, resulting in enhanced DNA damage and apoptosis [ 36 , 37 ]. Consistent with its mechanism of action, melflufen retains activity in several models of drug-resistant disease. In vitro studies have demonstrated cytotoxic effects in both melphalan- and bortezomib-resistant myeloma cell lines, with significantly lower IC 50 values compared with melphalan [ 26 ]. Beyond its direct cytotoxic effects, melflufen may also modulate the bone marrow (BM) microenvironment. Preclinical studies have shown that the drug inhibits the proliferation of BM-derived mesenchymal stromal cells, which are known to support MM cell growth and contribute to drug resistance [ 35 , 38 , 39 ]. In addition, melflufen has demonstrated anti-angiogenic activity and has been shown to inhibit monocyte proliferation, suggesting potential effects on osteoclastogenesis and bone remodeling [ 40 , 41 , 42 , 43 , 44 ]. Evidence from other malignancies further supports the tumor-selective activity of melflufen. Studies in breast cancer models have shown that malignant cells are more sensitive to melflufen than normal epithelial cells, while experiments in primary acute myeloid leukemia samples demonstrated marked cytotoxicity in leukemic cells, with relatively lower sensitivity observed in peripheral blood mononuclear cells [ 38 , 45 ]. Overall, these findings provide a strong biological rationale for the clinical development of melflufen in patients with relapsed or refractory MM.
4. Clinical Development
The clinical development of melflufen has primarily focused on patients with relapsed or refractory multiple myeloma (RRMM). Early-phase studies demonstrated encouraging anti-myeloma activity with a manageable safety profile, supporting further evaluation in larger trials.
The first clinical assessment of melflufen in RRMM was the multicenter phase I/II O-12-M1 study, which evaluated melflufen in combination with dexamethasone in patients who had received at least two prior lines of therapy, including lenalidomide or bortezomib, and were refractory to their most recent treatment [ 46 , 47 ]. Eligible patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The phase I portion established the maximum tolerated dose, while the phase II portion assessed efficacy and safety. In the phase II cohort, 45 patients received melflufen 40 mg intravenously every 28 days plus weekly dexamethasone. The median age was 66 years, and patients had received a median of four prior lines of therapy. The population was enriched for high-risk features: 67% were double-refractory, 58% had undergone prior ASCT, and 44% had high-risk cytogenetics. After a median follow-up of 27.9 months, the overall response rate (ORR) was 31%, including 20% partial responses and 11% very good partial responses. The clinical benefit rate was 49%, with a median duration of response (DOR) of 8.4 months. Median progression-free survival (PFS), overall survival (OS), and time to next treatment were 5.7, 20.7, and 7.9 months, respectively. Notably, responses were observed in patients with melphalan-resistant disease, and high-risk cytogenetics did not appear to adversely impact OS. Toxicity was predominantly hematologic, with thrombocytopenia, neutropenia, and anemia as the most common adverse events. Non-hematologic toxicities were generally manageable and included fatigue, pyrexia, gastrointestinal symptoms, and bone pain. Serious adverse events occurred in 38% of patients, most frequently infections and febrile neutropenia.
These findings were further explored in the phase II HORIZON (OP-106) study, a single-arm trial enrolling 157 heavily pretreated RRMM patients refractory to pomalidomide and/or an anti-CD38 monoclonal antibody [ 48 , 49 ]. Patients had received a median of five prior lines of therapy, and a substantial proportion had triple-class refractory disease. After a median follow-up of 14 months, the ORR was 29%, including 11% very good partial responses and 18% partial responses. Median DOR, PFS, and OS were 5.5, 4.2, and 11.6 months, respectively. Importantly, clinically meaningful activity was maintained in the triple-class refractory subgroup (ORR 26%).
The phase III OCEAN trial subsequently compared melflufen plus dexamethasone with pomalidomide plus dexamethasone in patients with RRMM refractory to lenalidomide after two to four prior lines of therapy [ 50 , 51 , 52 ]. Among 495 randomized patients, melflufen improved the primary endpoint of PFS (6.8 vs. 4.9 months) and achieved a numerically higher ORR (33% vs. 27%). However, overall survival favored the pomalidomide arm (25.0 vs. 19.8 months). Subgroup analyses suggested a differential effect according to prior transplant history: patients without prior ASCT or relapsing more than 36 months after transplantation appeared to benefit from melflufen, whereas those with early post-transplant relapse experienced inferior outcomes [ 53 , 54 ].
The discordance between PFS and OS in the OCEAN trial warrants careful interpretation and raises important biological and methodological questions. Importantly, the observed overall survival detriment cannot be dismissed as a purely methodological artifact and represents a clinically meaningful safety concern that substantially limits enthusiasm for broad clinical implementation of melflufen. At the same time, differences in post-progression therapies may have contributed to survival outcomes, particularly within a rapidly evolving therapeutic landscape characterized by heterogeneous access to subsequent treatments. In addition, the negative effect observed in specific subgroups, notably patients with early relapse after ASCT, suggests that prior treatment exposure and disease biology may significantly influence the therapeutic index of melflufen. Cumulative hematologic toxicity may also have affected treatment delivery or predisposed to complications impacting long-term survival. Trial design factors, including potential imbalances in patient characteristics and subsequent treatment strategies, may have further contributed to the observed survival outcomes. More broadly, these findings highlight the limitations of PFS as a surrogate endpoint in heavily pretreated MM populations and underscore the need for refined patient selection and more nuanced interpretation of efficacy outcomes.
