Background: Multiple myeloma (MM) is a malignant and heterogenous plasma cell disorder. It is characterized by the clonal proliferation of B cells located in the bone marrow. The treatment of MM is based on complex therapy algorithms, and the introduction of targeted therapies has significantly improved the prognosis. However, the disease is still considered incurable, and relapses or resistance to therapy are likely to occur.

Melphalan flufenamide (melflufen) is a novel peptide-drug conjugate which passively diffuses predominantly into MM cells releasing alkylating agents to induce apoptosis. Despite its proven efficacy and safety in patients with normal to mildly impaired renal function, there are no reports addressing the use of melflufen in patients with severely impaired renal insufficiency (GFR < 30 ml/min). Therefore, 2 clinical cases with severe renal insufficiency are presented.

Clinical Case 1: A 82-year-old male was diagnosed with MM Stage III in 2018. Comorbidities were arterial hypertension, diabetes type II, renal insufficiency, osteolysis incl. soft tissue and pleura. At initial diagnosis the laboratory parameters were as follows: M spike (IgG): 55.9 g/l; leukocytes: 7,700 /µl; hemoglobin: 7.8 mmol/l; thrombocytes: 188,000 /µl; beta-2 microglobulin: 4.78 mg/l; albumin: 34 g/l; calcium: 2.23 mmol/l; GFR: 34.7 ml/min; ESR: 53 mm/h; LDH: 153.6 U/l. Before melflufen, the patient received 5 prior therapies all of which were discontinued due to different reasons: VMP (10 mo) – progredient disease (PD), Rd (3 mo) – drug exanthema, Vd (7 mo) - PD, DaraKd (10 mo) – heart insufficiency, and DaraPd (4 mo) which was adjusted to daratumumab monotherapy due to side effects on pomalidomide. After another PD, melflufen 20 mg (d1 + q28) was administered in 09/2024. At this point, laboratory parameters were as follows: M spike: 10.9 g/l; leukocytes: 9,000 /µl, hemoglobin: 9.1 mmol/l, thrombocytes: 190.000 /µl, beta-2 microglobulin: 7.41 mg/l; albumin: 42 g/l; calcium: 2.42 mmol/l, GFR: 24.3 ml/min, ESR: 7 mm/h; LDH: 145.2 U/l. Partial remission occurred and was persistent ever since and the last measured laboratory parameters (03/2025) were as follows: M spike: 3.3 g/l; leukocytes: 7,400 /µl, hemoglobin: 8.3 mmol/l, thrombocytes: 131.000 /µl, beta-2 microglobulin: 5.26 mg/l; albumin: 36 g/l; calcium: 2.2 mmol/l, GFR: 39.7 ml/min, ESR: 36 mm/h; LDH: 180.6 U/l.

Clinical Case 2: In 2007, a 83-year-old male was diagnosed with MM type IgG/ kappa at Stage III. The patient presented with osteolysis and pathological fractures at thoracic vertebra as well as lumbar vertebra including posterior edge involvement, peri- and intraspinal soft tissue tumor (EMD) and renal insufficiency (GFR: 33 ml/min). Laboratory parameters at initial diagnosis were the following: creatinine: 1.9 mg/dl, hemoglobin: 9.2 g/dl (anaemia), IgG: 83 g/l. In total, 9 different prior therapies were administered and discontinued before the use of melflufen: thalidomide/doxorubicine/dexamethasone (12 mo) with thalidomide as a maintenance therapy (2 y) – PD, Vd (12 mo) – polyneuropathy, bendamustine/prednisolone (5 mo) - PD, KRd (4 mo) – VGPR, discontinuation due to patient's request, EloRd (9 mo) – VGPR, DaraRd (2 y) and daratumumab monotherapy (4 mo) - PD, IsaPomd (5 mo) – PD, and liposomal doxorubicine/bortezomib (2 mo). After laboratory parameters changed to IgG: 73 g/l, GFR: 14 ml/min, therapy with melflufen 20 mg was initiated in 08/2023. In 01/2024, after 6 cycles of dose reduced melflufen, IgG was 58.32 g/dl, GFR changed to 25 ml/min, and no severe side effects occurred. After 6 mo, the disease progressed again and KCyd was administered. One month later, the patient was admitted to the emergency room due to infection and metabolic acidosis. He deceased one month later due to an accident with cerebral trauma.

Conclusion: Both clinical cases showed that melphalan flufenamide (melflufen) can be administered in a reduced dose of e.g. 20 mg and is a highly effective and well-tolerated therapy in patients with severely reduced renal function (GFR < 30 ml/min). Even in heavily pretreated patients (> 5 prior treatments), no severe side effects occurred with melflufen, and the therapy led to long-lasting response. Therefore, melflufen represents a highly effective treatment option for this group of frail patients and with close monitoring and dose reduction can even be applied in patients with severe renal insufficiency.

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2025
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