Treatment Advances Updates for Monoclonal Gammopathy of Renal Significance (MGRS)

Monoclonal gammopathy of renal significance (MGRS) is a rare complication of plasma disorders in which abnormal M proteins damage the kidneys. Over time, this often leads to a loss of kidney function. Recent studies have explored new therapies and real-world outcomes that offer hope but also highlight ongoing obstacles.

In this article, you will find three key updates on MGRS treatments, their impact on kidney health, and the questions that remain for patients and researchers.

Isatuximab to improve kidney function in people with MGRS

An ongoing clinical trial (NCT04614558) is evaluating how isatuximab, a monoclonal antibody, can help people with MGRS.

In this study, people with MGRS who had high levels of protein in their urine but well-functioning kidneys received six cycles of isatuximab. Protein in the urine, also called proteinuria, can be a sign of kidney damage. 

Isatuximab was generally well tolerated, with manageable side effects. Kidney function improved in 87% of patients, meaning people had proteinuria reduction of 67%, and a median time to response of 90 days. Only one person progressed to end-stage renal disease. 

These are early results and the clinical trial is still ongoing. More research is required to determine if isatuximab is an effective therapeutic option for people with MGRS.

Combination therapies to treat MGRS, yet PGNMID and heavy proteinuria remain high-risk factors

Because MGRS disorders are rare, it can be challenging to diagnose and treat. A recent analysis shared real-world data about 31 people with MGRS to help better understand these disorders and how they may affect people.

The most common findings were proliferative glomerulonephritis with monoclonal immune deposits (PGNMID), light chain deposition disease (LCDD), and light chain proximal tubulopathy (LCPT). Patients were typically diagnosed in their early 60s, and nearly 40% presented with nephrotic range protein in the urine. 

Most received combination therapy that frequently included bortezomib, cyclophosphamide, and daratumumab, leading to a 58% renal response rate after first-line therapy and additional stability in 20%. At a median follow-up of 29 months, two-year renal progression-free survival was 77%, though patients with PGNMID or heavy proteinuria had worse outcomes. These findings underscore the need for biomarker development and larger collaborative studies to standardize management in MGRS.

Real-world data show strong responses in MGRS, but relapse remains a key challenge

Because MGRS is so rare, it is difficult to monitor the long-term results of novel therapies. A real-world study of 26 patients with biopsy-confirmed MGRS treated between 2014 and 2024 examined outcomes. Most patients had proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) or C3 glomerulopathy, with advanced kidney involvement at diagnosis. Treatment approaches included proteasome inhibitor–based regimens, often combined with daratumumab and, in some cases, autologous stem cell transplantation. 

Most of the participants (70%) achieved complete or very good partial response, and 83% had renal response. At a median follow-up of five years, the overall survival was 84%, but relapse-free survival was only 50%. This highlights the challenge of disease recurrence despite initial treatment success. These findings emphasize the effectiveness of clone-directed therapy while underscoring the need for novel strategies to improve long-term disease control in MGRS.

More research is required to fully expand treatment options for MGRS, it can be accelerated with people’s participation in clinical trials 

Taken together, these studies reflect both progress and limitations in the treatment of MGRS. For people living with MGRS, these findings highlight the importance of ongoing clinical trials, biomarker development, and the exploration of new therapies to secure longer-term kidney health.

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