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MM Challenges
My Thoughts on Today’s Biggest Challenges in Myeloma Care

Released: October 22, 2019

Expiration: October 20, 2020

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Treatment approaches for multiple myeloma (MM) have changed significantly during the past decade. New therapies and combinations have led to increased survival, and patients are now living as much as 3 times longer. However, a significant proportion of patients with MM still present with disease that is challenging to manage.

High‑Risk MM
The most important issue we face today is the management of patients with high‑risk MM, which constitutes about 15% to 25% of total cases. There are various ways to define high‑risk disease; the common defining feature of this group of patients is that they respond to current treatments, but their response is less durable. These patients become refractory to the available drugs in a relatively short time frame and eventually succumb to the disease, with a median survival of less than 3 years. It remains a challenge to identify these patients; however, we have made significant progress in the available tools. The most commonly used tool is FISH to assess cytogenetic abnormalities that represent high‑risk genetic markers. In addition, there are other characteristics of high-risk MM, such as a high proliferation rate and the presence of circulating plasma cells. Newer technology such as next-generation sequencing has also been used to assess genomic mutations that confer excess risk. There are also ongoing studies aiming to better understand the pathophysiology of MM in order to improve the identification of high‑risk patients. This is important so we can design clinical trials specifically for patients with high-risk disease and understand how to treat these patients with a more tailored approach.

So, how do we treat these patients now? This continues to be a challenge. Recent findings suggest that if high‑risk patients achieve a very low tumor burden, qualifying as minimal residual disease (MRD) negative, they have improved survival. Although there are currently no prospective data suggesting that converting an MRD‑positive patient to an MRD‑negative state by giving additional therapy or more intense therapy changes patient outcome, I think in the setting of high‑risk MM where options are limited, the goal of therapy needs to be MRD‑negative status. This can be achieved by sequencing different types of therapies or using more intense regimens up-front.

Of importance, I think high‑risk patients, whether identified at diagnosis or at relapse, should get a second opinion from an MM specialist. A recent publication in JNCCN looked at outcomes based on volume of MM patients and demonstrated that high‑volume providers, even in the community setting, achieved better patient outcomes. I think that this is an important indication that we should all collaborate to take care of these patients.

Challenges Faced at Relapse
Patients often present with unique challenges upon relapse, including unusual manifestations of the disease. In particular, we see more patients with significant extramedullary disease, involving either the soft tissue or different organs, who present with high numbers of circulating plasma cells or who have secondary plasma cell leukemia. It is unlikely that the treatment regimens that we are currently using specifically contribute to the development of these manifestations; however, it cannot be ruled out. My suspicion is that this is a consequence of prolonged survival compared with historical data, which is revealing a natural history of the disease that was not evident before.

The best course of action for treating these patients remains a challenge. Many of us tend to use some of the older, traditional chemotherapy combinations in an attempt to get the disease under control. However, keeping these patients in response is often difficult. Again, we still need to figure out how best to treat these patients, especially in the long term. It remains unclear if we should employ some of the newer immune-modulating approaches, such as CAR T-cell therapy or other BCMA-targeting therapies, or if we need to figure out a better way to sequence the different drugs that we have available today including various combinations of IMiD/PI with monoclonal antibodies, nuclear export inhibitors, and HDAC inhibitors.

With current therapies there are likely fewer than 5% of patients who present with primary refractory disease, which means they do not respond or relapse right away following multiagent combination treatment incorporating proteasome inhibitors, IMiDs, and anti-CD38 monoclonal antibodies. This represents another particularly challenging subset of patients, and we need a better understanding of what causes their lack of response.

Finally, there are also patients who relapse very early after their initial treatment; these patients respond initially to therapy but their response is not long lasting. They may not be identified as high risk at diagnosis because they lack the traditional markers, but their disease behaves like high‑risk disease. We remain unsure of the best approach to treat these patients. Should we use modern immune therapies like CAR T-cells or genetically guided therapies based on what cytogenetic mutations they have? These questions are currently being investigated; for example, the MMRF MyDrug clinical trial is an umbrella trial for patients with relapsed/refractory MM to explore the use of various targeted agents based on the specific genetic abnormalities each patient has.

Long‑term Survival
The good news is that many patients with MM are living 10 years or more after diagnosis of their disease, but this is also leading to the presentation of new complications. For example, some treatments used as maintenance therapy may lead to increased risk for second malignancies, so we have to carefully monitor these patients for the development of new cancers and intervene appropriately.

Another concern for long‑term survivors is that of bone health. Even though bisphosphonates and other bone‑protective agents, such as denosumab, are often used, it is important to be aware that treatments, and even the bisphosphonates themselves, can lead to bone complications later on.

Finally, being exposed to a variety of these drugs can also affect cardiovascular health and result in treatment-related peripheral neuropathy, which needs to be taken into consideration as we manage these patients over the long term. Patients would benefit from multidisciplinary care with a team of clinicians, including internists who are familiar with the complications that may arise in long‑term survivors. In the hematologic space, we should take the lead from those who care for patients with other types of cancers, such as breast cancer, and form partnerships with the internists who manage surviving patients on a daily basis.

To hear more about these and other challenges facing clinicians who care for patients with MM, please join me and my colleagues for the annual CCO/IMF CME-certified symposium at ASH 2019, “Approaches to Achieve the Best Possible Outcomes in Myeloma.” Brian G.M. Durie, MD; Thomas G. Martin, MD; Philippe Moreau, MD; S. Vincent Rajkumar, MD; Jesús F. San-Miguel, MD; and I will discuss patient case studies and key clinical trial data on recent advances in the treatment of MM. Click here to register!

Your Thoughts
What are your biggest challenges regarding the care of patients with MM in your practice? Please share your thoughts in the comments box below.

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In your current practice, which of the following types of challenging MM cases do you encounter most often?
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