In a retrospective study of over 350 multiple myeloma patients who had a com­plete response to their initial line of ther­apy, researchers in the United States have found that a longer duration of response is asso­ci­ated with sub­stan­tially longer over­all survival.

In addi­tion, the study authors found that patients who started second-line treat­ment due to a biochemical relapse had longer over­all survival than those who started second-line treat­ment due to a symp­tomatic relapse.

A symp­tomatic relapse is one in which the patient ex­peri­ences new bone lesions, anemia, or other defining symp­toms of multiple myeloma. A biochemical relapse, in contrast, is one where there are no new symp­toms of the disease, but the patient's M-spike or serum free light chain levels increase by a sub­stan­tial amount.

Patients in the study who sustained a com­plete response for 24 months or longer after the start of their initial treat­ment had median over­all survival of 150 months (12.5 years) compared to 81 months (6.75 years) for patients who kept their com­plete response for less than 24 months.

The difference in over­all survival between the two groups of patients remained statistically sig­nif­i­cant even when the researchers controlled for the poten­tial influence of patient age, whether the patients had received a stem cell trans­plant or not as part of their initial ther­apy, and whether they had received main­te­nance ther­apy.

The difference in over­all survival between the two groups was not simply the result of the one group staying in remission longer than the other. Length of remission also was asso­ci­ated with longer over­all survival when it was measured from the time of disease pro­gres­sion, rather than from the start of treat­ment after initial diag­nosis.

Overall survival from the time of relapse was 89 months (7.4 years) for patients who kept their com­plete response for 24 months or longer, versus 56 months (4.7 years) for patients who kept their com­plete response for less than 24 months.

The type of relapse a patient ex­peri­enced also was asso­ci­ated with differences in over­all survival. Patients in the study who started second-line treat­ment due to biochemical relapse had longer over­all survival (125 months, or 10.4 years) than patients who started second-line treat­ment because of symp­tomatic relapse (81 months, or 6.75 years).

The researchers speculate that differences in disease biology across patients in their sample are likely to account for many of the survival differences they observed. Patients with more aggressive disease, for example, are likely to have both shorter durations of response and shorter over­all survival. Aggressive disease also may be more likely to lead to symp­tomatic rather than biochemical relapse, leading to an association between symp­tomatic relapse and shorter over­all survival.

The study authors also speculate, however, that treat­ment before the onset of new symp­toms may im­prove survival by preventing organ damage that can hamper patient health and limit future treat­ment options.

Background Information

Previous research has shown that achieving a deep response to initial treat­ment is asso­ci­ated with im­proved over­all survival (see, for example, the study results summarized in this Beacon news article).

Previous research also has indicated that sustained deep responses are asso­ci­ated with better survival than short responses. However, according to the authors of the new study, these findings have been mainly in studies involving patients who had a stem cell trans­plant as part of their initial ther­apy.

In the current study, the researchers sought to assess the the impact of duration of response in patients who achieved a com­plete response during initial ther­apy, re­gard­less of whether or not a patient had a stem cell trans­plant as part of their initial treat­ment. The authors also sought to in­ves­ti­gate what sort of relapses occur when patients come out of remission, and whether the type of relapse affects a patient's survival prognosis.

Study Design

The new study was conducted by researchers at the Mayo Clinic. The study authors retrospectively analyzed data from 351 multiple myeloma patients who were seen at their institution between July 2004 and January 2016 and had achieved a com­plete response to their first-line treat­ment.

The median patient age at the time of diag­nosis was 61 years old. About one fifth of patients (21 per­cent) had high-risk chromosomal ab­nor­mal­i­ties, defined as t(4;14), t(14;16), t(14;20), del(17p), and monosomy 17.

All but three patients received induction ther­apy with novel agents. Three quarters of the patients received an au­tol­o­gous (own) stem cell trans­plant, and 39 per­cent received main­te­nance ther­apy as part of their first-line ther­apy. Maintenance ther­apy was mostly Revlimid- or Velcade-based (57 per­cent and 36 per­cent, re­spec­tive­ly).

