MGUS to myeloma

Chapters

[00:00] Introduction of Professor Hilda Quach
[01:14] The Improving Survival Landscape in Myeloma
[03:27] What is Multiple Myeloma?
[05:31] The Disease Spectrum: MGUS to Smouldering to Active Myeloma
[09:13] What Causes Progression from MGUS to Myeloma?
[10:31] Risk of Progression: MGUS vs. Smouldering Myeloma
[11:44] Identifying High-Risk Smouldering Myeloma
[13:52] Modern Myeloma-Defining Events: CRAB & SLiM CRAB Criteria
[15:20] The Pathobiology of Myeloma: A Three-Part Problem
[17:50] Evolution of Myeloma Treatment: Chemotherapy to Immune Therapy
[19:02] Depth of Response: From Partial to MRD Negativity
[20:29] The Concept of “Operational Cure”
[21:16] The Critical Role of the Immune System
[23:45] Immune Therapies: CAR T-Cells and Bispecific T-Cell Engagers
[27:10] The Future: Personalized Therapy (e.g., BCL2 Inhibitors)
[28:51] Accessing New Treatments: The Vital Role of Clinical Trials
[30:02] Q&A: Why is Myeloma Incidence Increasing?
[31:12] Q&A: The Availability and Use of MRD Testing in Australia

Transcript

[00:00] Our first speaker today is Professor Hilda Quach who is the departmental head of clinical haematology and clinical haematology research at St. Vincent’s Hospital in Melbourne and professor of haematology at the University of Melbourne. She is passionate about increasing therapy options and ensuring access to effective treatment. I will now hand you over to Professor Quach who is going to speak to us about MGUS to myeloma.

[01:14] Thank you, Deborah. I want to start on a positive note: there has been a significant improvement in survival for people with multiple myeloma over recent decades. Back before the 1990s, average survival was less than two years. With autologous stem cell transplant, survival improved to 3-4 years. With immunomodulatory drugs and proteasome inhibitors, survival improved to 5-6 years. Currently, median survival is around seven years. We are heading towards overall survival in excess of 20 years and starting to talk about the concept of “operational cure”—living with a disease that does not progress.

[03:27] What is multiple myeloma? It is a blood cancer involving plasma cells, which normally produce antibodies. When they overgrow in the bone marrow, they produce abnormal antibodies called paraprotein, which we detect in the blood. There are various types: IgG, IgA, IgD, or light-chain myeloma. If left untreated, myeloma causes end-organ damage: bone lesions (lytic lesions), high calcium, kidney damage, anemia, low blood counts, and increased infection risk.

[05:31] We now know all myeloma is preceded by a pre-malignant condition called MGUS (monoclonal gammopathy of undetermined significance). In MGUS, abnormal cells produce paraprotein but are “sleeping” and cause no damage. About 5% of people over 55 have MGUS. With time, these cells may grow. If they occupy >10% of the bone marrow but are still “asleep,” it’s called smouldering multiple myeloma. If they grow and cause damage, it becomes active (symptomatic) myeloma. The risk of MGUS progressing to myeloma is about 1% per year. The risk for smouldering myeloma is more variable.

[09:13] What causes progression? It’s based on three factors: 1. Increasing genetic abnormalities in the plasma cells themselves. 2. Changes in the bone marrow “microenvironment” (the fertile soil). 3. Progressive immune dysfunction, where the immune system fails to control the myeloma cells.

[10:31] This curve shows the risk of progression. For MGUS (bottom line), the risk is stable at 1% per year. For smouldering myeloma (top curve), the risk is highest at diagnosis (about 10% per year), then decreases after 5 and 10 years if no progression occurs.

[11:44] There is a subgroup with “high-risk” smouldering myeloma, defined as a >50% chance of developing end-organ damage within two years. We identify them using four parameters: light chain level, paraprotein level, percentage of bone marrow involved, and myeloma cell genetics. Based on a risk score, we divide patients into four groups. The high-risk group has a 75% chance of progression in two years. For this group, research is exploring whether earlier treatment is beneficial. However, the current standard is still watchful waiting.

[13:52] So, what defines active myeloma? Traditionally, we wait for end-organ damage, remembered by the acronym CRAB: high Calcium, Renal damage, Anemia, Bone lesions. Now, even without CRAB features, we treat if there’s a >90% risk of damage within two years. These new criteria are called SLiM CRAB: 60% bone marrow involvement, Light chain ratio >100, or more than one lesion on MRI. So, the new diagnostic criteria are CRAB and SLiM CRAB.

[15:20] To understand treatment, let’s look at myeloma’s pathobiology. It’s a three-part problem: 1. The myeloma cells themselves. 2. The fertile bone marrow microenvironment. 3. Impaired immune function. In the past, chemotherapy only killed myeloma cells. Newer drugs (immunomodulators, proteasome inhibitors) also disrupt the microenvironment. We are now in the era of immune therapies that address the immune impairment.

[17:50] We are heading towards an era of small molecules and combination therapies that address all three problems, aiming for deep responses. Think of myeloma like an iceberg. A partial response means reducing the burden by 50%. A complete response (CR) means no detectable disease by conventional tests. Minimal Residual Disease (MRD) negativity means less than one cancer cell in 100,000 normal cells—a very good prognosis.

[19:02] Achieving MRD negativity is a powerful predictor of long remission, but it’s not the only goal. The duration of response is equally important.

[20:29] This leads to “operational cure.” If a response is maintained for many years (e.g., 12+ years), the immune system seems to regain control, and the person lives with myeloma as if it were MGUS. This can happen even in patients who only achieved a partial response, not just a deep response.

[21:16] The immune system’s role is critical. In health, immune cells (like antigen-presenting cells and T-cells) recognize and kill cancer. In myeloma, the cancer cells corrupt this process, downregulating recognition molecules and turning immune cells “blind.”

[23:45] New immune therapies overcome this. CAR T-cells are a patient’s own T-cells genetically engineered with a “cyborg arm” to specifically target myeloma cells. Bispecific T-cell engagers are man-made molecules with one arm binding to the myeloma cell and another to the T-cell, forcing the T-cell to recognize and kill the cancer. Both are exciting new treatments.

[27:10] We are entering an era of personalized therapy. For example, about 20% of patients have a specific genetic change (t(11;14)) that makes their myeloma exquisitely sensitive to a drug class called BCL-2 inhibitors (e.g., venetoclax). These drugs force the cancer cells to commit suicide.

[28:51] Many of these new agents are accessed through clinical trials. In Australia, while we have good standard care via the PBS, clinical trials offer access to cutting-edge treatments not yet widely available. I encourage you to discuss trial options with your doctor.

[30:02] Q&A: Why is the incidence of myeloma increasing? I don’t think it’s the biology. We are more aware, detecting more MGUS, and monitoring people closer. There may be environmental factors, but we don’t know. The increase is a global trend.

[31:12] Q&A: Is MRD testing done in Australia? Yes, but it’s not routine. The main reason is that, with current limited treatment options, a result doesn’t always change what we do. It’s a prognostic tool, not yet a standard guide for therapy. However, future trials will explore MRD-directed treatment, and we need to push for its availability.