Multiple Myeloma


High-Risk and Ultra-High-Risk Multiple Myeloma: Stratification for Tailored Treatment

clinical topic updates by S. Vincent Rajkumar, MD


High-risk and ultra-high-risk multiple myeloma, characterized by the presence of cytogenetic abnormalities and/or extramedullary disease, represent a treatment challenge. Risk stratification and early aggressive treatment are key to improving outcomes in this difficult-to-treat population.

Expert Commentary

S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine
Mayo Clinic
Rochester, MN

“Although we have made progress because of the early use of transplant and doublet maintenance, we still need to do more for patients with ultra-high-risk disease.”

S. Vincent Rajkumar, MD

Multiple myeloma is composed of several different subtypes, and the prognosis can vary among patients depending on the cytogenetic risk. For example, patients with trisomies alone, or hyperdiploid multiple myeloma in the absence of high-risk features, tend to do very well, whereas those with high-risk cytogenetics have a higher risk of relapse and a shorter progression-free survival and overall survival (OS). The high-risk cytogenetic category in multiple myeloma is defined by the presence of t(4;14), t(14;16), or t(14;20) translocation; chromosome 1q gain; 17p deletion (del[17p]); or p53 mutation.  

The presence of extramedullary disease at diagnosis is also considered a high-risk feature. Extramedullary presentations include the infiltration of other organs, such as the lymph nodes, liver, lung, pleura, skin, and central nervous system, or circulating plasma cells in the blood, which is referred to as plasma cell leukemia.

Further, we now know that patients with 2 or more high-risk features, or hits, are considered to have ultra-high-risk disease. For instance, the presence of del(17p) with a p53 mutation on the other chromosome is a double hit. Or the same patient may have a combination of these factors, such as 3 high-risk genetic abnormalities plus extramedullary disease. Thus, we are able to stratify the risk level of patients to identify ultra-high-risk scenarios for which more aggressive treatments may be appropriate.

Currently, the question at hand is: How can we further improve risk stratification and advance tailored treatment accordingly? For the vast majority of patients, testing is conducted to detect the most common cytogenetic abnormalities (eg, t[4;14], t[14;16], or t[14;20] translocation; del[17p]; or chromosome 1q gain); such testing is routine across the country. Depending on the academic center, some patients may be undergoing more comprehensive gene expression profiling or gene sequencing to identify additional risk factors. For example, some centers may also be looking for 1p32 deletion, which is an additional risk factor. The more information we have, the more we are able to risk stratify patients as having high-risk or ultra-high-risk disease. Our goal is to conduct appropriate testing in newly diagnosed multiple myeloma to determine whether patients have high-risk cytogenetic abnormalities, and, if so, to determine how many risk factors they have. 

The good news is that OS is improving for all patients with multiple myeloma. OS in high-risk multiple myeloma used to be approximately 2 to 3 years; however, we now see a 7-year median OS in the 2020 study by Joseph et al at Emory University. This was a study of 1000 consecutive patients with newly diagnosed multiple myeloma who were treated with lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance. The study showed that early transplantation and doublet maintenance therapy improves outcomes for high-risk patients. Although we have made progress because of the early use of transplant and doublet maintenance, we still need to do more for patients with ultra-high-risk disease.

In terms of escalating treatment beyond the standard of care, ideally, we would like to have data from randomized controlled trials before we change practice. But in high-risk multiple myeloma, we are willing to adopt some changes to our treatment strategy based on selected nonrandomized data. Whether quadruplet induction therapy will prolong OS to a greater extent than triplet therapy is still an open question, but we have evidence that minimal residual disease negativity rates are higher with quadruplets and that progression-free survival rates may also be higher. Although we do not have clear data for OS benefit with quadruplets, it is reasonable to consider quadruplet induction at least for high-risk patients. Thus, I would favor the use of quadruplet induction therapy for transplant-eligible patients with high-risk disease and autologous transplantation early in the disease course followed by maintenance therapy with at least 2 agents.

My overall philosophy is that we need to do everything possible to get high-risk patients to a minimal residual disease–negative status. I also believe that, whenever possible, a consideration of clinical trials should be the default option for all patients with multiple myeloma, in all stages of the disease, including newly diagnosed and relapsed.


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S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine
Mayo Clinic
Rochester, MN