Using bispecific antibodies in a patient with peritoneal dialysis for relapsed multiple myeloma

Introduction

Bispecific antibodies (BsAbs) are an emerging class of immunotherapy agents designed to enhance antitumor immune response by retargeting T-cell specific molecules and tumor-associated antigens. To date, three BsAbs agents—teclistamab, talquetamab, and elranatamab, have been approved by the Food and Drug Administration (FDA) for treating relapsed or refractory multiple myeloma (RRMM). ¹ Despite ongoing research, dose adjustments for BsAbs in patients with renal impairment, particularly those requiring dialysis, remain poorly defined. Renal insufficiency affects 20–40% of MM patients, with 9% requiring dialysis.^2–4 While small studies have reported variable outcomes with BsAbs in MM patients on hemodialysis (HD),^5–7 data on other renal replacement modalities are lacking. Here, we report a case of BsAb use in a patient with RRMM with end-stage renal disease (ESRD) on peritoneal dialysis (PD).

Case report

A 72-year-old post-menopausal woman with ESRD on home PD presented with worsening chronic left arm pain for two months. Her medical history included ESRD on PD, secondary hypercalcemia, vitamin D deficiency, and anemia of chronic disease, and a family history of MM. X-ray of the left arm showed a lytic lesion and pathologic fracture of the humerus, with biopsy confirming a lambda chain plasma cell neoplasm positive for CD138, MUM1, CD117, CD56 and lambda light chain. Bone marrow biopsy (BMBx) showed 20–30% clonal plasma cells. Serum protein electrophoresis (SPEP) revealed an M-spike (Alpha 2 globulin 1.6 g/dL). Lambda free light chain (FLC) was significantly elevated (16262 mg/L) and Serum beta-2-microglobulin was 18.7 mg/L. Positron emission tomography/computed tomography (PET/CT) demonstrated extensive skeletal involvement (Figure 1 A-D). A final diagnosis of MM was made.

OPEN IN VIEWER

Figure 1.

PET/CT before and after Dara-CyBorD. A-D: red circles indicate the areas of increased radiotracer uptake within the bone marrow of left femur and right iliac wing before Dara-CyBorD; E-H: red circles indicate the areas of increased radiotracer uptake within the bone marrow of left femur and right iliac wing after Dara-CyBorD. Dara-CyBorD: daratumumab, cyclophosphamide, bortezomib, and dexamethasone.

Management and outcomes

Multidisciplinary discussion, including a malignant hematologist and radiation oncologist recommended upfront palliative multi-focal radiation therapy while awaiting surgical evaluation for the possible endometrial malignancy. Daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) were initiated, with dose adjustment based on renal clearance, and she completed six cycles while on home PD with good response, as reflected by improved FLC levels, BMBx, and PET/CT (Figure 1 E-H and Figure 2). Though autologous stem cell transplant was comprehensively discussed, the patient opted for maintenance with daratumumab. Six months later, progression was noted given rising FLC levels, prompting the switch to carfilzomib, lenalidomide, and dexamethasone (KRd) regimen. However, due to suboptimal response and severe diarrhea, this regimen was then discontinued. Subsequently, chimeric antigen receptor T-cell therapy (CAR-T) and BsAbs were offered, and despite limited data of using BsAbs in patients on PD, the decision was made jointly to start teclistamab while being evaluated for CAR-T, according to the MajesTEC-1 trial (NCT03145181) dosing. ⁸ After five months of weekly injection, the patient showed significant improvement in SPEP and FLC levels demonstrated great response (Figure 2), and prompting a switch to monthly maintenance therapy. Patient tolerated the teclistamab well with no hematologic adverse events (AE), but she endorsed intermittent fatigue and generalized itchiness. Unfortunately, the FLC levels rose again (Figure 2) around 8 months after the initiation of teclistamab. Given patient had excellent response to BsAbs, we reviewed the data and evidence of talquetamab in MonumenTAL-1 trial (NCT03399799) ⁹ and decided to start this regimen. After a week of step-up dosing, patient started every-two-week dosing, and initially had decrease of FLC but rebounded again (Figure 2), but overall, she tolerated talquetamab with no AE reported. She was then started on elotuzumab, pomalidomide, and dexamethasone with no response. Selinexor was then initiated as bridge to CART therapy which she is being prepared for. Patient's written consent was obtained for publication.

OPEN IN VIEWER

Figure 2.