Study Results

Across all patients in the study, the median time to achieving a com­plete response was eight months.

The median duration of com­plete response was 24 months. Overall, 9 per­cent of the patients stayed in com­plete remission for less than 6 months, 12 per­cent for 6 to 12 months, 14 per­cent for 12 to 18 months, 14 per­cent for 18 to 24 months, and 51 per­cent stayed in com­plete remission for 24 months or longer.

At the time of last follow-up, 68 per­cent of patients had re­lapsed / progressed.

Type Of Relapse / Progression

The researchers established four categories of relapse / pro­gres­sion:

1. Symptomatic relapse – Progression with lytic lesions, anemia, a plasmacytoma, or other symptoms of myeloma-related end-organ damage
2. Biochemical relapse / progression – A 25 percent or more increase in M-spike with at least a 0.5 g/dL increase
3. Biochemical loss of complete response with re-emergence of a monoclonal protein – Two consecutive positive immunofixation values in serum / urine, or rise in M-spike not meeting the criteria for biochemical or symptomatic progression
4. Biochemical loss of complete response with abnormal free light chain ratio only – Two consecutive abnormal free light chain ratios in patients with light chain myeloma who do not meet criterion (3) for relapse / progression

Of the patients who had re­lapsed, 25 per­cent ex­peri­enced a symp­tomatic relapse, 24 per­cent a biochemical relapse, 37 per­cent had a positive urine/serum immuno­fix­a­tion or a rise in M-spike, and 14 per­cent had a loss of com­plete response with an ab­nor­mal free light chain ratio.

Characteristics Of Patients With Long And Short Durations Of Response

When the researchers compared the char­ac­ter­istics of patients who sustained their com­plete response for 24 months or longer after their initial treat­ment with the char­ac­ter­istics of patients who kept their com­plete response for less than 24 months, they found no difference in age, gender, bone marrow plasma cell per­cent­age at diag­nosis, share of patients with high-risk chromosomal ab­nor­mal­i­ties, or share of patients who received a stem cell trans­plant as part of their first-line treat­ment.

However, patients who sustained their com­plete response for 24 months or longer after their initial treat­ment were less likely to have ad­vanced disease (ISS Stage 3) than patients who kept their com­plete response for less than 24 months (22 per­cent with ISS Stage 3 disease versus 37 per­cent, re­spec­tive­ly).

In addi­tion, patients who sustained their com­plete response for 24 months or longer were more likely to have received main­te­nance ther­apy than patients who kept their com­plete response for less than 24 months (42 per­cent versus 31 per­cent, re­spec­tive­ly).

Overall Survival

After a median follow-up time of 72 months from the start of ther­apy, the median over­all survival for all patients was 123 months (10.25 years).

Patients who sustained their com­plete response for 24 months or longer after their initial treat­ment had sig­nif­i­cantly longer over­all survival (150 months / 12.5 years) than patients who kept their com­plete response for less than 24 months (81 months / 6.75 years).

The association between duration of response and over­all survival was lessened somewhat when the researchers controlled for patient age, disease stage at diag­nosis, and whether or not the patient had a stem cell trans­plant or main­te­nance ther­apy. The association, however, was still large and statistically sig­nif­i­cant.

There also was an association between duration of initial com­plete response and a patient's survival from time of relapse. Over­all survival was 89 months (7.4 years) from the time of relapse for patients who kept their com­plete for 24 months or longer, compared to 56 months (4.7 years) for patients who kept their com­plete response for less than 24 months.

When the researchers looked at patients who started second-line treat­ment because of biochemical or symp­tomatic pro­gres­sion, they found that over­all survival from the start of first-line treat­ment was longer for patients who started second-line treat­ment for biochemical pro­gres­sion (125 months / 10.4 years) compared to those who started second-line treat­ment for symp­tomatic pro­gres­sion (81 months / 6.75 years).

For more in­­for­ma­tion, please see the study by Sidana, S. et al., “Relapse after com­plete response in newly diag­nosed multiple myeloma: implications of duration of response and patterns of relapse,” in Leukemia, October 15, 2018 (abstract).