Transcript
00:02] Introduction of Professor Andrew Spencer
Deborah: So I would like to warmly welcome Professor Andrew Spencer. Professor Spencer is head of the malignant hematology and stem cell transplantation service at the Alfred Hospital, professor of hematology at Monash University and group leader of the myeloma research group within the Australian Centre for Blood Diseases in Melbourne. He has been an invited speaker to numerous international meetings on genomics, therapeutics and disease monitoring in multiple myeloma. He serves on the scientific advisory boards of the International Myeloma Foundation and the International Myeloma Working Group and chairs the Myeloma and Related Diseases Registry and the Australasian Myeloma Research Consortium. So great to have you with us today Andrew and over to you.
Prof. Andrew Spencer: Thank you very much Deborah for that kind introduction.
[00:57] The Core Question: Why Is My Myeloma Unique?
So my topic today is “Why is my myeloma so unique?” This is a very complex question. I’ve taken the position to try and explain this by saying what are the various factors which impact how your myeloma behaves. I think the way to look at this most sensibly is to think about the disease itself, to think about you the patient, and then to think about your treatment. All of these things influence how your myeloma behaves.
[02:11] The Disease: Spectrum of Plasma Cell Disorders
First, if we think about the disease itself, myeloma is one of a complicated group of disorders called plasma cell dyscrasias, characterized by abnormal populations of plasma cells. Plasma cells normally reside in the bone marrow and are the cells that make antibodies. There’s a whole pile of other disorders which affect plasma cells, and sometimes it can be very difficult differentiating some of them from multiple myeloma. The commonest plasma cell disorder is monoclonal gammopathy of undetermined significance (MGUS). Everybody that has myeloma has had MGUS before they got myeloma. We know that only 1% of patients with MGUS each year will develop myeloma. So there’s dramatic differences even at the MGUS level.
[04:27] Inside the Bone Marrow: Clonal vs. Polyclonal Plasma Cells
The cardinal features of myeloma are anemia, kidney problems, bone problems, high calcium, the presence of a paraprotein, and risk of infection. This is what the bone marrow looks like with multiple myeloma. These cells are plasma cells. In myeloma, they are clonal (all the same). Whereas in an individual without myeloma, the cells are polyclonal (making different antibodies). Patients with myeloma have a massive expansion of clonal plasma cells which don’t make useful antibodies and they pack out the bone marrow.
[05:06] The Paraprotein “Smoke Signal” & Different Types
One cardinal feature is that it makes, in most cases, a protein detectable in blood called a paraprotein. We look at proteins with a test called serum protein electrophoresis (SPE). In a healthy person, the gamma globulin region shows a broad smear representing all different antibodies. In a person with myeloma, that is replaced by a sharp band or “M band” – the paraprotein. It’s like smoke to a fire; it’s the biomarker your doctor monitors. But this biomarker is different in different patients. A paraprotein is made of four bits: two heavy chains (IgG, IgA, etc.) and two light chains (kappa or lambda). About 20% of myelomas only make light chains (light chain myeloma). Lambda light chains have a greater tendency to affect the kidneys.
[08:14] Identifying Your Specific Paraprotein Type
We identify what sort of paraprotein people have with a test called immunofixation. This tells us, for example, if it’s an IgG kappa myeloma.
[08:54] Genetic Complexity: Subclones & Spatial Heterogeneity
The trouble is, even though the plasma cells are clonal, within that population there are distinct little families or subclones. Each patient might have different subclones, which is why it’s such a variable or heterogeneous disease. We’ve done DNA sequencing of abnormalities in plasma cells. In one patient, we did a biopsy of the bone marrow and a rib lesion and showed they were quite different genetically. Even in the same patient the disease can be different at different locations – what we call spatial genomic heterogeneity. This can underlie why, when we treat, parts of the body get better but others might not.
[11:05] Clinical Features at Diagnosis: Symptoms vs. Signs
When you’re suspected of having myeloma, you’ll have tests like blood count, kidney function, protein electrophoresis. It’s important to understand the difference between symptoms (what the patient complains of, like bone pain, tiredness) and signs (objective things on X-rays or blood tests). Looking at symptoms: the commonest is bone pain (58% of patients), but that means 42% didn’t. A quarter had weight loss, but three-quarters didn’t. Looking at signs: most have a paraprotein. About two-thirds have evidence of bone lesions on scans, but one-third don’t. Some never get bone lesions. A lot of people get anemia, but a quarter don’t. These features can be very different.
[13:43] Bone Disease: Lytic Lesions & Skeletal Events
These are X-rays showing lytic lesions – little holes or punched-out lesions in the bone due to abnormal plasma cells. They are a cardinal feature; some patients have them and some don’t. They can occur in critical areas like the spine. The different skeletal-related events patients can get include fractures, spinal cord damage, needing radiation, or needing surgery (like prophylactic rods in bones). If you mix and match these, you see a dramatic difference between patients.