These results led to a complex regulatory trajectory. In the United States, melflufen initially received accelerated approval in 2021 for patients who had received at least four prior lines of therapy but was subsequently withdrawn following the OCEAN findings, with formal confirmation by the U.S. Food and Drug Administration [ 24 , 55 ]. In contrast, the European Medicines Agency granted conditional approval in 2022 for a more selected population, namely patients with at least three prior lines of therapy who had not undergone prior ASCT or had relapsed more than three years after transplantation [ 56 , 57 ].
Melflufen has also been investigated in combination strategies aimed at improving efficacy. The phase I/IIa ANCHOR study investigated melflufen plus dexamethasone in combination with daratumumab or bortezomib in patients who had received one to four prior lines of therapy [ 58 ]. In the daratumumab cohort ( n = 33), the ORR was 73%, with a median PFS of 12.9 months and a median OS of 26.1 months. In the bortezomib cohort ( n = 23), the ORR was 78%, with a median PFS of 14.7 months, although OS data remained immature. Toxicity was consistent with previous studies and predominantly hematologic. However, given the limited sample size and non-randomized design, these results should be interpreted with caution. The phase III LIGHTHOUSE trial evaluated melflufen in combination with daratumumab and dexamethasone versus daratumumab alone in patients with RRMM who had received at least three prior lines of therapy or were refractory to both an immunomodulatory drug and a proteasome inhibitor [ 59 ]. Although the triplet regimen demonstrated improved response rates (ORR 59% vs. 30%), the study was prematurely terminated following a partial clinical hold requested by the U.S. Food and Drug Administration during the regulatory reassessment of melflufen ( Table 1 ).
5. Real-World Evidence and Special Populations
Evidence on the real-world use of melflufen in RRMM patients remains limited but provides important insights into its activity in heavily pretreated populations that are often underrepresented in clinical trials. One of the earliest retrospective analyses, conducted at the Dana-Farber Cancer Institute, included 12 patients who had received a median of 5.5 prior lines of therapy [ 60 ]. Treatment with melflufen plus dexamethasone achieved an ORR of 55%, including complete responses in 27% of patients. The median duration of response was 21.3 weeks, and the median time to treatment failure was 29.7 weeks. Adverse events were predominantly hematologic and generally manageable with supportive measures such as transfusions and growth factor support. Infections were relatively uncommon, and no cases of mucositis, alopecia, or secondary malignancies were reported.
Additional real-world experiences from small European retrospective cohorts have yielded broadly consistent results. A Spanish series including seven heavily pretreated patients reported an ORR of 57% [ 61 ], while a multicenter cohort of 19 patients demonstrated an ORR of 26% and a median progression-free survival (PFS) of 4.8 months despite a high prevalence of triple- and penta-class refractory disease [ 62 ]. Similar outcomes have been observed in Italian cohorts, with response rates ranging from 37.5% to 47% in advanced disease settings [ 63 , 64 ]. Across studies, hematologic toxicity, particularly thrombocytopenia, neutropenia, and anemia, represented the predominant adverse event profile and frequently required dose modifications and supportive care measures. Although these retrospective observations suggest potential activity in selected heavily pretreated patients, their interpretation remains substantially limited by small cohort sizes, selection bias, heterogeneous patient populations, and the absence of randomized comparisons. Notably, several cohorts included patients previously exposed to T-cell-redirecting therapies or BCMA-targeted agents, raising the possibility that melflufen may retain activity in immunotherapy-exposed disease. Beyond advanced RRMM, emerging evidence supports the feasibility of melflufen in specific clinical subgroups. The phase I/II BRIDGE (OP-107) study evaluated its pharmacokinetics and safety in patients with renal impairment [ 65 ]. Although systemic exposure to melphalan increased with decreasing estimated glomerular filtration rate (eGFR), no clinically meaningful differences in toxicity were observed, suggesting that melflufen can be administered in patients with moderate renal dysfunction without dose adjustment.
Taken together, these observations suggest potential activity in heavily pretreated and immunotherapy-exposed patients. However, these findings should be interpreted cautiously given the retrospective design, small sample sizes, and heterogeneity of patient populations. These limitations preclude definitive conclusions and highlight the need for prospective studies and registry-based analyses to better define the effectiveness, safety, and optimal positioning of melflufen in routine clinical practice.
