Long-term clinical follow-up of patients with monoclonal gammopathy of undetermined significance (MGUS), regardless of risk stratification, may improve the outcome of those eventually diagnosed with multiple myeloma, according to a study now online ahead of print in JAMA Oncology (doi:10.1001/jamaoncol.2015.23).
“Our observations stress the importance of clinical follow-up in MGUS. The results reflect the importance of life-long follow-up for individuals diagnosed with MGUS, independent of risk score, and highlight the need for better risk models based on the biology of the disease,” said the lead author, Sigurdur Y Kristinsson, MD, PhD, Professor of Hematology at the University of Iceland and Karolinska University Hospital.
Multiple myeloma is always preceded by MGUS, a precursor condition characterized by a detectable monoclonal protein in patients without evidence of end-organ damage or other related plasma cell or lymphoproliferative disorders, he explained. “MGUS is very common and is detected in approximately five percent of persons age 70 or older. However, only a small proportion of MGUS progresses to a malignant disorder.
“In fact, the annual risk of progression to multiple myeloma or other related disorders is on average one percent, with varying risks according to risk groups.”
He said that current guidelines suggest (depending on the individual patient's clinical risk score) life-long monitoring of those with MGUS to detect progression to multiple myeloma or related disorders. At the moment, though, the impact of annual monitoring on the outcome of patients who eventually develop multiple myeloma is unclear.
Asked for his perspective, one of the authors of an accompanying “Invited Commentary” (JAMA Oncology doi:10.1001/jamaoncol.2015.33), S. Vincent Rajkumar, MD, Professor of Medicine in the Division of Hematology at the Mayo Clinic, said: “This paper suggests that people with known diagnosis of MGUS seem to have better prognosis than those not known to have MGUS. The authors believe this finding is related to early diagnosis of multiple myeloma and justifies recommendation to follow MGUS patients. But it cannot be determined whether multiple myeloma patients with a known MGUS were followed more closely than those in whom an MGUS was not recognized. Therefore, it is difficult to attribute a causal relationship between follow-up and better prognosis.
“We feel the risk of myeloma-related disease is so low—two percent lifetime in low-risk MGUS patients—that there is no reason to change International Myeloma Working Group [IMWG] recomendations on follow-up,” Rajkumar continued. “Half of MGUS diagnoses are low-risk patients. Three to four percent of the U.S. general population over age 50 has MGUS, so about five million people in the U.S. have MGUS. It doesn't make sense to follow millions of people since only a small number will get the disease.”
In response, one of Kristinsson's coauthors, Ola Landgren, MD, Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, said: “Any epidemiologic study is an association. In a 2010 study, Mayo Clinic researchers showed that MGUS patients have a greater association with multiple myeloma [Bianchi et al: Blood 1010; 116:2019-2025]. The results of our study are similar to another recent report [Go et al: Clinical Lymphoma, Myeloma & Leukemia 2015;15:177-186] that found fewer complications and longer survival in multiple myeloma patients with a prior diagnosis of MGUS compared with those diagnosed without a history of MGUS. And now we have epidemiologic evidence that diagnosis of MGUS impacts survival.
I think when two population-based studies show the same thing, this confirms that there is a true association.”
Using data from a large population-based study on nearly 15,000 multiple myeloma patients diagnosed in Sweden from 1976 to 2005, with follow-up through 2007, Kristinsson and colleagues estimated the impact of prior knowledge of MGUS diagnosis and comorbidities on multiple myeloma survival. About three percent of patients had been clinically diagnosed as having MGUS prior to their multiple myeloma diagnosis.
Patients with prior knowledge of having MGUS had a 14 percent longer overall survival from myeloma (median of 2.8 years), despite having significantly more comorbidities, than patients without prior knowledge of MGUS (median 2.1 years).
“Interestingly, the patients with low-risk MGUS (i.e., who had very low M-protein) had the highest risk of death. The observation that low M-protein concentration at MGUS diagnosis was associated with poorer multiple myeloma survival may reflect less frequent clinical follow-up,” Kristinsson said.
“Based on available data, we consider the main reason for the prolonged survival observed in our study to be that MGUS patients are evaluated more often for signs of multiple myeloma progression and may be diagnosed and started on anti-myeloma therapy at an earlier stage.”
Screening for MGUS in the general population could translate into earlier detection and treatment of multiple myeloma, Kristinsson continued. “By screening persons in particular risk groups, people with MGUS would be followed for signs and symptoms of a malignant transformation. According to our findings, this leads to better overall survival in those who progress.”
