Results of a retro­spec­tive­ study conducted at the Mayo Clinic indicate that multiple myeloma patients who respond more gradually to their initial treat­ment may have better over­all survival.

Specifically, the authors of the new study find that newly diag­nosed patients who required more than 120 days to achieve their best response to initial treat­ment had better pro­gres­sion-free and over­all survival than patients who achieved their best response in 120 days or less.

The five-year survival rate was 77 per­cent for patients who achieved their best response to initial treat­ment in more than 120 days, and 56 per­cent for patients who achieved their best response in 120 days or less.

The pos­i­tive impact on survival of a more gradual response to treat­ment was seen both in patients who re­ceived a stem cell trans­plant as part of their initial treat­ment and in patients who did not.

The impact also was present when the researchers controlled for a variety of other factors that could affect prognosis, such as the patient’s age, their best response to treat­ment, and whether or not they had high-risk chromosomal ab­nor­mal­i­ties.

The study is based on data for more than 1,000 multiple myeloma patients who were diag­nosed be­tween 2005 and 2015 at the Mayo Clinic in Rochester, Minnesota.

Based on their findings, the study authors suggest that patients who respond more gradually to initial treat­ment may rep­re­sent a subgroup of patients whose disease is less likely to progress rapidly and less likely to develop resistance to treat­ment.

Background

Overall survival in multiple myeloma patients has in­­creased markedly since the in­tro­duc­tion of novel ther­a­pies such as thalido­mide, Revlimid (lena­lido­mide), and Velcade (bor­tez­o­mib) in the last 20 years (see related Beacon news article ^[1]).

The new treat­ments have given physicians more options with which to treat multiple myeloma, extending the time each patient has until treat­ment options are exhausted.

In addi­tion, the new treat­ments have made it possible to achieve deeper responses to treat­ment, which generally lengthens the time until a patient’s disease progresses and a new treat­ment must be tried.

Yet a deep response to initial treat­ment does not always guar­an­tee long over­all survival. The authors of the new study note that “survival analyses in both trans­plant and non-transplant pop­u­la­tions have dem­onstrated that up to 20 per­cent of patients achieving a [complete response to initial treat­ment] will die within four years.”

Researchers there­fore are trying to identify addi­tional factors to better predict survival in myeloma patients. Knowledge of such factors could make it easier for doctors to customize ther­apy based on a patient’s prognosis.

Extensive research has dem­onstrated that both the duration of a patient’s initial response to treat­ment, and their depth of response, are strong (but not perfect) predictors of patient survival.

There has been conflicting evi­dence, how­ever, about whether the speed of a patient’s response to initial treat­ment pos­i­tively or neg­a­tively affects patient prognosis.

Studies done before the in­tro­duc­tion of novel myeloma ther­a­pies suggested that a rapid response to initial treat­ment was asso­ci­ated with poorer survival out­comes. Studies involving patients who have received treat­ment with novel myeloma ther­a­pies have had more mixed results. For example:

• Relapsed patients who received treatment with Velcade-based regimens in a clinical trial had longer time to progression if their M-spike decreased fast after the start of treatment (reference ^[2])
• Newly diagnosed patients in a combined analysis of results from three European clinical trials had survival outcomes that were unaffected by whether or not the patients achieved a complete response before or after six months (reference ^[3])
• Newly diagnosed patients in a single center U.S. clinical trial had lower overall survival if their serum free light chain level dropped rapidly after the start of treatment (reference ^[4])
• Relapsed patients in an international trial testing the efficacy of a Ninlaro (ixazomib)-based regimen had longer progression free survival when they took longer to achieve their best response to treatment (reference ^[5])

Given the lack of consensus in studies investigating speed of response in the age of novel ther­a­pies, the authors of the new study decided to in­ves­ti­gate the issue using data from patients at their own institution.

Study Design

The study authors retro­spec­tive­ly analyzed data from all 1,099 multiple myeloma patients who were diag­nosed at the Mayo Clinic's Rochester, Minnesota location be­tween 2005 and 2015, received initial treat­ment with novel agents, and achieved at least a very good partial response to initial treat­ment.

