Systemic Therapy For Mucosal Melanoma

The uncommon and aggressive kind of melanoma known as mucosal melanoma (MM) is caused by melanocytes found on the mucosal surfaces of the body, including the gastrointestinal, respiratory, and urogenital tracts. MM differs from cutaneous melanoma (CM) in that it has a different biological behaviour and a worse prognosis. The systemic therapeutic options for mucosal melanoma are examined in this article, with an emphasis on current developments, obstacles, and potential future paths for treatment.

Introduction

Only a small portion of melanoma cases are mucosal melanoma, and its frequency is noticeably higher in some cultures, especially Asians.¹ Treatment options are greatly complicated by the aggressive character of this disease and its rarity, which frequently results in advanced-stage presentation and delayed diagnosis. Less than 20% of MM patients survive for five years on average, underscoring the critical need for efficient treatment approaches.^2,4 Mucosal melanoma affects internal organs, primarily those in the gastrointestinal, respiratory, and urogenital tracts, in contrast to cutaneous melanomas. Your mouth, nose, sinuses, throat, stomach, gallbladder, intestines, vagina and vulva, and anus can all develop mucosal melanoma. It is yet unknown what causes mucosal melanoma. It is not linked to UV radiation exposure, in contrast to cutaneous melanoma. Rather, gene mutations have been linked to certain mucosal melanomas.⁶

Differences between mucosal and cutaneous melanoma

There are some significant differences between cutaneous and mucosal melanoma.

• Epidemiology: Unlike CM, which is primarily linked to UV exposure, MM is less prevalent and more often develops in non-sun-exposed parts of the body
• Genetic Mutations: About 50% of patients with MM have c-KIT mutations, which are common in genes like BRAF, NRAS, and MM. Treatment outcomes and effects are influenced by this genetic variability^2,4

Clinical Presentation: Bleeding, discomfort, and blockage are some of the symptoms of multiple myeloma (MM), which can cause a delay in diagnosis. On the other hand, CM frequently manifests as easily identifiable, visible skin lesions.^2,4 

Stages of mucosal melanoma

Although they all adhere to a similar melanoma staging framework based on tumour progression, lymph node contribution, and metastasis, the staging standards for mucosal melanoma differ from the ones for cutaneous melanoma.⁶

The AJCC-TNM staging approach, also known as the Tumour, Node, and Metastasis (TNM) staging system, is utilised for the staging of mucosal melanoma of the head and neck, vulva, and vagina.⁶

These mucosal melanoma areas are staged as follows:

T3: Mucosal illness is identified and diagnosed initially.
T4A: The Deep soft tissue, the skin above it, and the cartilage are now affected by moderately advanced mucosal illness.
T4B: Highly developed mucosal illness now affecting any or all of the aforementioned structures and tissues: The base of the skull, lower cranial nerves managing the throat and voice box, neck muscles, and tongue masticator muscles (used for chewing) are all part of the brain's dura mater, which is the outermost layer of the meninges in the brain.
carotid arteries in the neck, mediastinal tissues such as the trachea, heart, blood vessels, lymph nodes in the chest, and prevertebral space.⁶
There is currently no established staging classification for mucosal melanomas of the vagina or the anorectum. As a result, the following fundamental clinical stage classification scheme is usually applied:

Stage 1: Localised tumours of mucosal melanoma
Stage 2: Local lymph nodes have been affected by the cancer's dissemination
Stage 3: The malignancy has metastasised or spread to other organs and areas⁶

Systemic therapy options

Surgery is usually the initial course of action when a patient gets diagnosed with mucosal melanoma, much like with cutaneous melanoma. Early detection is crucial for many diseases, including mucosal melanoma, however, it can be challenging in this case. Because tumours can have very generic symptoms that vary depending on where they have formed, diagnosis can frequently be challenging. Mucosal melanoma is still an extremely difficult illness to cure, even with major advancements in knowledge and treatment. For people who have cutaneous (skin) melanoma, the novel immunotherapy and targeted therapies have benefited outcomes; however, they are less effective in mucosal melanoma.⁷

Immunotherapy

With multiple medicines licensed for use against advanced melanoma, immunotherapy has completely changed the landscape of melanoma treatment. In contrast to CM, the effectiveness of these treatments in MM has not been as strong.