[15:55] The Patient: Impact of Age & Overall Health
Now speaking about the patients themselves. Myeloma is largely a disease of older people (average age ~70), but there are young patients in their 30s and 40s. The age of the patient has a significant impact. Data from the Australian registry shows a significant difference in outlook for patients under 70 versus over 70. This is driven largely by the fact that older patients have more significant health issues (heart disease, lung disease, etc.), which impacts how well they tolerate the disease and its treatment. We’ve studied patient-related factors: age over 75, cardiac disease, pulmonary disease – these increase the odds of a worse outcome largely because they impact how you can treat the patient. These different patient characteristics add to why the disease in an individual is unique.
[19:39] Treatment: Standard Pathways & Response as an Arbiter
The disease responds to treatment but then after a variable period relapses – it could be within months or over 10 years in patients receiving the same therapy. That’s driven by the underlying disease biology; there are “good versions of a bad disease” and “bad versions.” The major decision in Australia boils down to transplant eligibility. Transplant-eligible patients get induction therapy, a transplant, possibly more therapy, then maintenance. Non-eligible patients get similar induction therapy continued ongoing, usually followed by lenalidomide maintenance.
[21:36] The Power of Minimal Residual Disease (MRD) Testing
What about response to treatment as the final arbiter? We now have super-sensitive tests for Minimal Residual Disease (MRD), which can pick up one myeloma cell in 100,000 normal cells. Data shows patients who achieve MRD negativity and go on to maintenance therapy stay in remission significantly longer than those who do not. The response to therapy and interaction with ongoing therapy is a huge determinant of how the disease behaves.
[23:55] Summary: The Triad of Disease, Patient & Treatment
So, there are disease characteristics, patient characteristics, and treatment variation/response. All of which impact how your myeloma behaves, and we only have control over some of those elements. That’s why you can have a room full of people with myeloma and it’s all behaving differently.
[24:34] Q&A: Difficulty of Personalized Treatment & Frailty
Deborah: You explained the uniqueness and complexity. This almost makes it incredibly difficult to treat person to person. Can you expand?
Prof. Spencer: One real issue is that for reasons (like limited therapy options on the PBS), we treat everybody largely the same way at first presentation, apart from transplant vs. no transplant. This belies the massive variation in prognosis. I think a more personalized approach is coming. At the moment, we treat optimally with available therapies. The one variation is for very elderly/frail patients, where we may adjust to ensure treatment isn’t too toxic, as keeping people on treatment is critical.
[27:22] Q&A: Preventing Progression from Smouldering Myeloma
Peter’s Question: With smouldering myeloma, it’s hard to sit still and wait for the inevitable. Is there anything we can do to prevent it moving into myeloma?
Prof. Spencer: A couple of points. For MGUS, only a small proportion ever develop myeloma; you’d all have to live 100 years. With smouldering myeloma, only about 50% will get active myeloma. It’s not inevitable. The challenge is we can’t accurately identify who will progress. If we had drugs, we’d risk treating many who’d never need it. The real challenge is understanding who’s going to get symptomatic myeloma, and we can’t do that accurately yet.
[29:58] Q&A: The Role of PET Scans in Management
Pauline’s Question: Do PET scans identify different areas affected? Would it help decide what treatment is suitable?
Prof. Spencer: A whole-body low-dose CT scan shows anatomy – is there a bone lesion? A PET scan is functional; it shows areas of active disease, which may or may not match CT lesions. It can also detect disease outside the bone marrow. In most cases, a PET scan at diagnosis won’t change how you’re managed initially. It’s a more sensitive way to gauge extent and monitor response, but it won’t necessarily change management.
[32:25] Q&A: Stopping Lenalidomide Maintenance & Second Cancers
Donna’s Question: What is your opinion on stopping lenalidomide maintenance after three years due to the risk of other malignancies?
Prof. Spencer: This is highly contentious. French studies suggested stopping after two years due to risk of second primary malignancies; American studies say continue until progression. My opinion: if it’s adversely affecting quality of life, you should stop. If you’re tolerating it, you should stay on it. The biggest danger is the myeloma itself. If you’ve succumbed to myeloma, the risk of a second malignancy is irrelevant. The myeloma is the big fish to fry. So, if tolerating it, stay on. If not tolerating it, stop.
[35:40] Q&A: Impact of Kidney Symptoms on Prognosis
Question: Does having renal symptoms make my prognosis worse?
Prof. Spencer: The short answer is yes, but largely because if your kidneys aren’t working properly, it can impact which drugs or what doses are used. The kidney function not working normally has no bearing on how the myeloma itself behaves; it’s a patient factor that impacts treatment. We’ve even had patients get kidney transplants to restore function and open up more therapeutic options. So yes, it impacts how the disease can be managed.
[37:16] Closing Thanks
Deborah: Well, Andrew, thank you so very much today for taking time out of your busy schedule to inform us. It’s been a great talk. Thank you so very much.
