Early Treatment of Smoldering Myeloma: Is It Time?

Alexander M. Castellino, PhD

July 19, 2016

Patients diagnosed with smoldering myeloma are usually followed with observation until they start to develop symptoms, but now long-term results have confirmed that early treatment can delay progression. So should this strategy of early treatment move from clinical trials to clinical practice?

The new results come from a long-term follow-up of patients taking part in the phase 3 QuiRedex study, which reported in 2013 that the early treatment of high-risk smoldering myeloma with lenalidomide (Revlimid, Celgene Corporation) and dexamethasone (multiple brands) was associated with significantly high response rates (N Engl J Med. 2013;369:438-447).

The long-term follow-up, published online July 8 in Lancet Oncology, now shows that in patients receiving lenalidomide and dexamethasone, the median progression to myeloma had not been reached after 75 months; for those patients followed with observation alone, which is currently the standard of care, median progression was 23 months. The hazard ratio for progression was 0.24 (95% confidence interval [CI], 0.14 - 0.41; P < .0001). This translates to a 75% reduced risk for myeloma progression for patients receiving early treatment.

"[To] our knowledge, this is the first randomised trial in which early treatment has been assessed in selected patients with high-risk disease," Maria-Victoria Mateos, MD, of the Hospital Universitario de Salamanca, Salamanca, Spain, and colleagues comment.

"Positive results from ongoing trials would support the use of early treatment for patients with high-risk smouldering multiple myeloma in the near future," they colleagues write.

"[This study] of early treatment in patients with high-risk smouldering myeloma is likely to change the present strategy of no treatment," Heinz Ludwig, MD, of the Wilhelminen Cancer Research Institute, Vienna, Austria, writes in an accompanying commentary.

However, he indicated that before proceeding to treat all such patients, these results need to be confirmed in a large prospective study. In addition, all patients should undergo whole-body low-dose CT scanning or positron-emittion tomography CT scanning at baseline to rule out early myeloma.

"Until then, watchful follow-up or inclusion in one of the several ongoing trials (NCT01169337, NCT02415413, NCT02316106) remains standard," Dr Ludwig concludes.

The notion is supported by myeloma expert Sagar Lonial, MD, chair and professor in the Department of Hematology and Medical Oncology and chief medical officer at the Winship Cancer Institute, Emory University, Atlanta, Georgia.

Dr Lonial told Medscape Medical News, "This study is important, as it shows that treatment of smoldering patients does not limit their outcomes, which was the case with previous types of treatment. However, there are issues with the patients enrolled that limit the ability for this single study to change practice."

He indicated that patients in the QuiRedex trial needed more imaging and closer follow-up to better define how this new information should be used. "Many of the patients in the observation group had adverse events and death occur very early, suggesting that there were several patients who probably had active multiple myeloma rather than smoldering disease," Dr Lonial said.

Updating Diagnostic Criteria for Multiple Myeloma

The study authors point out that when the trial was designed (patients started enrolling in 2007), it was not yet common practice to use diagnostic investigations, as are used now. "[We] are unable to establish whether or not these new criteria would have affected the results because these criteria were not applicable when we designed the study," Dr Mateos and colleagues write.

In 2014, following the positive results of this study, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for multiple myeloma to include three biomarkers, Dr Mateos and colleagues note.

Dr Lonial explained that in addition to the clinical criteria known as CRAB (hypercalcemia, renal failure, anemia, and bone lesions), the updated IMWG diagnostic criteria include three additional findings for further defining active myeloma. These include serum free–light chains ratio >100, ≥60% plasma cells, and ≥1 focal lesion by MRI.

"These new criteria are now required in the assessment of patients with smouldering multiple myeloma and, if present, patients should be considered as candidates with active disease necessitating immediate treatment," Dr Mateos and colleagues write.

As noted in the updated diagnostic criteria: "The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.”

The QuiRedex Study

QuiRedex was an open-label, randomized, controlled phase 3 study conducted across several centers in Spain and Portugal. Risk stratification was based on the Mayo Clinic model and the Spanish Myeloma Group model. High-risk disease was defined as ≥10% bone-marrow plasma cell infiltration and presence of monoclonal component (IgG ≥3 g/dL or IgA ≥2 g/dL or Bence-Jones proteinuria >1 g/24 hr) or one of the two criteria in addition to ≥95% phenotypically aberrant plasma cells in the bone-marrow plasma cell compartment with immunoparesis. Analysis by risk stratification using the two models separately was also undertaken.

The primary endpoint of the study was progression to symptomatic myeloma, defined as the presence of high-risk disease meeting one or more of the CRAB criteria.

Of 125 patients who were enrolled between 2007 and 2010, 57 were randomly allocated to receive combination therapy, and 62 were assigned to the observation arm of the study. Patients receiving combination therapy were given nine 4-week cycles of oral lenalidomide and dexamethasone as induction therapy followed by maintenance therapy for a total of 2 years (induction+maintenance).

