Results of a recent British study in­di­cate that the rel­a­tive­ importance of factors affecting sur­vival in multiple myeloma patients changes with patient age.

In particular, the re­searchers found that the older a patient is at diag­nosis, the more their sur­vival is affected by their general health and by how ad­vanced their multiple myeloma is at diag­nosis.

In contrast, the impact of high-risk chromosomal ab­nor­mal­i­ties on sur­vival de­creases with patient age.

The study findings are based on an analysis of data for almost 4,000 newly diag­nosed multiple myeloma patients who par­tic­i­pated in the Myeloma XI ran­dom­ized clin­i­cal trial in the United Kingdom, which began in 2010.

The study authors believe their findings are im­por­tant for the treat­ment of multiple myeloma because they sug­gest dif­fer­en­t treat­ment ap­proaches may need to be con­sidered for dif­fer­en­t age groups. For younger patients, the re­searchers sug­gest focusing on whether or not the patient has high-risk chromosomal ab­nor­mal­i­ties, while for older patients, they rec­om­mend focusing on the patient’s general health, treat­ment type, and treat­ment intensity.

Background

Substantial progress has been made in the past decade in the treat­ment of multiple myeloma. Patients are experiencing longer times in remission after starting treat­ment and longer over­all sur­vival.

There con­tinues to be, how­ever, a group of patients with high-risk dis­ease that has rel­a­tive­ly poor out­comes com­pared to the rest of multiple myeloma patients.

In addi­tion, time in remission and over­all sur­vival con­tinue to be strongly tied to a patient’s age at diag­nosis. Older myeloma patients generally spend less time in remission after the start of their initial treat­ment, and their over­all sur­vival is not as long as ex­peri­enced by younger myeloma patients.

Factors that con­trib­ute to poor treat­ment out­comes in multiple myeloma are both patient-related, such as a patient’s over­all health, and dis­ease-related, such as whether or not a patient’s dis­ease in­volve­s high-risk chromosomal ab­nor­mal­i­ties.

According to the British re­searchers, a lot of re­search has been conducted to assess the effect of chromosomal ab­nor­mal­i­ties on sur­vival, and it is well estab­lish­ed that age has a sizable impact on sur­vival out­comes (see, for example, Figure 2 in this Beacon article about sur­vival in U.S. myeloma patients.)

What has not been clear, how­ever, is whether the importance of patient and dis­ease char­ac­ter­istics varies with patient age. The British re­searchers there­fore sought to de­ter­mine how dif­fer­en­t factors affect sur­vival in multiple myeloma of dif­fer­en­t ages who re­ceived the same treat­ment.

Study Design

The analysis the British re­searchers conducted was based on data from the Myeloma XI trial, a large, multi-center Phase 3 trial conducted in the UK. The trial in­cluded 3,894 newly diag­nosed multiple myeloma patients who were recruited from academic and district general hos­pi­tals around the UK be­tween 2010 and 2016.

The median patient age was 68 years old.

Patients re­ceived initial treat­ment with either cyclo­phos­pha­mide (Cytoxan), Revlimid (lena­lido­mide), and dexa­meth­a­sone (CRD), or cyclo­phos­pha­mide, thalido­mide, and dexa­meth­a­sone (CTD). Patients who achieved less than a very good partial re­sponse­ were ran­dom­ized to re­ceive either cyclo­phos­pha­mide, Velcade (bor­tez­o­mib), and dexa­meth­a­sone, or no further initial ther­apy.

Transplant eli­gible patients underwent stem cell trans­plan­ta­tion with mel­phalan.

After initial treat­ment and, when relevant, stem cell trans­plan­ta­tion, patients were ran­domly assigned to re­ceive Revlimid main­te­nance ther­apy or observation.

For their analysis, the re­searchers categorized patients into four dif­fer­en­t age groups: 60 years old and younger; 61 to 70 years old; 71 to 80 years old; and older than 80 years.

Similarly, they categorized patients’ myeloma into standard risk, high risk, and ultra-high risk based on the presence of chromosomal ab­nor­mal­i­ties t(4;16), t(14;16), t(14;20), del(17p) and gain(1q). The absence of these chromosomal ab­nor­mal­i­ties was defined as standard risk, the presence of one as high risk, and the presence of more than one as ultra high risk.

For their analysis, the re­searchers also con­sidered the patients’ over­all health, which they measured using data about each patient’s “performance status,” a variable that reflects a patient's ability to per­form cer­tain activ­i­ties of daily living without the help of others.

The measure of per­for­mance status used in the Myeloma XI trial is from the World Health Organi­za­tion (WHO). In the WHO per­for­mance status scale, a score of 0 in­di­cates a patient is fully able to carry out daily activ­i­ties on their own, while a score of 4 in­di­cates a patient is unable to carry out any activ­i­ties on their own.