“It is important to note that most individuals with MGUS will never develop myeloma or a related disease. We do not at this moment recommend screening programs for MGUS. This needs to be discussed thoroughly, taking into account all aspects of this, including costs, benefits, and potential patient anxiety.”
But those diagnosed as having MGUS should have lifelong follow-up, he said. “As individuals with MGUS are at an increased risk of myeloma and other related diseases, it is recommended by the IMWG guidelines to follow these patients indefinitely. The current recommendations suggest less frequent monitoring for low-risk patients, but not the absence of follow-up for these individuals.
“Our observations stress the importance of clinical follow-up in MGUS, regardless of risk stratification.”
Practicing oncologists need to present patients in MGUS with information about the risk of progression to malignant neoplasm, which, on average, is one to two percent. “However, this varies somewhat based on risk stratifications. Patients should receive balanced information stressing both the overall very low risk of progression to malignant disease, but also about what symptoms could signal such development and the need to consult their physician.”
Summing up, Kristinsson said his message to clinicians is: “Keep following MGUS patients and inform them about the signs and symptoms of progression, as we do not see these patients very often.”
MGUS Randomized Trial?
Rajkumar noted that the 2010 Mayo Clinic study (of which he was senior author) “showed that if we follow MGUS patients frequently, we do not catch much multiple myeloma. Only in 16 percent of MGUS patients did we have a timely diagnosis of multiple myeloma, based on careful follow-up.”
He said that at the Mayo Clinic, patients diagnosed with low-risk MGUS are checked at six months and then rechecked only if they develop symptoms that are suggestive of a multiple myeloma-related disorder. “Any MGUS patient who is not low-risk, we recommend checking at six months and one year thereafter indefinitely,” he said.
“In MGUS, everyone agrees that we should not screen low-risk patients because only small numbers go on to multiple myeloma. There is no proof that screening is helpful. Most MGUS diagnosis is made with an annual blood screen when patients come in for another condition. Annual follow-up of low-risk MGUS patients has to be proven by a randomized trial.”
But Kristinsson said that the hypothesis that detection and follow-up of MGUS may influence survival in multiple myeloma is unlikely to ever be tested in a prospective clinical study due to the large sample size needed and the very high resulting costs.
Landgren agreed that a randomized trial is never going to happen, and is not necessary: “Many questions in oncology, such as breast cancer screening and PSA testing, have not been proved in a randomized trial. It is not a practical solution to say that everything has to be done in a randomized trial.
“The consensus guidelines for MGUS follow-up were not developed from a randomized trial, but were based on observations. Now we have evidence to support the guidelines. The data do not change the guidelines, but help the guidelines to exist.”
In 2003, guidelines recommended that MGUS patients be followed annually, and the 2010 guidelines recommended that low-risk MGUS patients be followed less often. “The new data may indicate that that recomendation may not be in the best interest of individual patients in 2015,” he said, adding that it is always a challenge to write guidelines that use resources in a cautious way and offer patients the best potential benefits.
Costs of Screening
Rajkumar said, though, that the cost, inconvenience, and anxiety produced by the awareness of potential progression of a recognized MGUS, in addition to the low absolute risk of progression, probably override the possible potential benefit of screening for MGUS.
Landgren suggested that the cost of long-term testing is low compared with the cost of a major disease with complications: “Current therapy for multiple myeloma could cost from $10,000 to $15,000 per month, for an extended time. If we look at the cost of complications in that light, then lifetime testing for MGUS patients is not that expensive. With a survival benefit now shown in two studies, it is difficult for an individual physician to say there is no benefit for screening.”
He likens this to preventive maintenance for an automobile: “If you never check your car's brakes, one day the brakes may fail, and you crash. If you can maintain your car, you can prevent a problem. The two new MGUS studies show that maintenance is better. If we follow low-risk MGUS patients annually, the issue is not that we can prevent progression, but if we monitor, we can act earlier and the patients live longer.”
With the advent of new biomarkers, in November 2014 diagnostic criteria for multiple myeloma stated there is no longer a need to wait for symptomatic disease, Landgren added. “Clinicians need to know we can detect multiple myeloma by doing a blood workup, and may find a patient has disease that requires treatment. An MGUS patient who has biomarker levels outside the cutoff may require multiple myeloma therapy. The two new MGUS studies therefore support guidelines to follow patients who have this precursor disease to myeloma.”