The median patient age at diag­nosis was 63 years old.

The most common initial treat­ments the patients received in­cluded Revlimid and dexa­meth­a­sone (33 per­cent of patients), Velcade, cyclophosphamide, and dexa­meth­a­sone (24 per­cent), and Velcade, Revlimid, and dexa­meth­a­sone (16 per­cent). One third of the patients received a stem cell trans­plant as part of their initial treat­ment, which was defined as receiving a trans­plant within 12 months of starting initial treat­ment.

The median follow-up time was 3.8 years. The median length of initial ther­apy across all patients in the sample was 1.8 years, the authors told The Beacon. First-line ther­apy varied in length across patients depending, for example, on whether patients had an up­front trans­plant and whether they underwent main­te­nance ther­apy.

The median over­all survival from initial diag­nosis was 8.8 years.

Study Results

The study authors found that median time to best response among the patients in their dataset was 4.9 months, and the median duration of best response was 1.8 years.

More im­por­tantly, the researchers found that the time it took for patients to achieve their best response to initial treat­ment affected both their pro­gres­sion-free survival and over­all survival.

The researchers divided the patients in the study into two groups:

1. Patients who achieved their best response to treatment in 120 days or less
2. Patients who took more than 120 days to reach their best response.

Median pro­gres­sion-free survival was 2.1 years for patients in the first (fast-responding) group, and 3.3 years in the second (slow-responding) group.

Median over­all survival was about six years in the first (fast-responding) group, and has not yet been reached in the second (slow-responding) group.

The five-year survival rates are 56 per­cent and 77 per­cent for the fast- and slow-responding groups, re­spec­tive­ly.

These dif­fer­ences in survival be­tween the two patient groups are statistically very sig­nif­i­cant.

Just as im­por­tantly, the dif­fer­ences were found to persist even when the authors controlled for other factors that could affect a patient’s prognosis.

For example, the researchers divided patients into two dif­fer­en­t age groups, with 65 years of age as the dividing line. In both age groups, time to best response still had a sig­nif­i­cant impact on survival. Patients who reached their best response in longer than 120 days had longer pro­gres­sion-free survival and over­all survival than patients in the same age group who had more rapid responses to treat­ment.

The researchers got the same result when they divided patients into two groups based on whether or not they had an up­front trans­plant as part of their initial ther­apy. Once again, the patients in both these groups who took more than 120 days to reach their best response had the better survival out­comes.

The study authors also esti­mated several dif­fer­en­t statistical models to test further whether other factors, such as gender, best response to initial treat­ment, type of initial treat­ment, size of initial M-spike, stage at diag­nosis, or presence of high-risk chromosomal ab­nor­mal­i­ties could explain away the impact of time to best response.

In all models, how­ever, time to best response was still a sig­nif­i­cant factor.

Given these results, the authors write that “it is possible that multiple myeloma responding more gradually to initial treat­ment portends some biologic advantage that is independent of, and not simply a surrogate for,” a patient’s disease stage or chromosomal ab­nor­mal­i­ties. Myeloma patients who respond more gradually to treat­ment, the authors con­tinue, may be “less prone to devel­op­ing treat­ment resistance and sub­se­quent disease pro­gres­sion.”

Modified vs. Standard Survival Metrics

In most of their analyses, the study authors focus on “modified” measures of pro­gres­sion-free survival and over­all survival. The measures use as their starting point the time when a patient reaches their best response to treat­ment, rather than the usual starting point (either time of diag­nosis or time when treat­ment starts). Using modified survival measures avoids statistical problems that could occur with the kind of analyses the authors do in this study.

This summary by The Beacon of the researcher’s work, how­ever, reports standard survival metrics because they are easier to interpret.

For more in­­for­ma­tion, please see the study by Mellors, P.W. et al., “Time to plateau as a predictor of survival in newly diag­nosed multiple myeloma,” American Journal of Hematology, April 16, 2018 (abstract ^[6]).