6. Positioning of Melflufen in the Evolving Treatment Landscape of MM
In the current immunotherapy-driven era, the clinical positioning of melflufen should move beyond a purely descriptive framework toward a more decision-oriented approach grounded in mechanism, patient characteristics, and treatment sequencing [ 12 , 66 , 67 ]. Rather than competing directly with T-cell-redirecting therapies, melflufen may be conceptualized as a complementary, non-immune-based strategy in selected clinical contexts. Compared with CAR T-cell therapies and bispecific antibodies, melflufen does not rely on immune competence or antigen expression, which may represent an advantage in patients with T-cell exhaustion or antigen escape [ 68 , 69 , 70 , 71 ]. However, its overall efficacy appears more modest, suggesting that melflufen may be more appropriately considered a complementary rather than competing therapeutic strategy. Despite the limitations emerging from OCEAN, selected clinical scenarios have been proposed in which melflufen could still retain relevance as a non-immune-based therapeutic option [ 72 ]. First, melflufen may serve as a bridging strategy in patients awaiting access to CAR T-cell therapies or bispecific antibodies. In this setting, its rapid cytotoxic activity and independence from immune effector function may allow for disease control without impairing subsequent immunotherapy, particularly in patients with high disease burden requiring prompt cytoreduction. Second, melflufen may represent a therapeutic option in patients relapsing after T-cell-redirecting therapies. Post-immunotherapy relapse is increasingly characterized by antigen escape, T-cell exhaustion, and limited responsiveness to further immune-based interventions. Given its mechanism of action, which is independent of both antigen expression and T-cell fitness, melflufen may retain activity in this setting and provide a mechanistically orthogonal approach. Third, melflufen may be relevant in patients who are not candidates for cellular or T-cell-redirecting therapies due to advanced age, comorbidities, frailty, or limited access to specialized centers. In this population, there remains a need for additional non-immune-based therapeutic options [ 49 , 52 ].
Importantly, available data suggest that patient selection is a key determinant of benefit–risk balance. Subgroup analyses from the OCEAN trial indicate that prior ASCT and timing of relapse significantly influence outcomes, with improved results observed in patients without prior ASCT or with late relapse after transplantation [ 54 ]. Conversely, inferior outcomes in early post-transplant relapse highlight the need for careful selection. In clinical practice, the selection of melflufen should be weighed against available alternatives, including CELMoDs, bispecific antibodies, and CAR T-cell therapies, considering treatment availability, prior exposure, disease kinetics, and patient fitness [ 12 , 73 , 74 , 75 , 76 ].
Taken together, these considerations support a more restrictive, biology- and context-driven use of melflufen. Ideal candidates may include patients with heavily pretreated disease requiring rapid disease control, those relapsing after immunotherapy, and individuals ineligible for T-cell-redirecting approaches ( Figure 3 ). In contrast, patients with early relapses after ASCT or those with highly effective alternative options available may derive limited benefit. Future efforts should aim to refine this positioning through prospective studies and biomarker-driven strategies, enabling a more precise integration of melflufen within an increasingly complex therapeutic landscape. To contextualize the clinical positioning of melflufen within the current therapeutic landscape, a comparison with selected available treatment options is summarized in Table 2 . However, cross-trial comparisons should be interpreted cautiously given differences in patient populations, prior therapies, and study design.
7. Safety Profile
The safety profile of melflufen is predominantly characterized by hematologic toxicity [ 72 ]. The most frequently reported adverse events include thrombocytopenia, neutropenia, and anemia, which are generally manageable through dose modifications, treatment delays, and supportive measures such as transfusions or growth factor support. Non-hematologic adverse events occur less frequently and primarily include infections, fatigue, and gastrointestinal symptoms. Nevertheless, in a substantial proportion of patients these toxicities were dose-limiting and frequently required treatment interruptions, dose reductions, transfusion support, or growth factor administration [ 58 ]. However, the overall survival findings reported in the phase III OCEAN trial raised concerns regarding potential long-term risks in specific patient subgroups, particularly in relation to prior transplant exposure. These observations underscore the importance of careful patient selection and the need for continued evaluation of safety outcomes in both clinical trials and real-world settings.
8. Future Perspectives
Despite the regulatory challenges encountered during its clinical development, melflufen represents a compelling proof of concept for enzyme-targeted intracellular drug delivery. By exploiting tumor-associated aminopeptidase activity to enhance intracellular accumulation of cytotoxic agents, this approach represents a mechanistically distinct strategy for selective intracellular delivery of alkylating agents. More broadly, it highlights the potential of peptide–drug conjugates to achieve tumor-selective intracellular activation of cytotoxic agents through exploitation of cancer-associated enzymatic activity. Future research should extend beyond melflufen itself and focus on the development of next-generation peptide–drug conjugates that exploit tumor-specific enzymatic vulnerabilities.
In parallel, a deeper understanding of the biological determinants of response and toxicity will be essential to optimize the clinical application of these agents within an increasingly complex therapeutic landscape. A critical unmet need is the identification of predictive biomarkers to guide patient selection [ 77 ]. Given its mechanism of action, aminopeptidase expression and activity represent biologically plausible candidates. Candidate biomarkers may include CD13 (ANPEP) expression levels, which could be assessed by immunohistochemistry or transcriptomic profiling to stratify patients prior to treatment [ 27 ]. Preclinical data suggest that higher aminopeptidase activity enhances intracellular activation of melflufen and cytotoxic efficacy; however, these approaches remain exploratory and lack prospective validation.
At present, no validated biomarkers are available for routine clinical use, and aminopeptidase-based stratification remains investigational. Future studies should aim to identify the most relevant aminopeptidases, standardize methods for their assessment (including immunohistochemistry, transcriptomic profiling, and functional enzymatic assays), and define clinically meaningful thresholds. Importantly, biomarker analyses should be prospectively integrated into clinical trials to enable validation of their predictive value. Ultimately, a biomarker-driven approach may allow for more precise patient selection, improving the benefit–risk balance of melflufen and supporting its integration into a personalized, mechanism-based treatment strategy in MM.
