New treatment regimens are prolonging the lives of patients with multiple myeloma, whether or not they are eligible for a transplant. However, as new research findings emerge, clinicians learn to manage the real-world considerations associated with these therapies, from the effects on the
immune system to concerns surrounding treatment sequencing.
Ajai Chari, MD spoke with ONCOLOGY® in the rapidly evolving field of multiple myeloma. He began by explaining how he first became interested in this therapeutic area and why it is so rewarding to work with these patients every day.
Chari also specifically explained the need for diversity among multiple myeloma patients participating in clinical trials. Additionally, he explained how COVID-19 can severely affect and alter the immune system of multiple myeloma patients undergoing treatment.
Why did you enter the field of oncology?
Chari: No one in my family has ever been a doctor. I didn’t know what I was getting myself into. When I got to medical school, I loved it. I loved internal medicine, but my eyes lit up in oncology. It was a combination of incredible patient relationships – the depth and continuity of relationships you get from [patients with] the cancer is unprecedented and the intellectual stimulation. The challenge of complex care is exciting. There are so many unanswered questions, and therefore, from an intellectual point of view, there is so much research to be done.
What [drew me to] myeloma was, first, that diagnostic testing can be so complicated. It’s almost like a scientific equivalent of a Wordle because you have to understand light chains, urine proteins, and marrow imaging; there is a lot of data to integrate. I find it interesting that there are no two identical patients. What drives me is medicine, and I feel like we should be providing the same care as we would for our loved ones. When it’s your benchmark, we get amazing results. What could be more gratifying than living people in complete remission for years beyond [what we originally] thought? For newly diagnosed patients, you have bedridden or bedridden patients who, within months, regain their previous quality of life because treatments are so effective and myeloma symptoms can be reversed so quickly. It’s really rewarding.
What challenges do community oncologists face with the introduction of new therapies?
Chari: With T cell redirection [therapies come] a steep learning curve and management of cytokine release syndrome [CRS]. It needs to be recognized and treated properly, and it’s an interdisciplinary effort. It starts with the nurses; we need them to know if the patient has a fever or is confused, and [if they are, to] alert the first-line provider. Then, the service provider must activate the processing of the SRC. The pharmacy must take this into account as a priority, so that drugs such as tocilizumab [Actemra] [are
administered]. Then, the recognition of neurological problems must be very sensitive [as well], and so it is a parameter. The patients [can also] show up urgently [department]. Neurologists and infectious disease physicians need to be trained in this. The T cell [redirecting therapies] require a lot of experience and learning, and it will take time.
[Chimeric antigen receptor] T-cell therapy will likely only be performed in transplant centers due to the specialized nature of this process. Bispecific [antibodies] have the advantage of being ready to use, so that a specialized center is not necessary to collect T cells. This means that community doctors will have to learn how to do these bispecific tests. [antibodies].
Currently, many of these T-cell referrals are performed in the hospital, for initial treatments of bispecific disease [antibodies]. If we start doing them on an outpatient basis because of COVID-19, that’s a big deal. For one thing, fevers can easily be mistakenly attributed to something other than the study drug or bispecific [antibody]. The other issue is that some of the T cell redirections affect outcomes with COVID-19, as we’ve seen in myeloma and COVID-19 patient deaths. It will be important for community physicians to utilize the full arsenal of COVID therapies that are now available, as myeloma patients are compromised. Specifically, drugs that target B-cell maturation antigen [BCMA] [can make patients] particularly vulnerable to COVID-19, [possibly causing] death. These patients need [very] thoughtful management of COVID-19.
Can you discuss your recent article on the effects of COVID-19 on patients with multiple myeloma?
I was the main author [analyzing] a global dataset; this was a very collaborative effort to review the results of COVID-19 at the end of 2020.1 We found that the risk factors for the worst myeloma outcomes were older age, kidney failure, high-risk myeloma, and uncontrolled myeloma. Interestingly, at that time we found no difference [due to myeloma] treatment. Now, subsequent work from our institution has shown that treatments can [indeed] affect vaccine responses to a particular BCMA-directed therapy, and that C38 antibody therapy does not affect [allow] response to COVID-19 vaccines. These patients should receive booster shots, and [they should receive] COVID-19 therapy [if they contract the virus], due to their weakened immune system. In some ways, myeloma is a canary in the coal mine, because our patients [may have] immunoparesis, [meaning] their plasma cells don’t work. Unfortunately, we have seen adverse effects of COVID-19. The results [in general] have improved a lot with therapeutic vaccines, but we are [still] in the trenches with COVID-19.
What are the unmet needs in myeloma, especially for the elderly or frail?
Our youngest patient at Mount Sinai was diagnosed at the age of 18 and our eldest is [aged more than] 100 years, it is therefore a very heterogeneous disease. You can’t have one size [approach] because there is no way that someone [aged more than] 80 [years] will be able to tolerate the therapy as well as someone in their 20s or 30s. People come to the table as they get older with more medical issues, and [these can] affect not only their overall lifespan, but also their tolerance to therapies and [adverse effects. The problem with older patients is that they don’t always get to the umpteenth line of therapy. Sometimes you get [only] 1 or 2 [attempts to reach the best outcome possible].
One of the biggest advancements for this population is the diet
daratumumab [Darzalex]lenalidomide [Revlimid]and dexamethasone, from the MAIA study [NCT02252172].2 In this current follow-up study, the
the remission duration of newly diagnosed patients with a median age of 73 years is greater than 4 years. These are not transplant patients; they just get this cocktail of drugs. This is huge progress and a survivability improvement as well. We still need more therapies for this population because really frail and elderly people don’t necessarily come to academic medical centers. They are treated in the community. One of the limitations of myeloma research, and oncology research in general, is that patients in clinical trials don’t understand the real world. We have huge discrepancies in results between eligible studies [patients] and real-world patients. To close this gap, universities, pharmaceutical companies, the FDA, nonprofits, and patient advocacy groups need to work together. We need to work collectively to change these very restrictive eligibility criteria and try to make [study eligibility] more permissive and adapted to the real world.
- Chari A, Samur MK, Martinez-Lopez J, et al. Clinical features associated with the course of COVID-19 in multiple myeloma: first results from the International Myeloma Society dataset. Blood. 2020;136(26):3033-3040. doi:10.1182/blood.2020008150
- Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomized, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6