Melflufen for relapsed and refractory multiple myeloma

Figures & data

Box 1. Drug summary.

Drug name (generic)	Melphalan flufenamide (melflufen)
Phase (for indication under discussion)	I, II, and III study
Indication (specific to discussion)	Multiple myeloma
Pharmacology description/mechanism of action	Peptide-drug conjugate
Route of administration	40 mg IV (on day 1 of each 28-day cycle)
Chemical formula	C24H30Cl2FN3O3
Pivotal trial	HORIZON [16]

IV: intravenous.

Figure 1. Clinical structure of melflufen hydrochloride and its metabolites melphalan and desethylmelflufen.

Figure reproduced with permission from Schjesvold F, Robak P, Pour L, et al. Future Oncol. 2020;16(11):631–41 [32].

Figure 2. Melflufen mechanism of action.

Melflufen targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Peptidases are expressed in several types of cancer cells, including those of MM. Melflufen is rapidly taken up by mylema cells due to its high lipophilicity. Once inside the multiple myeloma cell, the activity of melflufen is dependent on its immediate hydrolysis by peptidases, which unleashes its more hydrophilic alkylator payloads that remain entrapped within the cell.

Table 1. Melflufen clinical trials summary table.

Trial name	No. of patients	Key inclusion criteria	Treatment(s)	Efficacy
0–12-M1: Phase II study of melflufen + dexamethasone in RRMM [18]	45	RRMM ≥2 prior lines of therapy Prior lenalidomide and bortezomib Refractory to last line of therapy (relapsed ≤60 days after completing treatment)	Melflufen + dexamethasone	Median follow-up: 27.9 mo ORR: 31% CBR: 49% mDOR: 8.4 mo mPFS: 5.7 mo mOS: 20.7 mo
HORIZON (OP-106): Pivotal phase II study of melflufen + dexamethasone in RRMM refractory to pomalidomide anti-CD38 mAb, or both [19]	154	RRMM ≥2 prior lines, including an IMiD and a PI Refractory to pomalidomide, anti-CD38 mAb, or both	Melflufen + dexamethasone	Follow-up (n = 125): ≥20 wks ORR: 29% CBR: 44% mDOR: 4.4 mo mPFS: 4.2 mo mOS: 11.6 mo
ANCHOR (OP-104): Phase I/II study of melflufen + dexamethasone + bortezomib or daratumumab in RRMM [20]	33	RRMM 1–4 prior lines of therapy Refractory (or intolerant) to IMiDs, PIs, or both	Melflufen + dexamethasone + daratumumab	Median follow-up: 6.6 mo ORR: 76% CBR: 79% mPFS: 14.3 mo
	6	RRMM 1–4 prior lines of therapy Refractory (or intolerant) to IMiDs, PIs, or both	Melflufen + dexamethasone + bortezomib	Median follow-up: 13.4 mo ORR: 67% CBR: 83%
OCEAN (OP-103): Phase III study of melflufen + dexamethasone in RRMM refractory to lenalidomide [32]	~450	RRMM 2–4 prior lines of therapy Relapsed and refractory or refractory to last line of therapy Refractory to lenalidomide administered ≤18 mo prior to randomization	Melflufen + dexamethasone vs pomalidomide + dexamethasone	–
LIGHTHOUSE [57]	170 (planned)	RRMM Double refractory (or intolerant) to an IMiD and a PI or ≥3 prior lines of therapy including an IMiD and a PI	Melflufen + daratumumab vs daratumumab (2:1)	–

CBR: clinical benefit rate; IMiD: immunomodulatory agent; mAb: monoclonal antibody; mDOR: median duration of response; mOS: median overall survival; mPFS: median progression-free survival; ORR: overall response rate; PI: proteasome inhibitor; RRMM: relapsed/refractory multiple myeloma.

Table 2. Most common treatment-emergent AEs with melflufen and dexamethasone in O-12-M1 [18].

Adverse events, n (%)	Melflufen in combination with dexamethasone (n = 45)
	All grades	Grade 3–4	Grade 5
Thrombocytopenia	33 (73)	28 (62)	0 (0)
Neutropenia	31(69)	27 (60)	1 (2)
Anemia	29 (64)	20 (44)	0 (0)
Pyrexia	18 (40)	2 (4)	0 (0)
Asthenia	14 (31)	3 (7)	0 (0)
Fatigue	13 (29)	2 (4)	0 (0)
Nausea	12 (27)	0 (0)	0 (0)
Diarrhea	11 (24)	1 (2)	0 (0)
Pneumonia*	7 (16)	3 (7)	2 (4)

*There was one case each of a grade 3 and a grade 5 pneumonia overlapping with a grade 4 neutropenia.

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Schjesvold F, Robak P, Pour L, et al. OCEAN: a randomized phase III study of melphalan flufenamide + dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol. 2020;16(11):631–641.

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Richardson P, Bringhen S, Voorhees P, et al. 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(5):e395–e407.

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Mateos MV, Oriol A, Larocca A, et al. Clinical activity of melflufen in patients with triple-class refractory multiple myeloma and poor-risk features in an updated analysis of HORIZON (OP-106), a phase 2 study in patients with relapsed/refractory multiple myeloma refractory to pomalidomide and/or daratumumab. Poster presented at: 61st American Society of Hematology Annual Meeting and Exposition; 2019 Dec 7-10; Orlando (FL). Abstract 1883.

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Ocio EM, Efebera YA, Granell M, et al. ANCHOR (OP-104): updated efficacy and safety from a phase 1/2 study of melflufen and dexamethasone plus bortezomib or daratumumab in patients with relapsed/refractory multiple myeloma (RRMM) refractory to an IMiD or a proteasome inhibitor (PI). Poster presented at: 61st American Society of Hematology Annual Meeting and Exposition; 2019 Dec 7-10; Orlando (FL). Abstract 3124.

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Oncopeptides. Summary – our clinical studies. 2020 [cited 2020 Apr 21]. Available from: https://oncopeptides.se/en/our-clinical-trials-summary/

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