Transcript
[0:00] It is now my absolute pleasure to welcome our first presenter, Dr. Peter Malay. Associate Professor Peter Malay practises as a consultant haematologist in clinical and laboratory haematology at the Princess Alexandra Hospital and is associate professor with the University of Queensland Medical School. He holds appointments with the medical scientific advisory group of Myeloma Australia, the Australian Amyloidosis Network and the national blood cancer task force. He is a past chairman of ALLG and current chair of the Australian Amyloidosis Network. He heads the myeloma service as well as the Queensland Amyloidosis Centre. We are so grateful he’s with us today to present on advances in myeloma treatment in the current Australian climate. Thank you, Peter.
[0:44] Thanks very much, Kath. It’s now my pleasure to talk a little about the role of treatments, particularly new treatments like CAR T and bispecifics, in the current Australian climate. I’d like to thank one of my colleagues, Dr. Cindy Lee in Adelaide, who lent me several of her slides.
This is what I’m going to talk about: an overview of where we are with current therapies, where we’ve come from, and the role of the immune system in cancer. Understanding this has led to an explosion of new therapeutic approaches: the use of CAR T-cells and bispecific antibodies, as well as antibody-drug conjugates in managing multiple myeloma. I’ll briefly mention other new therapies around the corner.
[2:01] So, what’s our goal in treating myeloma? It’s a highly treatable cancer. It probably remains incurable, but I’m not so sure anymore. I think a proportion of patients are experiencing incredibly long remissions in excess of two decades. With new immunotherapies, therapeutic outcomes may indeed be changing.
Practically, when a patient presents, we’re trying to achieve remission, manage complications, and control bone disease.
[3:18] Management of bone disease is very important. Pain remains a common presenting symptom. Radiotherapy is important for lesions pressing on something like the spinal cord. It’s also important for all myeloma patients to be treated with a drug to reduce future fractures, like bisphosphonates (pamidronate, zoledronate). Patients live longer if they’re on one. A more recent agent is denosumab, approved for other cancers but not yet reimbursed in Australia.
[5:03] What have we got to treat myeloma? Here’s a list, marked for PBS availability, Medicines Access Programme, or trial-only status. We have immunomodulatory drugs (lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), traditional chemotherapy (cyclophosphamide, melphalan for transplant), monoclonal antibodies (daratumab, isatuximab), antibody-drug conjugates (belantamab), T-cell engagers (available in trials/MAP), CAR T-cells (trials only), and new classes like BCL2 inhibitors.
[7:58] Here’s how they’re used now versus potentially in the future. Currently, initial treatment is often lenalidomide/dexamethasone or VRD (bortezomib/len/dex). For younger, fit patients (<75), an autologous stem cell transplant consolidates the response, followed by lenalidomide maintenance. At relapse, treatment is individualised using various regimens.
In the future, we hope to get daratumab in first-line treatment, newer agents for maintenance, CAR T-cells and bispecifics approved for later lines, and to find a place for venetoclax.
[10:45] Autologous stem cell transplant has been around since the mid-90s. ‘Autologous’ means using your own stem cells. The process involves mobilising stem cells from the bone marrow, collecting them, giving high-dose chemotherapy (melphalan) to kill myeloma, then reinfusing the stem cells to rescue the bone marrow. It’s arduous but effective.
[12:18] Just to show progress: a French trial in 1996 first showed transplant improved survival. Now, median survival for standard-risk patients having a transplant is over 12 years, a marked advance. Recent trial data (VRD + transplant + maintenance) shows over 90% of patients alive at four years. Definite progress is being made.
[14:47] We don’t know for sure what causes myeloma. It’s probably bad luck, not caused by infections. Nearly all cases are preceded by MGUS. There’s a link between the immune system and cancer. Myeloma cells learn to evade the immune system. Can we retrain the immune system to fight it?
[16:41] We can use the immune system to direct B-cells, T-cells, or NK cells to target the myeloma. This includes vaccines, CAR T-cells, monoclonal antibodies (like daratumab), bispecific antibodies, antibody-drug conjugates, and checkpoint inhibitors (not yet useful in myeloma).
[18:18] To target the immune system, you need a target on the cancer cell. In myeloma, we have BCMA (B-cell maturation antigen). It’s expressed on all plasma/myeloma cells but little elsewhere, making it a good target. There are other targets too (GPRC5D, FcRH5, SLAMF7).
[19:27] BCMA-targeted immunotherapies include antibody-drug conjugates (belantamab), CAR T-cells, and bispecific antibodies (teclistamab, elranatamab).
[20:04] What are CAR T-cells? CAR stands for Chimeric Antigen Receptor T-cell therapy. It’s an immunotherapy that changes a patient’s own T-cells in a lab to better fight cancer. The process is complicated: collect T-cells, manufacture them in a lab to express the target (e.g., BCMA), give bridging therapy to control disease, give chemotherapy (lymphodepletion), then reinfuse the CAR T-cells.
