In most malignancies, early detection and intervention are prerequisites for a possible cure. Consequently, why is the standard of care for myeloma a watch-and-wait approach, with no treatment until progression?
Asymptomatic, active, 53-year-old woman was found to have an elevated erythrocyte sedimentation rate (ESR) with elevated serum proteins (90 g/L) in routine examination
Complementary studies revealed normal hemoglobin, creatinine, and serum beta-2-microglobulin
M component: 35 g/L; plasma cells (PCs) in bone marrow (BM): 33%
FISH analysis: Rb deletion and t(4:14)
No lytic lesions were detected; magnetic resonance imaging (MRI) showed osteoporosis with 1-2 focal lesions
a(The full-panel discussion can be accessed at:http://www.youtube.com/watch?v=FNw7bctXqfgThe panel was sponsored jointly by the International Myeloma Foundation, the Annenberg Center for Health Sciences, and Clinical Care Options) Before the presentations, audience members voted on whether or not to recommend starting systemic myeloma therapy for the following patient. The result: 61% no, 39% yes. At the conclusion of the presentations and discussion, the vote was essentially unchanged.
Thus, before the opening of the official 55th Annual American Society of Hematology (ASH) meeting in December 2013, two members of an international panel of myeloma experts, one from Spain and one from the United States, presented opposing arguments for the treat versus watch-and-wait approaches for a sample patient case of HR-SMM (Table). The panel, which featured three other presentations on current research regarding myeloma, was moderated by Brian G.M. Durie, MD, founder and chair of the International Myeloma Foundation and hematologist/oncologist at Cedars-Sinai Medical Center in Los Angeles, California.
A consensus emerged from both sides that while patients with “early myeloma or ultra-high-risk SMM require treatment,” a better definition of HR-SMM is needed, along with clinical trials that may answer the critical question of whether or not early intervention changes the natural history of the disease.Results from clinical trials in SMM have been mostly consistent in finding no benefit from early treatment.
In studies of bisphosphonates versus observation, the bisphosphonates have been found to delay the time to skeletal events, but not the time to progression (TTP). More recently, studies with thalidomide plus zoledronic acid (ZOL) versus no ZOL for early versus delayed intervention found no benefit in TTP, in symptomatic disease, or in overall survival (OS).
However, the risk of progressive disease to active disease is “heterogeneous,” said Jesús F. San Miguel, MD, PhD, from Universidad de Navarra, Spain. “None of these trials discriminates between low-risk patients who are not likely to benefit from intervention (and) highrisk patients who may well benefit from therapy,” San Miguel stated.
One recent trial is an exception. The randomized, phase III trial from the Spanish myeloma group produced the first evidence of an improvement in OS in a group of patients with SMM whose disease met either the Mayo or the Spanish classification criteria for HR-SMM, defined as 50% risk of progression within 2 years. These criteria require 10% or more PCs in the BM plus ≥3 g/dL of MC1or most of the PCs (>95%) being clonal plus immunoparesis.2
In this study, 119 patients were randomized to receive either lenalidomide plus dexamethasone or no treatment for nine cycles, followed by lenalidomide maintenance. Patients who progressed on lenalidomide maintenance could receive low-dose dexamethasone based on biologic progression alone (not clinical progression).
At a median of 40 months, the response rate (RR), TTP, and OS favored the experimental treatment arm. “Over 80% of patients (in the lenalidomideplus- dexamethasone arm) responded, with over 15% [experiencing] complete responses,” San Miguel said. “During the maintenance phase, the sCR plus CR rate increased to 26%.”
This RR was clearly different from what has been previously reported for thalidomide, and very similar to the RR that the Spanish group observed with lenalidomide/dexamethasone in symptomatic patients.
“The simplest explanation for me is that we are dealing with different populations of patients,” said San Miguel.
The primary endpoint of the Spanish study was TTP. Median TTP was significantly longer in the treatment group than in the observation group (the median was not reached at 21 months; hazard ratio [HR] for progression .18; 95% confidence interval [CI] .09-32;P<.001). A total of 76% of patients had already progressed in the observation arm, indicating a veryhigh- risk population, versus only 23% clinical progression in the experimental arm.”
What was most striking to myeloma experts was the OS data in the Spanish trial. With a median follow up of 47 months, there was a clear OS advantage for the lenalidomide/dexamethasone arm. “At 5 years, 95% of the patients are alive versus 78% of patients in the no treatment arm.”