Lambda free light chain trend with treatment timeline. Post C: post cycle; Post W: post week; Dara-CyBorD: daratumumab, cyclophosphamide, bortezomib, and dexamethasone; KRd: carfilzomib, lenalidomide, and dexamethasone; EPd: elotuzumab, pomalidomide, and dexamethasone.

Discussion

This case reported using BsAbs in a patient on home PD for relapsed MM. Following the failure of multiple prior therapies, BsAbs agents were used based on MajesTEC-1 and MonumenTAL-1 trial protocol, resulting in significant improvement in FLCs. However, the response to both products was limited in duration.

Teclistamab and talquetamab both activate cytotoxic T cells via CD3, with teclistamab targeting B-cell maturation antigen (BCMA) and talquetamab targeting G protein–coupled receptor, class C, group 5, member D (GPRC5D) on MM cells, leading to selective myeloma cell killing through T-cell-mediated cytotoxicity.^10,11 The MajesTEC-1 trial showed that teclistamab achieved an ORR of ∼63%, while the MonumenTAL-1 trial demonstrated that talquetamab achieved an ORR of ∼74% (0.4 mg/kg weekly) and ∼73% (0.8 mg/kg every 2 weeks).^8,9 Both products were subsequently approved by the FDA for relapsed or refractory MM. ¹² Both agents showed no significant differences in patients with mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 ml/min/1.73m²].^10,11 However, the data on its pharmacokinetics and efficacy in patients with severe renal impairment (eGFR: 30 ml/min/1.73m²) or ESRD on dialysis remains unknown.^10,11

The clearance of BsAbs involves an endocytosis elimination process called target-mediated drug disposition (TMDD). ¹³ Additionally, renal clearance can also play a role, particularly in patients with renal dysfunction, as the ability to clear certain antibody fragments may be impaired.^13,14 In patients on dialysis, the contribution of TMDD can be more pronounced due to significantly reduced renal clearance, which could influence the circulation concentration of BsAb, but it remains poorly understood. ¹³

In real-world studies, small cohorts have reported promising results with teclistamab in patients with severe renal dysfunction, including those on dialysis. One cohort of seven patients, including four on hemodialysis (HD), showed that five patients achieved very good partial response (VGPR), while two had disease progression. ⁷ Similarly, a French study involving 13 patients with ESRD on dialysis demonstrated that all patients achieved VGPR or better, although the dialysis modality was not specified. ⁵ A study by Nachar et al. reviewed four patients on HD who completed teclistamab step-up dosing and at least one full dose, with favorable response observed. ⁶ However, data specific to RRMM patients on PD remain scare. No real-world data regarding the use of talquetamab in RRMM patients on dialysis have been reported yet.

As for toxicity profile in our patient, she experienced only mild toxicities during treatment with teclistamab, specifically fatigue and intermittent pruritus, both of which were manageable and did not require treatment interruption or dose modification. Notably, she did not experience cytokine release syndrome (CRS), neurotoxicity, or hematologic toxicity, which are commonly reported in clinical trials. In the MajesTEC-1 trial, CRS occurred in approximately 72% of patients, and neurotoxicity in 14%. ⁸ During treatment with talquetamab, the patient did not report any treatment-related toxicities. This is particularly relevant considering that the MonumenTAL-1 trial reported CRS in 77% of patients and skin-related toxicities such as rash and nail changes in over 50%. ⁹ Despite the patient's ESRD on PD, she did not exhibit increased toxicity risks, suggesting that BsAb pharmacokinetics and immune-mediated toxicities may not be significantly altered in the setting of peritoneal dialysis. Nevertheless, further studies are needed to confirm safety in this population.

Compared to HD, PD is more permeable to larger molecule, including proteins such as albumin, which increases the risk of malnutrition and hypoalbuminemia. ¹⁵ While the PD membrane permeability to proteins is variable, given its prolonged time of dialysis, its clearance of BsAbs remains unclear. In our case, for teclistamab, the patient achieved VGPR 2 weeks after initiation and maintained CR for 7 months before she relapsed (Figure 2); for talquestamab, VGPR was achieved 1 month after the first dose however, the FLCs went up significantly three months after. These findings, along with existing data, suggest that both teclistamab and talquestamab hold potential for use in MM patients on HD or PD, despite the limited generalizability of this case.

Conclusion

Overall, our case demonstrates both teclistamab and talquestamab may be an effective treatment for relapsed or refractory MM in this population. This an example to show its efficacy in patients receiving peritoneal dialysis, and further studies are needed to explore the pharmacokinetics, optimal dosing, and long-term outcomes of this approach.