9. Current Limitations and Unresolved Questions
Despite encouraging mechanistic rationale and early clinical activity, several major limitations continue to prevent a clear definition of the clinical role of melflufen in MM. Most importantly, the negative overall survival signal observed in OCEAN remains incompletely understood and represents a major unresolved safety concern. In addition, no validated biomarkers are currently available to identify patients more likely to benefit from aminopeptidase-targeted drug delivery strategies. Interpretation of currently available real-world evidence is further limited by retrospective study design, small cohort sizes, and substantial clinical heterogeneity. Finally, the rapidly evolving therapeutic landscape of MM, particularly following the introduction of highly active T-cell-redirecting therapies, further complicates the positioning of alkylating-based approaches. Addressing these challenges will require prospective biomarker-driven studies, improved understanding of treatment-related toxicity, and more refined patient selection strategies.
10. Conclusions
Melflufen represents a therapeutic strategy based on enzyme-targeted intracellular delivery of alkylating agents, developed to enhance selective drug accumulation in MM cells. Early clinical studies demonstrated encouraging activity in heavily pretreated patients, leading to accelerated regulatory approval. However, the results of the phase III OCEAN trial raised important concerns, particularly regarding overall survival in specific patient subgroups, prompting a substantial reassessment of its clinical role. Despite these limitations, the clinical development of melflufen provided important insights into enzyme-targeted drug delivery and biomarker-guided therapeutic positioning in MM. These concepts may inform the future development of next-generation peptide–drug conjugates and other biology-driven therapeutic strategies.
In the current immunotherapy era, the role of melflufen is likely to be confined to selected clinical scenarios, including patients with limited therapeutic options, those ineligible for cellular therapies, and individuals relapsing after T-cell-redirecting approaches. In these settings, its mechanism of action may offer a complementary, non-immune-based strategy.
Ultimately, the trajectory of melflufen highlights a broader principle for modern myeloma therapy: effective treatment increasingly depends on the rational integration of mechanistically distinct approaches guided by disease biology and patient-specific factors. Future progress will require precise patient selection, biomarker-driven strategies, and optimized treatment sequencing to fully exploit the potential of emerging therapeutic platforms.
Acknowledgments
Some of the icons used in the figures were created with BioRender.com under a licensed version.
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Author Contributions
Conceptualization M.G. and M.C.; writing—original draft preparation, figures and tables M.G. and M.C.; supervision and review, D.S., A.C. and R.M.L. All authors have read and agreed to the published version of the manuscript.
Data Availability Statement
No new datasets were generated or analyzed in this study.
Conflicts of Interest
The authors declare no competing conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript: ADC Antibody–drug Conjugate ASCT autologous stem cell transplantation BM bone marrow Bz bortezomib CAR-T chimeric antigen receptor T CELMoDs cereblon E3 ligase modulators Dara Daratumumab DEX dexamethasone DOR duration of response MDR1/ABCB1 multidrug resistance protein 1 MM Multiple Myeloma NR Not reached ORR overall response rate OS Overall Survival PFS progression-free survival PI Proteasome inhibitor Pom Pomalidomide RRMM relapsed or refractory multiple myeloma SINE selective inhibitors of nuclear export TCE T-cell engagers
References
1. Palumbo A. Anderson K. Multiple myeloma N. Engl. J. Med. 2011 364 1046 1060 10.1056/NEJMra1011442 21410373
2. Rajkumar S.V. Dimopoulos M.A. Palumbo A. Bladé J. Merlini G. Mateos M.V. Kumar S. Hillengass J. Kastritis E. Richardson P. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol. 2014 15 e538 e548 10.1016/S1470-2045(14)70442-5 25439696
3. Kumar S.K. Rajkumar V. Kyle R.A. van Duin M. Sonneveld P. Mateos M.V. Gay F. Anderson K.C. Multiple myeloma Nat. Rev. Dis. Primers 2017 3 17046 10.1038/nrdp.2017.46 28726797
4. Malard F. Neri P. Bahlis N.J. Terpos E. Moukalled N. Hungria V.T.M. Manier S. Mohty M. Multiple myeloma Nat. Rev. Dis. Primers 2024 10 45 10.1038/s41572-024-00529-7 38937492
5. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 2024 74 229 263 10.3322/caac.21834 38572751
6. Zanwar S. Rajkumar S.V. Current risk stratification and staging of multiple myeloma and related clonal plasma cell disorders Leukemia 2025 39 2610 2617 10.1038/s41375-025-02654-y 40702148 PMC12589131
7. Rajkumar S.V. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management Am. J. Hematol. 2024 99 1802 1824 10.1002/ajh.27422 38943315 PMC11404783
8. Kumar S. Baizer L. Callander N.S. Giralt S.A. Hillengass J. Freidlin B. Hoering A. Richardson P.G. Schwartz E.I. Reiman A. Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee Blood Cancer J. 2022 12 98 10.1038/s41408-022-00695-5 35768410 PMC9243011
9. Chen Q. Zhang M. Zheng S. Tong Y. Tan Y. Therapeutic progress in relapsed/refractory multiple myeloma Ann. Hematol. 2024 103 1833 1841 10.1007/s00277-024-05730-y 38609727
10. van de Donk N.W.C.J. Pawlyn C. Yong K.L. Multiple myeloma Lancet 2021 397 410 427 10.1016/S0140-6736(21)00135-5 33516340
11. Wang P.F. Yee C.W. Gorsh B. Zichlin M.L. Paka P. Bhak R.H. Boytsov N. Khanal A. Noman A. DerSarkissian M. Treatment patterns and overall survival of patients with double-class and triple-class refractory multiple myeloma: A US electronic health record database study Leuk. Lymphoma 2023 64 398 406 10.1080/10428194.2022.2140284 36408998
12. Dimopoulos M.A. Terpos E. Boccadoro M. Moreau P. Mateos M.V. Zweegman S. Cook G. Engelhardt M. Delforge M. Hajek R. EHA–EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma Nat. Rev. Clin. Oncol. 2025 22 680 700 10.1038/s41571-025-01041-x 40624367
13. Mateos M.V. Weisel K. De Stefano V. Goldschmidt H. Delforge M. Mohty M. Dytfeld D. Angelucci E. Vincent L. Perrot A. LocoMMotion: A study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma—2-year follow-up (final analysis) Leukemia 2024 38 2554 2560 10.1038/s41375-024-02404-6 39322709 PMC11588650
14. Riedhammer C. Truger M. Lee H. Leypoldt L.B. Meggendorfer M. Hutter S. Müller H. Mersi J. Kadel S.K. Buchwald T. The evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D Leukemia 2026 Epub ahead of printing 10.1038/s41375-026-02889-3 PMC13056581 41703032
15. Talarico M. Barbato S. Maisnar V. Delimpasi S. Puppi M. Rizzello I. Pantani L. Tacchetti P. Martello M. Vigliotta I. Exceptional long-term responses from OCEAN and HORIZON trials: Melflufen-dexamethasone as an expansion of treatment options for relapsed/refractory multiple myeloma in the era of new immunotherapies? J. Cancer Res. Clin. Oncol. 2025 151 288 10.1007/s00432-025-06326-3 41065854 PMC12511461
16. Neupane K. Wahab A. Masood A. Faraz T. Bahram S. Ehsan H. Hannan A. Anwer F. Profile and management of toxicity of selinexor and belantamab mafodotin for the treatment of triple class refractory multiple myeloma J. Blood Med. 2021 12 529 550 10.2147/JBM.S317966 34234609 PMC8257048
17. Bobin A. Gruchet C. Guidez S. Gardeney H. Nsiala Makunza L. Vonfeld M. Lévy A. Cailly L. Sabirou F. Systchenko T. Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article Cancers 2021 13 5210 10.3390/cancers13205210 34680358 PMC8534104
18. Dhillon S. Melphalan Flufenamide (Melflufen): First Approval Drugs 2021 81 963 969 10.1007/s40265-021-01522-0 33961277
19. Sgherza N. Curci P. Rizzi R. Musto P. Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor Front. Oncol. 2021 11 716751 10.3389/fonc.2021.716751 34660279 PMC8514936
20. Schjesvold F. Oriol A. Current and Novel Alkylators in Multiple Myeloma Cancers 2021 13 2465 10.3390/cancers13102465 34070213 PMC8158783
21. Kazandjian D. Dew A. Hill E. The changing role of high dose melphalan with stem cell rescue in the treatment of newly diagnosed multiple myeloma in the era of modern therapies—Back to the future! Best. Pract. Res. Clin. Haematol. 2020 33 101150 10.1016/j.beha.2020.101150 32139015
22. Wickström M. Nygren P. Larsson R. Harmenberg J. Lindberg J. Sjöberg P. Jerling M. Lehmann F. Richardson P. Anderson K. Melflufen—A peptidase-potentiated alkylating agent in clinical trials Oncotarget 2017 8 66641 66655 10.18632/oncotarget.18420 29029544 PMC5630444
23. National Center for Biotechnology Information PubChem Compound Summary for CID 9935639, Melphalan Flufenamide 2026 Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Melphalan_flufenamide (accessed on 16 March 2026)
24. Cliff E.R.S. Janakiram M. Kesselheim A.S. Melflufen: Post-hoc subgroup analyses and the US FDA Oncologic Drugs Advisory Committee Lancet Haematol. 2023 10 e314 e317 10.1016/S2352-3026(23)00056-X 37142342