[21:38] They work by being re-engineered to recognise something on myeloma cells and attack them.
[22:11] The CARTITUDE-4 trial was a recent gold-standard randomised trial. It compared a CAR T-cell (cilta-cel) to a best-available combo (pomalidomide/daratumab/dexamethasone) in patients whose myeloma progressed on lenalidomide after 1-3 prior lines. Results showed markedly improved deep response rates and progression-free survival with CAR T-cells, proving its efficacy.
[24:28] But patients still relapse. Why? The myeloma might be too aggressive, the CAR T-cells less effective or not persistent, or the myeloma cells learn to stop expressing the target (BCMA) or develop other evasion mechanisms.
[25:21] Future work involves using CAR T earlier, developing ‘off-the-shelf’ allogeneic CAR T or CAR NK cells, using other targets, and optimising manufacturing.
[26:08] Alternatives are bispecific antibodies. These are manufactured antibodies: one half binds to the myeloma cell, the other to your T-cell, forcing them together to kill the myeloma. They are ‘off-the-shelf’ products available anytime. They have manageable side effects (like cytokine release syndrome) but can increase infection risk. They are given as IV or subcutaneous injections, initially weekly then less frequently.
[28:28] Many trials have reported on bispecifics. Over 30 trials are underway. Drugs like teclistamab (anti-BCMA) and elranatamab have shown impressive response rates (62-83%) in heavily pre-treated patients, prompting investigation in earlier lines of therapy.
[29:40] In summary, several bispecifics are in advanced trials. They target different molecules on myeloma cells, force T-cell attack, and their maximum response/duration is still being determined. Future work involves combinations and improving safety, especially regarding infections.
[30:28] CAR T-cells and bispecifics both use the immune system. Pros/Cons: Bispecifics are available immediately; CAR T requires complex manufacturing. CAR T is a one-off treatment; bispecifics are ongoing. Both have toxicities and will be expensive.
[31:45] Other therapies: Belantamab (antibody-drug conjugate) is effective but has unique eye toxicity; its optimal use is being defined. Next-gen CELMoDs (iberdomide, mezigdomide) are powerful oral agents for combination or maintenance therapy.
[32:48] In conclusion, the future is bright. Significant progress has been made. Multiple active immunotherapies are promising. The current issue is optimising their availability, timing, sequencing, and side-effect management.
[33:16] Forty years ago, we only had melphalan/prednisone (2% complete remission). Now, with VRD/daratumab, we see 80% complete response rates. With CAR T-cells, we get similar deep responses even in heavily pre-treated patients. Relative survival has improved from ~25% decades ago to over 50% now. We aim for 100% – to make myeloma a chronic disease or cure it. Progress is being made. Thank you.
[34:55] Thanks, Dr. Malay. We have questions. One from Babsy: “How far away are we from daratumab as first line, and will we get quad therapy in Australia?” We don’t know. Daratumab with len/dex has been submitted twice to the PBAC. It’s TGA-approved but price is an issue. We hope it becomes available. For quadruplets upfront, the company hasn’t submitted yet; that data is newly published, so likely not this year.
[36:19] A question from Bill: “Do we know what causes myeloma?” No, we don’t. I mentioned bad luck. High levels of radiation (e.g., Hiroshima) increase risk, but otherwise, there’s a lot of uncertainty.
[37:11] A question about whether transplant is still the best therapy available in Australia. For younger patients who can tolerate it, autologous stem cell transplant remains the gold standard for consolidating a first remission. It is the treatment that has the longest track record of delivering very long-term disease control for a significant proportion of patients.
However, the landscape is evolving. With the arrival of highly effective immunotherapies like CAR T-cells and bispecific antibodies, we are actively investigating in clinical trials whether these newer treatments could eventually replace or be used before transplant for some patients. But today, in standard practice, transplant remains a cornerstone of curative-intent therapy for eligible patients.
[38:00] Thank you. A final question from Sarah: “What is the most exciting development on the horizon for you?” That’s easy. It’s the shift towards truly targeted immunotherapies. The fact that we can now re-engineer a patient’s own immune system or use a drug to redirect it to specifically hunt down myeloma cells is a paradigm shift. It moves us away from non-specific chemotherapy. The depth of response we’re seeing with these agents, even in very advanced disease, gives me great hope that we are moving closer to making myeloma a chronic illness for most, and perhaps finding functional cures for some. The key challenge now is making these transformative treatments accessible and sustainable within our healthcare system.
[38:50] Thank you so much, Associate Professor Malay, for that incredibly comprehensive and optimistic overview. We are out of time. On behalf of everyone, thank you for sharing your expertise.