• Checkpoint Inhibitors: Although they have demonstrated potential in treating MM, agents such as ipilimumab (anti-CTLA-4) and nivolumab or pembrolizumab (anti-PD-1) typically have lower response rates than those observed in CM. According to clinical trials, PD-1 inhibitor response rates in multiple myeloma (MM) fluctuate between 26% to 44%⁴
• Combination Therapies: Nivolumab with ipilimumab together have shown better results in CM, while their efficacy in MM is still being studied. Relatimab, an anti-LAG-3 antibody, and nivolumab may open up new therapeutic options, according to a recent trial, albeit MM-specific data are not forthcoming⁴

Specialised treatment

Targeted therapy aims to utilise certain genetic abnormalities found in tumour cells. Limited but developing targeted therapeutic options are available for MM. Targeted treatments like imatinib have been investigated because of the high frequency of c-KIT mutations in multiple myeloma (MM). The total benefit is still small, even though some patients have demonstrated partial responses, which calls for greater research into more potent targeted agents.^1,2

Combination with Immunotherapy: Current research assesses whether certain mutations can be treated more effectively in patients receiving immunotherapy with targeted therapies.⁴

Chemotherapy

Chemotherapy has always been a staple for treating melanoma, but it's unclear how it works for MM.

• Adjuvant Chemotherapy: In resected MM patients, a randomised trial evaluated the effectiveness of temozolomide plus cisplatin chemotherapy and high-dose interferon-alpha. Although there was a tendency towards better survival with chemotherapy, all treatment groups' prognoses were still dire¹
• Palliative Chemotherapy: Chemotherapy is frequently saved for palliative treatment in advanced cases because of the aggressive character of MM and the low efficacy of systemic therapies²

Difficulties during therapy

Despite progress in systemic therapy, several obstacles still exist in the treatment of multiple myelitis:

• Late Diagnosis: Because early-stage multiple myeloma is asymptomatic, it frequently takes longer to diagnose, culminating in advanced stages at presentation. This severely restricts the efficacy of systemic treatments
• Reduced Clinical Trials: Standardised treatment strategies are challenging to establish due to the scarcity of clinical trial data resulting from the uncommon nature of multiple myeloma. The majority of the evidence that is currently available originates from CM data or short studies, which might not apply directly^1,4
• Heterogeneity of reaction: Developing successful treatment plans is made more difficult by patients with MM's variable reaction to treatment. To maximise treatment success, genetically tailored strategies might be required^2,4

Prospective paths

There are various potential avenues for systemic treatment for mucosal melanoma in the future.

• Biomarker Development: By pinpointing particular biomarkers linked to therapy response, medicines can be more individually tailored to each patient, leading to better results. Intending to find new targets for treatment, investigations into the genetic and molecular background of MM are still underway⁴
• Novel Therapeutics: It is imperative to investigate novel medicines, such as those that target distinct pathways implicated in the growth of melanoma. Additional therapeutic options may be provided by novel treatments that target immune regulation and the tumour microenvironment^2,4
• Combination Strategies: Researching the possibility of combining current treatments, like targeted therapy and immunotherapy, may improve the effectiveness of treatment. To assess each of these combinations in the setting of multiple myeloma (MM), additional clinical trials are necessary^1,4

Conclusion

Because of its uncommon appearance and advanced-stage diagnosis, mucosal melanoma (MM), an uncommon and destructive form of melanoma, poses major treatment hurdles. MM is not linked to UV exposure, in contrast to cutaneous melanoma (CM); however, it frequently results from genetic alterations, especially in c-KIT. With a five-year survival probability of less than 20%, the prognosis for people with multiple sclerosis remains bleak, highlighting the dire need for more efficacious treatment approaches.
Comparatively speaking to their effect on CM, systemic medicines for MM, such as immunotherapy and targeted interventions, have had comparatively little success. However, checkpoint inhibitors with lower response rates in multiple myeloma (MM) have potential, such as ipilimumab and pembrolizumab. Although they have some benefits, targeted treatments that target c-KIT mutations have limited overall effectiveness. Chemotherapy is still a palliative treatment with a low success rate.

To overcome these challenges, current research is concentrating on creating personalised therapeutics driven by biomarkers and investigating innovative therapeutic agents that target pathways unique to melanoma. Combination approaches that combine targeted therapies with immunotherapy present a viable way to enhance results.
To improve the prognosis and quality of life for individuals with multiple myeloma (MM), future research endeavours should prioritise prompt detection, thorough clinical trials, and inventive therapeutic modalities. As science progresses, a better comprehension of the distinct biology and genetic background of MM will be essential for creating efficient systemic treatments and enhancing prognosis.