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Identifying Novel Therapies for Multiple Myeloma: Paul Richardson, MD

Paul Richardson, MD.

In the following interview, Dr. Paul Richardson, the Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, discusses some important factors in the development of drugs to target "the queen of immunological cancers," multiple myeloma, and why this disease is difficult to cure. Recently, he led the development and clinical trials of the novel targeted cytotoxic peptide-drug, melphalan flufenamide (Pepaxto®, Oncopeptides AB) for the treatment of patients with relapsed and refractory multiple myeloma. These studies are responsible for the approval of melphalan flufenamide (melflufen) by the FDA in combination with dexamethasone for patients with multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one CD38-directed monoclonal antibody, one proteasome inhibitor, and one immunomodulatory agent.

What challenges do you face in the development of drugs to treat multiple myeloma?

Paul Richardson, MD: The biology of myeloma is incredibly complicated, as it is arguably the queen of immunological cancers. As a terminally differentiated B cell, plasma cells are designed to recognize an antigen when a person is exposed to it at, for example, the age of 12, and then 20 years later, to wake from dormancy, switch on, and produce antibodies to respond to that same antigen that their body last saw 20 years ago.

That's a clever cell, and really sophisticated; plus, it has to be able to do a lot of things as it repurposes from dormancy. Unfortunately, when the plasma cell becomes malignant, it's very challenging, and treating it becomes a real chess game. Something to share that's sobering is that even though we have 14 new drugs for myeloma, we are not curing anyone. Multiple myeloma is a heterogeneous disease; it's extremely sophisticated, and its complexity of resistance mechanisms is especially remarkable. With whole genome sequencing on someone's disease at diagnosis, the median number of mutations is approximately 7,000.

Then when the patient relapses after lenalidomide/bortezomib/dexamethasone (RVD), for example, that goes up by a median of around 1,500 mutations. If you expose the patient to high-dose melphalan, almost 6,000 mutations are added. This is why we have to be very careful—because somehow, you've got to engender lethality, but not at the price of paying later. There are likely a number of reasons why high-dose therapy and transplantation, for example, generate progression-free survival benefit but no overall survival benefit, which the randomized trials are now showing when continued with novel therapies. One potential reason is that when relapse occurs, the mutational burden of disease is worse, and that's what we've now got to better understand and move beyond.

Why do B cells have such a high mutation rate?

Dr. Richardson: This is an excellent question. Because that's what a terminally differentiated B cell is there to do. If it's exposed to an antigen, it has to quickly repurpose, class switch, and organize a protein. Genetics are like social media: it's got to be Facebook, Instagram, and Twitter, all in one, with the ability to quickly respond. If the cell becomes malignant, this process appears to go up a notch with class switching. Importantly, myelomas probably start in the lymph node, and then the myeloma cell egresses into the bone marrow where it proliferates.

The good news for patients is that this complexity has provided therapeutic approaches particularly in the tumor microenvironment. In fact, with numerous novel drugs, we converted multiple myeloma to a chronic disease, and the really good news is that the more recent harnessing of the immune response has been truly transformative. Immune therapies and other strategies are really going to make the difference in my view and not least that if you're fighting such a high mutational burden, a targeted agent on its own is not going to do enough.

In myeloma, we have another adage, "Dirty drugs do better," because you have to throw a broad net around that disease and shut it down. Immune therapies such as chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers hold great promise in this respect. Small molecules, however, are incredibly important in myeloma, so it's never going to be one versus the other; it's going to be a combination of all.

Can you comment on the best approaches to identify novel therapies?

Dr. Richardson: We've done very well over the last 20 years, but a key point to this is that there is a partnership with an outstanding laboratory program and a real cross-fertilization. Our laboratory leader and my mentor, Ken Anderson, always leads the lab meetings by saying, "How does this translate to the patient?" I'm part of the lab meetings as a clinician, and it's very helpful for our scientists, because then they're seeing it right in front of them: both the translation to the clinic and also the integrated approach are critical.

For example, I want to especially acknowledge my colleague Dharminder Chauhan, PhD, who tested melflufen in various systems in our laboratory; it's incredibly valuable to be informed by the lab, because essentially your shot on goal is far more likely to be successful as a result. But laboratory science is informative, not predictive, and we are very lucky that at Dana-Farber, we have wonderful laboratory partners who are outstanding.

The partnership is uniquely powerful because you can see a clinical signal of unclear significance, but with lab teams telling you to please keep drilling because there's really something there, it's so much more likely to be beneficial in providing a new agent that helps patients. This is not least that clinical trials are incredibly difficult, and you can frequently see either a signal that's over-emphasizing benefit or under-emphasizing it, and translational research at every level really helps us get to the best outcome for all our patients.

About Dr. Richardson

Paul G. Richardson, MD, a hematologist-oncologist, is the Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, and he is the RJ Corman Professor of Medicine at Harvard Medical School. Dr. Richardson has led or co-led the study and clinical development of numerous drugs in the treatment of multiple myeloma, including lenalidomide, bortezomib, ixazomib, panobinostat, pomalidomide, elotuzumab, daratumumab, selinexor, isatuximab, and belantamab mafadotin.In addition to the study of the now-established lenalidomide/bortezomib/dexamethasone (RVD) combination approach, a new standard first-line therapy for multiple myeloma, he has also developed other combinations in the relapsed/refractory setting, including pomalidomide, bortezomib, and dexamethasone (PVP) and isatuximab, pomalidomide, and dexamethasone (Isa-Pd). Currently, in addition to his work on melflufen for the treatment of relapsed and refractory myeloma, Dr. Richardson is leading the first-in-human studies of cereblon E3 ligase modulators (so-called CELMoDs). He has been the recipient of many awards, including the Warren Alpert Prize from Harvard Medical School, the Accelerator Award from the Multiple Myeloma Research Foundation, the Ernest Beutler Prize and Lecture from the American Society of Hematology, the COMy Award, the Robert Kyle Award from the International Myeloma Foundation, and the Morse Research Award.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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