25. Westermark U. Diao Y. Fasth K.-J. Färnegårdh M. Färnegårdh K. Hammer K. Lehmann F. Acs K. Svensson Gelius S. A rapid intracellular enrichment of alkylating payload is essential for melphalan flufenamide potency and mechanism of action Biochem. Biophys. Res. Commun. 2023 656 122 130 10.1016/j.bbrc.2023.03.009 37032581
26. Chauhan D. Ray A. Viktorsson K. Spira J. Paba-Prada C. Munshi N. Richardson P. Lewensohn R. Anderson K.C. In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells Clin. Cancer Res. 2013 19 3019 3031 10.1158/1078-0432.CCR-12-3752 23584492 PMC4098702
27. Miettinen J.J. Kumari R. Traustadottir G.A. Huppunen M.-E. Sergeev P. Majumder M.M. Schepsky A. Gudjonsson T. Lievonen J. Bazou D. Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen Cancers 2021 13 1527 10.3390/cancers13071527 33810334 PMC8036322
28. Bianchi G. Anderson K.C. Contribution of Inhibition of Protein Catabolism in Myeloma Cancer J. 2019 25 11 18 10.1097/PPO.0000000000000349 30694855
29. Wallace D.C. Mitochondria and cancer Nat. Rev. Cancer 2012 12 685 698 10.1038/nrc3365 23001348 PMC4371788
30. Porporato P.E. Filigheddu N. Pedro J.M.B.-S. Kroemer G. Galluzzi L. Mitochondrial metabolism and cancer Cell Res. 2018 28 265 280 10.1038/cr.2017.155 29219147 PMC5835768
31. Acs K. Miettinen J.J. Sergeev P. Heckel T. Diao Y. Witt-Mulder K. Thureson M. Bischler T. Huppunen M.-E. Suvela M. Efficacy of melflufen in multiple myeloma with mutated or deleted TP53 Exp. Hematol. Oncol. 2025 14 138 10.1186/s40164-025-00729-1 41437395 PMC12729255
32. Kühne A. Tzvetkov M.V. Hagos Y. Lage H. Burckhardt G. Brockmöller J. Influx and efflux transport as determinants of melphalan cytotoxicity: Resistance to melphalan in MDR1 overexpressing tumor cell lines Biochem. Pharmacol. 2009 78 45 53 10.1016/j.bcp.2009.03.026 19447222
33. Byrgazov K. Besse A. Kraus M. Slipicevic A. Lehmann F. Driessen C. Besse L. Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells HemaSphere 2021 5 e602 10.1097/HS9.0000000000000602 34136753 PMC8202573
34. Byrgazov K. Kraus M. Besse A. Slipicevic A. Lehmann F. Driessen C. Besse L. Up-regulation of multidrug resistance protein MDR1/ABCB1 in carfilzomib-resistant multiple myeloma differentially affects efficacy of anti-myeloma drugs Leuk. Res. 2021 101 106499 10.1016/j.leukres.2020.106499 33422770
35. Ocio E.M. Nadeem O. Schjesvold F. Gay F. Touzeau C. Dimopoulos M.A. Richardson P.G. Mateos M.V. Melflufen for the treatment of multiple myeloma Expert. Rev. Clin. Pharmacol. 2022 15 371 382 10.1080/17512433.2022.2075847 35723075
36. Flanagan K. Kumari R. Miettinen J.J. Haney S.L. Varney M.L. Williams J.T. Majumder M.M. Suvela M. Slipicevic A. Lehmann F. The Peptide-Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death Hemasphere 2022 6 e687 10.1097/HS9.0000000000000687 35243210 PMC8884539
37. Giliberto M. Thimiri Govinda Raj D.B. Cremaschi A. Skanland S.S. Gade A. Tjønnfjord G.E. Schjesvold F. Munthe L.A. Tasken K. Ex vivo drug sensitivity screening in multiple myeloma identifies drug combinations that act synergistically Mol. Oncol. 2022 16 1241 1258 10.1002/1878-0261.13191 35148457 PMC8936517
38. Strese S. Saadia H.B. Velander E. Haglund C. Höglund M. Larsson R. Gullbo J. In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia Oncotarget 2017 8 6341 6352 10.18632/oncotarget.13856 27974676 PMC5351636
39. Gebraad A. Ohlsbom R. Miettinen J.J. Emeh P. Pakarinen T.K. Manninen M. Eskelinen A. Kuismanen K. Slipicevic A. Lehmann F. Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen Cells 2022 11 1574 10.3390/cells11091574 35563880 PMC9103864
40. Strese S. Wickström M. Fuchs P.F. Fryknäs M. Gerwins P. Dale T. Larsson R. Gullbo J. The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo Biochem. Pharmacol. 2013 86 888 895 10.1016/j.bcp.2013.07.026 23933387
41. Byrgazov K. Lind T. Rasmusson A.J. Andersson C. Slipicevic A. Lehmann F. Gullbo J. Melhus H. Larsson R. Fryknäs M. Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes Bone Rep. 2021 15 101098 10.1016/j.bonr.2021.101098 34150958 PMC8192817
42. Wickström M. Larsson R. Nygren P. Gullbo J. Aminopeptidase N (CD13) as a target for cancer chemotherapy Cancer Sci. 2011 102 501 508 10.1111/j.1349-7006.2010.01826.x 21205077 PMC7188354
43. Sevcikova S. Minarik J. Stork M. Jelinek T. Pour L. Hajek R. Extramedullary disease in multiple myeloma—Controversies and future directions Blood Rev. 2019 36 32 39 10.1016/j.blre.2019.04.002 31005420