Details of Results

The initial analysis indicated that early treatment with lenalidomide and dexamethasone significantly delayed progression to symptomatic myeloma. In this long-term analysis, the clinical benefits were sustained with early treatment — median time to progression not reached (95% CI, 47 months to not reached) vs 23 months (95% CI, 16 - 31 months) for patients undergoing observation alone.

In a post hoc analysis, the Mayo risk model provided a 79% reduced risk for progression to multiple myeloma (HR, 0.21; 95% CI, 0.10- 0 .40; P < .0001), and the Spanish risk model provided a 73% reduced risk for progression to multiple myeloma (HR, 0.27; 95% CI, 0.15 - 0.46; P < .0001).

Progression to multiple myeloma was also seen in significantly fewer patients receiving early treatment — 39% (22/57 patients) vs 86% (53/62 patients).

Anemia was the most frequent myeloma-defining event — 64% (14/22) in the treatment group, and 53% (28/53 patients) in the observation group — followed by bone disease (45% vs 43% for observation), renal failure (13% vs 15% for observation), and hypercalcemia (5% vs 8% for observation).

Early treatment was also associated with a 57% reduced risk for death (HR, 0.43; 95% CI, 0.20 - 0.90; P = .027). Survival was significantly longer for the early-treatment group (not reached vs 117.6 months for observation only), with 18% and 36% mortality in the early-treatment group and observation group, respectively.

After progression to multiple myeloma, 39% of patients in the early-treatment group and 85% of patients in the observation group received subsequent treatment with protease inhibitor or immunomodulatory drug combinations, or high-dose chemotherapy followed by autologous stem cell transplant. Rescue treatment was associated with high overall response rates — 77% (17/22 patients) in the early-treatment group and 85% (45/53 patients) in the observation group.

Dr Lonial indicated that the risk/genetics of the patients in the two groups were unknown. "If they were imbalanced, it could impact the overall survival of the patients in one group vs another," he said.

“In addition, comprehensive bone imaging (with modern technology such as MRI) was not performed at study entry, so many of these patients may have fit the definition of symptomatic myeloma, not smoldering, calling into question the difference in progression-free survival and overall survival," Dr Lonial said.

Adding Another New Agent?

Before the advent of novel agents to treat multiple myeloma, improving outcomes for patients with smoldering myeloma was "futile," owing to the lack of available efficacious agents and the heterogeneous nature of smoldering disease, Dr Ludwig explains in his commentary. All this has now changed, he writes: risk stratification algorithms (Mayo and Spanish) are now available, as are a number of new myeloma drugs.

Commenting on the new QuiRedex results, he notes that early treatment was associated with 79% of patients achieving a response, including 14% complete or stringent responses after the induction phase.

"Although the rate of complete or stringent complete response increased to 26% during maintenance therapy, achievement of higher rates is desirable," he stated. "Therefore, new combinations including both an immunomodulatory

drug and a proteasome inhibitor should be explored."

He points out, as do the study authors, the recent results achieved with the addition of carfilzomib (Kyprolis, Amgen Inc) to the combination of lenalidomide and dexamethasone. This triplet achieved a near complete response or better in 100% of patients with high-risk smoldering myeloma, with 11 of 12 patients testing negative for minimal residual disease (JAMA Oncol. 2015;1:746-54). This provides a rationale to explore new combinations, which include a combination of an immunomodulatory drug and a proteasome inhibitor, Dr Ludwig indicates.

Approaches Investigated in Ongoing Studies

"Overall, these findings demonstrate the relevance of a treatment approach focused on early intervention with lenalidomide plus dexamethasone for patients with high-risk disease, rather than reserving optimum treatments until the moment of progression," Dr Mateos and colleagues write.

They note that the combination of carfilzomib, lenalidomide, and dexamethasone "would represent an optimum platform to design approaches to early intervention, with cure as a more ambitious objective."

The study authors point out other ongoing intervention trials in high-risk smoldering myeloma patients. These include testing lenalidomide, siltuximab (Sylvant, Janssen), elotuzumab (Empliciti, Bristol-Myers Squibb), and carfilzomib, some being evaluated alone and some in combination.

Dr Lonial notes that the National Cancer Institute's E3A06 trial (NCT01169337), which is also ongoing, is testing lenalinomide alone vs observation in patients with smoldering intermediate or high-risk myeloma. Patients are seen every month in each arm, and all patients must undergo MRI imaging at the minimum to be enrolled into the trial, he explained.

"Until that trial [E3A06] or another randomized trial is completed with results, smoldering patients should be observed or enrolled into a trial," Dr Lonial said, echoing the conclusion made by Dr Ludwig in the editorial.

The study was funded by Pethema—the Spanish Program for the Treatment of Hematologic Diseases. Several authors of the QuiRedex study receive honoraria, consulting fees, and/or grant support from industry. Dr Ludwig has disclosed no relevant financial relationships. Dr Lonial is a consultant for several pharmaceutical companies.

Lancet Oncol. Published online July 8. Abstract, Commentary

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