Presentation, medical history and initial treatment
A 69-year-old male, a retired school bus driver, presented to our medical unit in October 2023 with binocular diplopia and an Eastern Cooperative Oncology Group (ECOG) performance status of 0. His medical history included gout and hyperlipidaemia managed with medications. Investigation revealed a pituitary macroadenoma, for which a transsphenoidal excision was performed in March 2024.
On the day following surgery, acute kidney injury was noted, with serum creatinine (sCr) rising from 95 to 219 μmol/L. Significant proteinuria was observed, with spot urine protein-to-creatinine ratio (uPCR) reaching 6.06 mg/mg. A glomerulonephritis workup revealed a free lambda light chain (λ-LC) band on serum protein electrophoresis, with a serum free light chain (SFLC) ratio of <0.01 (κ, 12.0 mg/L; λ, 1,801 mg/L). The patient’s haemoglobin (Hb) level was 10–11 g/dL. He reported no bone pain, and there were no osteolytic lesions on X-ray or signs of hypercalcaemia.
Bone marrow examination on 26 March 2024 showed 48 percent clonal plasma cells with λ-LC restriction. Fluorescence in situ hybridization (FISH) revealed deletion of TP53 (17p13.1) in 94 percent of cells and a gain of CKS1B (1q21) in 55.5 percent. The patient was classified as stage III according to the Revised International Staging System (R-ISS) due to elevated beta-2 microglobulin at 8.14 μg/ mL and cytogenetic findings. A renal biopsy on 23 April 2025 confirmed cast nephropathy, and the diagnosis of multiple myeloma (MM) with cast nephropathy was communicated on 8 May 2024.
VTd (bortezomib, thalidomide, dexamethasone) under the Hospital Authority’s safety net as well as self-financed upfront DRd (daratumumab, lenalidomide, dexamethasone) were offered as treatment options to the patient. Due to financial concerns, the patient opted for the VTd regimen. Treatment commenced on 13 May 2024, with monthly intravenous zoledronic acid or denosumab (depending on renal function) starting on 18 June 2024.
After three cycles of VTd, his renal function declined, with sCr rising from 150 to 200 μmol/L despite a stable SFLC ratio of 0.01 (κ, 16.67 mg/L; λ, 1,173 mg/L). Given the worsening renal function and insufficient myeloma control, an application was made to the Samaritan’s Fund for the DRd regimen to be used.
Treatment with DRd and outcome
The first cycle of DRd began on 26 July 2024, with daratumumab 1,800 mg administered subcutaneously weekly, lenalidomide 5 mg orally daily for days 1–21 (dose reduced for suboptimal renal function), and dexamethasone 40 mg orally weekly.
At the 6th week of DRd treatment, the patient’s SFLC ratio improved to 0.29 (κ, 9.83 mg/L; λ, 34.29 mg/L) — a significant reduction from previous levels. His sCr stabilized from 200 to 160–180 μmol/L, and uPCR normalized. Notably, the patient experienced no major side effects, except for a single episode of nonfebrile salmonella gastroenteritis in September 2025 (around 60 weeks of DRd).
At the latest consultation on 7 November 2025, the patient had completed 69 weeks of DRd. His functional status remained good (ECOG 0) without fever, bone pain, or lower limb oedema. His Hb was 11–12 g/dL, sCr was 169 μmol/L, calcium levels were normal, and SFLC ratio had stabilized.
Discussion
Despite significant improvements in survival from immunomodulatory drug (IMID)–based and proteasome inhibitor (PI)–based combination regimens, MM remains a chronic, incurable disease. Survival benefits are less pronounced in older patients, with median survival decreasing from 5.2 years in those aged <50 years to just 2.6 years in patients aged ≥80 years.1 Ageing is often associated with organ dysfunction, reduced functional status, comorbidities and frailty, all of which can adversely affect the ability to tolerate aggressive MM treatment.1 Consequently, there is a critical unmet need for effective treatment options with a favourable benefit/risk profile, particularly for older patients who are not eligible for transplantation, as exemplified by our patient.
Daratumumab, a human monoclonal antibody targeting CD38, binds to this glycoprotein expressed on MM cells. This binding inhibits tumour growth through direct apoptosis and immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis.1 When combined with lenalidomide and dexamethasone (Rd), daratumumab demonstrates a superior survival advantage in patients with relapsed or refractory (R/R) MM.2
The phase III pivotal POLLUX study in patients with R/R MM (n=569) demonstrated an unprecedented progression-free survival (PFS) of 44.5 months for the DRd group vs 17.5 months for the Rd group (hazard ratio [HR], 0.44; 95 percent confidence interval [CI], 0.35–0.55; p<0.0001). The overall response rate was significantly higher in the DRd group (92.9 vs 76.4 percent; p<0.0001), with deep responses achieved more frequently (30.4 vs 5.3 percent).2 Notably, substantial improvements in overall survival (OS) were also observed with DRd at a follow-up of 79.7 months (HR, 0.73; 95 percent CI, 0.58–0.91; p=0.0044).3
Given these results, DRd represents a viable treatment option for patients with R/R MM previously treated with IMIDs or PIs and are willing to receive parenteral medication. While the POLLUX study highlighted that patients with 1–3 prior lines of therapy benefited significantly from DRd, those with only one prior line of therapy experienced the greatest clinical benefit, with a 58 percent reduction in risk of disease progression or death vs Rd alone.2 Moreover, significant PFS benefits were noted across various subgroups, including patients aged ≥65 years, failing one prior line of therapy, having impaired renal function, being lenalidomide-naïve, having high-risk cytogenetic profiles, and of Asian ethnicity, all of which align with our patient’s profile.2,4
Treatment-emergent adverse events (AEs) were common with DRd and Rd, and included neutropenia, febrile neutropenia, anaemia, thrombocytopenia, lymphopenia, pneumonia, diarrhoea and fatigue.2 However, the rates of AEs leading to treatment discontinuation were comparable between the two groups (14.8 vs 14.6 percent).2 Similar findings were reported in older age groups (≥65 years old).1 In our clinical experience, most patients tolerate DRd well, and granulocyte colony–stimulating factor support is effective in managing neutropenia.5 In severe cases, we suspend 1–2 doses of treatment until the AEs are resolved. We also monitor patients closely for infection risk and immunoglobulin G (IgG) levels; if hypogammaglobulinemia develops with IgG levels <5 g/L, we administer intravenous immunoglobulin replacement.5 Withholding daratumumab is infrequently needed; intolerable toxicities are sometimes attributed to lenalidomide, necessitating dose adjustments. For our patient with impaired renal function, we proactively reduced the lenalidomide dose to enhance tolerability and adherence.5
Our case illustrates the efficacy and safety of DRd in an older, lenalidomide-naïve patient with a high-risk cytogenetic profile (del17p) and impaired renal function. He achieved a deep and durable response while maintaining good quality of life with minimal side effects, highlighting DRd as a suitable and effective treatment option for older, transplant-ineligible patients with high-risk R/R MM.