44. Bladé J. Fernández de Larrea C. Rosiñol L. Cibeira M.T. Jiménez R. Powles R. Soft-tissue plasmacytomas in multiple myeloma: Incidence, mechanisms of extramedullary spread, and treatment approach J. Clin. Oncol. 2011 29 3805 3812 10.1200/JCO.2011.34.9290 21900099
45. Schepsky A. Traustadottir G.A. Joelsson J.P. Ingthorsson S. Kricker J. Bergthorsson J.T. Asbjarnarson A. Gudjonsson T. Nupponen N. Slipicevic A. Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines Cancer Med. 2020 9 6726 6738 10.1002/cam4.3300 32717133 PMC7520280
46. Bringhen S. Voorhees P.M. Plesner T. Mellqvist U.-H. Reeves B. Sonneveld P. Byrne C. Nordström E. Harmenberg J. Obermüller J. Melflufen plus dexamethasone in relapsed/refractory multiple myeloma: Long-term survival follow-up from the Phase II study O-12-M1 Br. J. Haematol. 2021 193 1105 1109 10.1111/bjh.17302 33403663 PMC8248157
47. Richardson P.G. Bringhen S. Voorhees P. Plesner T. Mellqvist U.-H. Reeves B. Paba-Prada C. Zubair H. Byrne C. Chauhan D. Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): A multicentre, international, open-label, phase 1–2 study Lancet Haematol. 2020 7 e395 e407 10.1016/S2352-3026(20)30044-2 32213344
48. Richardson P.G. Oriol A. Larocca A. Bladé J. Cavo M. Rodriguez-Otero P. Leleu X. Nadeem O. Hiemenz J.W. Hassoun H. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma J. Clin. Oncol. 2021 39 757 767 10.1200/JCO.20.02259 33296242 PMC8078327
49. Larocca A. Leleu X. Touzeau C. Bladé J. Paner A. Mateos M.-V. Cavo M. Maisel C. Alegre A. Oriol A. Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: Analyses from the Phase II HORIZON study Br. J. Haematol. 2022 196 639 648 10.1111/bjh.17887 34671975 PMC9135124
50. Schjesvold F. Robak P. Pour L. Aschan J. Sonneveld P. OCEAN: A randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma Future Oncol. 2020 16 631 641 10.2217/fon-2020-0024 32141766
51. Schjesvold F.H. Dimopoulos M.-A. Delimpasi S. Robak P. Coriu D. Legiec W. Pour L. Špička I. Masszi T. Doronin V. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): A randomised, head-to-head, open-label, phase 3 study Lancet Haematol. 2022 9 e98 e110 10.1016/S2352-3026(21)00381-1 35032434
52. Schjesvold F.H. Ludwig H. Delimpasi S. Robak P. Coriu D. Tomczak W. Pour L. Špička I. Dimopoulos M.-A. Masszi T. Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: Analyses from the phase III OCEAN study Haematologica 2024 109 2331 2336 10.3324/haematol.2023.284635 38426292 PMC11215352
53. Sonneveld P. Richardson P.G. Ludwig H. Dimopoulos M.-A. Schjesvold F.H. Hájek R. Abdulhaq H. Thuresson M. Norin S. Bakker N.A. Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses from Longer Follow-up of the OCEAN and HORIZON Studies Clin. Lymphoma Myeloma Leuk. 2023 23 687 696 10.1016/j.clml.2023.05.004 37355418
54. Schjesvold F.H. Ludwig H. Mateos M.-V. Larocca A. Abdulhaq H. Norin S. Thuresson M. Bakker N.A. Richardson P.G. Sonneveld P. Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study Eur. J. Haematol. 2024 112 402 411 10.1111/ejh.14127 37968873
55. FDA Final Decision on the Proposal to Withdraw Approval of Pepaxto (Melphalan Flufenamide) for Injection 2024 Available online: https://www.fda.gov/media/176510/download?attachment (accessed on 10 February 2026)
56. EMA Pepaxti: Melphalan Flufenamide. European Medicines Agency 2022 Available online: https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-pepaxti_en.pdf (accessed on 10 February 2026)
57. EMA Pepaxti—Annex 1—Summary of Product Characteristics EMA 2025 Available online: https://www.ema.europa.eu/en/documents/product-information/pepaxti-epar-product-information_en.pdf (accessed on 10 February 2026)
58. Ocio E.M. Efebera Y.A. Hájek R. Straub J. Maisnar V. Eveillard J.-R. Karlin L. Mateos M.-V. Oriol A. Ribrag V. ANCHOR: Melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: Final results of a phase I/IIa study Haematologica 2024 109 867 876 10.3324/haematol.2023.283490 37646657 PMC10905089
59. Pour L. Szarejko M. Bila J. Schjesvold F.H. Špička I. Maisnar V. Jurczyszyn A. Grudeva-Popova Z. Hájek R. Usenko G. Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: Results from the randomized, open-label, phase III LIGHTHOUSE study Haematologica 2024 109 895 905 10.3324/haematol.2023.283509 37646660 PMC10905085
60. Hossain S. Mo C. Patches S. Leblebjian H. Goodrich K. Regan E. O’Neill K. Noonan K. Richardson P.G. Laubach J. Outcomes of Melflufen Treatment in Patients with Relapsed/Refractory Multiple Myeloma Eur. J. Haematol. 2025 114 982 989 10.1111/ejh.14398 39988462 PMC12053961