Side effects were primarily grade 2 or lower and less than 10% of grade 3 side effects were seen.
To many, these data provide compelling evidence that early intervention could be beneficial for patients with HRSMM.
SanMiguel conceded that some physicians would argue that a proportion of patients even in the high-risk population will never progress, and, based on this, they would require that better criteria be used to define high risk.
But, he asked: “Can (the risk of) 30% of patient (overtreatment) justify the risk of undertreating the 70% who would benefit from treatment?”Two significant problems persist in the care of patients with MM. The first is that a correct definition of MM is lacking, according to S. Vincent Rajkumar, MD, professor of medicine at the Mayo Clinic, Rochester, Minnesota, speaking on behalf of the ’no treatment‘ choice of SMM. The second, he said, is that, “We are talking about multiple diseases but we are considering them as one disease.”
The disease definition of MM is currently based on end-organ damage, and according to Rajkumar and some colleagues, this needs to change.
In an effort to redefine MM,3Rajkumar, along with San Miguel and other myeloma colleagues, identified these subgroups of patients with SMM who have ultra-high-risk disease:
Rajkumar explained: “We need to recognize that the various cytogenetic subtypes of SMM progress to MM at different rates, and each subtype may actually represent a distinct disease entity.”
Rajkumar described three subgroups of SMM:
“What we have right now,” said Rajkumar, “is a small cohort of patients with myeloma who are ultra-high risk. Then we have patients with HR-SMM who have about a 25% high risk per year of progression.”
The real debate, according to Rajkumar, is not about the management of ultra-high-risk or low-risk SMM, but rather whether or not clinicians should treat patients in the middle, with HRSMM, who, according to most studies, have shown evidence of progressionfree survival but no survival advantage. Showing an improvement in OS, the Spanish myeloma trial poses the question of whether or not there should still be a debate about treatment of HR-SMM.
BMPC, bone marrow plasma cells; FLC, free light-chain ratio; PC, plasma cells; SMM, smoldering multiple myeloma.
In other words, the key clinical question is: should not all patients with HRSMM be treated?
Perhaps not, Rajkumar suggested. “The first problem with the Spanish trial that we need to address is that it is not generalizable to a large proportion of the (patient population). One-half of the patients in the Spanish trial1 were enrolled based on the results of a flow cytometrybased assay that is not generally available.”
The second problem, according to Rajkumar, is that the actual event rate in the Spanish trial is small. “The entire survival difference is based on a death rate of 4 deaths (of 57 patients) in the treatment group versus 13 deaths (of 62 patients) in the observation group. Even minor imbalances in the cytogenetics of the patients, such as deletion 17p and t(4;14) at baseline could have skewed the OS difference (between treatment groups).”
Another question is whether or not the survival benefit in the Spanish trial could have been conferred by the dexamethasone. This question will be investigated in a study under recruitment, led by Sagar Lonial, comparing lenalidomide versus observation in asymptomatic patients with HR-SMM.4
For patients whose disease bears ultra- high-risk features (≥60% PCs in BM, FLC ratio ≥100, and >1 focal lesion on MRI), Rajkumar urged: don’t wait, because these patients will progress rapidly or get renal failure very quickly.”
“This is not (the patient) we are speaking about,” he said. “We are speaking about the high-risk patients: abnormal immunophenotype, abnormal FLC ratio; ≥3 g M protein, and ≥10% plasma cells.” For this patient group, “We still need to do clinical trials if we are to make this a reality for patients,” he said (Figure).
A discussion led by moderator Durie established the contours of a consensus among panel members.
Although the typical clinical manifestations of MM are summarized by the CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone lesions), a significant proportion of patients with MM present with a variety of other clinical manifestations.5In one recent study,5among patients with symptomatic MM, 74% presented with CRAB symptoms, 20% presented with non-CRAB manifestations, and 6% had both clinical features.
“For patients who already have high risk of progression within 2 years (≥80%), there is no reason to wait for the other shoe to drop…and have some catastrophic problems before we initiate therapy. We basically have to take the 15% to 20% or so of patients who we currently call smoldering and treat them as early as possible, at pre-CRAB myeloma. The remaining 80% should be enrolled in clinical trials that will seek to answer the question whether early intervention changes the natural history of the disease,” Durie stated.
“The major issue is to update CRAB criteria (taking into account) the new criteria and new technology available to define early myeloma, and to better (discriminate) the benign tumor from the malignant tumor that is myeloma, taking out the gray zone that is the mix of the malignant and the benign,” Durie said.