The re­searchers used pro­gres­sion-free sur­vival to measure each patient’s time in remission after the start of treat­ment, and each patient’s Inter­na­tional Staging System (ISS) dis­ease stage was used as a measure of how ad­vanced a patient’s dis­ease was at diag­nosis.

(For results such as those from the Myeloma XI trial, pro­gres­sion-free sur­vival usually is defined as the time from trial enrollment until a patient ex­peri­ences either dis­ease pro­gres­sion or death prior to dis­ease pro­gres­sion. For a trial enrolling newly diag­nosed myeloma patients, this means median pro­gres­sion-free sur­vival is very close to median time to pro­gres­sion, or median time in remission, because only a small minority of newly diag­nosed myeloma patients die prior to dis­ease pro­gres­sion. Overall sur­vival for a study such as this one typically is defined as the time from trial enrollment until death.)

Study Results

The study authors found that patient age was strongly asso­ci­ated with both pro­gres­sion-free and over­all sur­vival. Younger patients under the age of 60 had sig­nif­i­cantly longer pro­gres­sion-free and over­all sur­vival than patients over the age of 80: 38.3 months vs. 13.6 months for pro­gres­sion-free sur­vival, and 65.6 months vs. 28.9 months for over­all sur­vival.

Chromosomal Abnormalities And Risk Status

Data on chromosomal ab­nor­mal­i­ties were avail­able for 1,567 patients. The re­searchers found that the share of patients with t(4;14) and del(17p) de­creased sig­nif­i­cantly with age while that of patients with gain(1q) in­creased. Overall, the share of patients with high-risk or ultra-high-risk chromosomal ab­nor­mal­i­ties was con­stant across the first three age groups, whereas it was slightly higher in patients older than 80 years.

The impact of chromosomal ab­nor­mal­i­ties on sur­vival varied, how­ever, across the age groups. Whether or not a patient was standard risk, high risk, or ultra high risk mattered in a con­sis­tent way in patients 60 years of age or younger and for patients 61 to 70 years of age, with sur­vival being the longest for standard-risk patients, shorter for intermediate-risk patients, and shortest for ultra-high-risk patients.

In older patients, on the other hand, risk status had less of an effect on sur­vival. In patients over 80 years of age, for example, there was essentially no dif­fer­ence in sur­vival be­tween those with standard risk and high risk dis­ease. In patients 71 to 80 years of age, standard risk patients clearly had better sur­vival, but there was not much dif­fer­ence in over­all sur­vival be­tween high-risk and ultra-high-risk patients.

Disease Stage And Overall Health

When the re­searchers looked at dis­ease stage, which like risk status is a dis­ease rather than patient char­ac­ter­istic, they found that it varied sub­stan­tially with age. More ad­vanced dis­ease, reflected in a higher dis­ease staging, became more common at higher patient ages. Less than a quarter of patients under the age of 60 had Stage 3 dis­ease at diag­nosis, whereas almost half of patients over the age of 80 were Stage 3.

As for over­all health at diag­nosis, it too varied with age, in the ex­pec­ted way. The share of patients with an excellent over­all health status de­creased from 82 per­cent in patients 60 years and younger to 67 per­cent in those over the age of 80.

Relative Importance Of The Factors

The re­searchers then assessed the rel­a­tive­ impact on sur­vival of risk status, dis­ease stage at diag­nosis, and over­all health in each of the four age groups.

To do this, they used a statistical model to esti­mate for each age group how much each of one of the three variables affected pro­gres­sion-free and over­all sur­vival in the group.

Then, re­searchers used the results from their statistical models, com­bined with the variability of each factor in each age group, to assess how much each factor accounts for dif­fer­ences in sur­vival in each age group.

The results of this modeling exercise for over­all sur­vival are shown in Figure 1 below.

The results in­di­cate that variation in dis­ease stage has little impact on sur­vival among patients under the age of 60, but then be­comes im­por­tant in a rather con­stant way across the three remaining older age groups.

The impact of over­all health on sur­vival declines as one goes from the group with the youngest myeloma patients to those 61 years of age to 70 years of age, but then be­comes in­creas­ingly im­por­tant as age grows.

Finally, the presence or absence of high risk chromosomal ab­nor­mal­i­ties has the greatest impact on sur­vival among young myeloma patients, and be­comes less im­por­tant with greater patient age.

For more in­for­ma­tion, please see the study by Pawlyn, C. et al., “The rel­a­tive­ importance of factors predicting out­come for myeloma patients at dif­fer­en­t ages: results from 3894 patients in the Myeloma XI trial,” in Leukemia, Octo­ber 14, 2019 (full text).