61. Gálvez Ruiz A.B. Sopeña Pell-Ilderton C. Lamas Rodríguez B. Suárez Terrón M. Delgado Palacios S. Bataller Alfonso A.M. Talegón de la Fuente E. Carril Barcia A. Eritzpokhoff L. Corcolés Molina M. Experiencia con melfálan-flufenamida en mieloma múltiple: Resultados de un hospital terciario Proceedings of the XIX Reunión Anual de la Asociación Valenciana de Hematología y Hemoterapia (AVHH) Valencia, Spain 26–28 February 2025
62. Martínez-Campuzano D. Lamas B. Sopeña C. Ruiz A. Moreno M.J. Cabañas V. de Arriba F. Sánchez M. Gascón A. Espinosa C. Real-World Use of Melflufen Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma: A Retrospective Study from the Valencian Community and the Region of Murcia (Spain) Proceedings of the International Myeloma Society Annual Meeting 2025 Toronto, ON, Canada 17–20 September 2025
63. Mancuso K. Masci S. Talarico M. Vitale A. Barbato S. Solli V. Puppi M. Rizzello I. Pantani L. Tacchetti P. Positioning of Melflufen in Heavily Pretreated RRMM Patients: Real-World Evidence in a Rapidly Evolving Therapeutic Landscape Eur. J. Haematol. 2026 116 928 936 10.1111/ejh.70156 41813608 PMC13141662
64. Giunta G. Longo E. Lo Faro C. Lavenia G. Del Fabro V. Elia F. Romano A. Di Raimondo F. Conticello C. Efficacy and tolerability of melflufen in relapsed multiple myeloma: A single-center real-life experience Proceedings of the European Myeloma Network (EMN) Meeting Athens, Greece 10–12 April 2025
65. Pour L. Delimpasi S. Legiec W. Minarik J. Špička I. Grosicki S. Rymko M. Najda J. Symeonidis A. Andersson B. BRIDGE (OP-107): A Phase 2 pharmacokinetic study of melflufen plus dexamethasone in patients with relapsed/refractory multiple myeloma and impaired renal function Clin. Lymphoma Myeloma Leuk. 2026 in press 10.1016/j.clml.2026.04.022 42215355
66. Costa L.J. Banerjee R. Mian H. Weisel K. Bal S. Derman B.A. Htut M.M. Nagarajan C. Rodriguez C. Richter J. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma Leukemia 2025 39 543 554 10.1038/s41375-024-02482-6 39870767 PMC11879857
67. Manier S. Jurczyszyn A. Vesole D.H. Bridging Chemotherapy: Multiple Myeloma The EBMT/EHA CAR-T Cell Handbook Kröger N. Gribben J. Chabannon C. Yakoub-Agha I. Einsele H. Springer Cham, Switzerland 2022 127 129 36122072
68. Da Vià M.C. Dietrich O. Truger M. Arampatzi P. Duell J. Heidemeier A. Zhou X. Danhof S. Kraus S. Chatterjee M. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma Nat. Med. 2021 27 616 619 10.1038/s41591-021-01245-5 33619368
69. Lee H. Durante M. Skerget S. Vishwamitra D. Benaoudia S. Ahn S. Poorebrahim M. Barakat E. Jung D. Leblay N. Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma Blood 2024 144 2637 2651 10.1182/blood.2024026212 39321344 PMC11738017
70. Lee H. Ahn S. Maity R. Leblay N. Ziccheddu B. Truger M. Chojnacka M. Cirrincione A. Durante M. Tilmont R. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma Nat. Med. 2023 29 2295 2306 10.1038/s41591-023-02491-5 37653344 PMC10504087
71. Friedrich M.J. Neri P. Kehl N. Michel J. Steiger S. Kilian M. Leblay N. Maity R. Sankowski R. Lee H. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients Cancer Cell 2023 41 711 725.e6 10.1016/j.ccell.2023.02.008 36898378
72. Ludwig H. Mai E.K. Högner M. Welslau M. Waldschmidt J.M. Optimizing the use of melflufen (melphalan flufenamide) in relapsed or refractory multiple myeloma: Recommendations for clinical practice Ann. Hematol. 2025 104 5593 5603 10.1007/s00277-025-06659-6 41207923 PMC12672761
73. Moreau P. Garfall A.L. van de Donk N.W.C.J. Nahi H. San-Miguel J.F. Oriol A. Nooka A.K. Martin T. Rosinol L. Chari A. Teclistamab in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2022 387 495 505 10.1056/NEJMoa2203478 35661166 PMC10587778
74. Lesokhin A.M. Tomasson M.H. Arnulf B. Bahlis N.J. Prince H.M. Niesvizky R. Rodríguez-Otero P. Martínez-López J. Koehne G. Touzeau C. Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results Nat. Med. 2023 29 2259 2267 10.1038/s41591-023-02528-9 37582952 PMC10504075
75. Berdeja J.G. Madduri D. Usmani S.Z. Jakubowiak A. Agha M. Cohen A.D. Stewart A.K. Hari P. Htut M. Lesokhin A. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study Lancet 2021 398 314 324 10.1016/S0140-6736(21)00933-8 34175021
76. Rodríguez-Otero P. Ailawadhi S. Arnulf B. Patel K. Cavo M. Nooka A.K. Manier S. Callander N. Costa L.J. Vij R. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma N. Engl. J. Med. 2023 388 1002 1014 10.1056/NEJMoa2213614 36762851
77. Wallington-Beddoe C.T. Mynott R.L. Prognostic and predictive biomarker developments in multiple myeloma J. Hematol. Oncol. 2021 14 151 10.1186/s13045-021-01162-7 34556161 PMC8461914