NEJM: REVLIMID + DEXAMETHASONE in plasma cell cancer. Dr.M.M. MATEOS; SALAMANCA

Revlimid Plus Dexamethasone Delays Progression And Extends Survival In High-Risk Smoldering Myeloma Results from a Spanish Phase 3 study published late Wednesday in the New England Journal of Medicine indicate that treatment of high-risk smol­dering multiple myeloma with Revlimid plus dexamethasone delays pro­gression to symptomatic multiple myeloma and extends overall sur­viv­al. In addition, the Revlimid (lenalidomide)-dexamethasone (Decadron) regi­men had an acceptable safety profile, according to the investigators. Despite these findings – which would tend to support active treatment of high-risk smoldering myeloma – myeloma experts believe it is too early to begin treating all high-risk smoldering myeloma patients with anti-myeloma therapies. Dr. María-Victoria Mateos of the University Hospital in Sala­manca, Spain is one of the lead investigators of the study. She told The Beacon that “This is the first randomized trial showing a significant benefit to early treatment of high-risk smoldering myeloma patients. However, Revlimid-dexamethasone is not an approved combination for newly diagnosed myeloma patients, and we therefore have to wait to obtain this approval and to obtain additional results of other trials that are currently ongoing in high-risk smoldering myeloma patients.” Whether or not Revlimid is officially approved as a treatment for smoldering myeloma, however, is likely to be a more important consideration outside of the United States. U.S. physicians typically have more flexi­bil­i­ty to prescribe drugs “off label” than their international counterparts. “These results are very promising and strongly support further studies of novel agents in this group of patients with early stage disease,” said Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston. Dr. Richardson, who was not involved with the study, added, however, that “to recommend that all high-risk smoldering myeloma pa­tients now receive combination therapy as a standard of care is premature in my view.” “Moreover, the need to re-evaluate definitions of high-risk smoldering myeloma is an important next step, especially given the striking differences seen in outcome between patients who were treated, and those who were only observed,” noted Dr. Richardson. Dr. Richardson stated that he currently recommends high-risk smoldering myeloma patients participate in clinical trials, and that he also considers treatment with bisphosphonates for patients with evidence of early bone disease, such as osteopenia. Common bisphosphonates include Aredia (pamidronate) and Zometa (zoledronic acid). Dr. Mateos added that other treatment regimens should also be studied in high-risk smoldering myeloma patients. “I think that high-risk smoldering multiple myeloma constitutes an attractive population in which to evaluate novel agents,” stated Dr. Mateos. She also said that there are several additional ongoing trials “evaluating the role of other agents – such as proteasome inhibitors, monoclonal antibodies, Revlimid alone without dexamethasone, etc. – in this patient population.” Background Smoldering, or asymptomatic, multiple myeloma is a precursor to multiple myeloma in which the patient experiences none of the symptoms typically associated with active (symptomatic) multiple myeloma, such as ele­vated calcium levels, kidney failure, anemia, or bone lesions. Smoldering myeloma is characterized by an excess of monoclonal protein in the blood and urine. A diag­nosis of smoldering multiple myeloma is made when a patient’s monoclonal protein level is at least 30 g/L or the proportion of plasma cells in the bone marrow is at least 10 percent, but the patient does not experi­ence any of the typical myeloma symptoms. The risk of progression from smoldering myeloma to symptomatic disease is around 10 percent during each of the first five years after diagnosis, and decreases to 3 percent per year for the following five years, and to 1 percent per year thereafter. This means that the median time to progression to active disease for a newly diagnosed smoldering myeloma patient is about five years. Although smoldering myeloma patients are at a higher risk of developing active myeloma than the general public, the current standard of care is the so-called “watch and wait” approach, in which smoldering mye­lo­ma patients are regularly monitored and treatment only begins once the disease progresses to multiple myeloma. However, certain factors have been shown to be associated with an increased risk of progression to symp­to­matic disease in patients with smoldering multiple myeloma. These include: a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10 percent in the bone marrow; an elevated level of abnormal plasma cells in the bone marrow; an abnormal ratio of small parts of antibodies (known as an abnormal free light chain ratio); the presence of chromosomal abnormalities in the plasma cells; and lower-than normal levels of one or more types of immunoglobulin. Studies at the Mayo Clinic and in Spain have found that patients with several of these risk factors can be considered to have “high risk” smoldering myeloma, meaning that the patients have a higher risk of pro­gressing to symptomatic myeloma than other smoldering myeloma patients. An earlier Spanish study showed, for example, that smoldering myeloma patients with several high-risk disease factors had a median time to progression of about two years. Several clinical trials during the past 30 years have investigated early treatment of smoldering myeloma patients with melphalan (Alkeran) plus prednisone, thalidomide (Thalomid), and/or bisphosphonates. None of these trials supported early treatment of smoldering myeloma patients, with no benefits seen in terms of significantly longer time to progression or overall survival. These older trials, however, did not distinguish between standard-risk and high-risk smol­dering multiple myeloma patients. The investigators of the current study state that high-risk smoldering myeloma patients are more likely to benefit from early treatment than standard-risk patients. Since these patients do not have any symptoms, the researchers add that the ideal therapy for them should have limited side effects. Dr. Mateos previously presented some of the results from this study and discussed their potential im­pli­ca­tions at the International Myeloma Workshop this spring (see related Beacon news). Additionally, Dr. Ola Landgren, a smoldering myeloma expert from the National Institutes of Health who was not involved with the study, discussed the implications of preliminary results from the study early last year (see related Beacon news). Study Design In this Phase 3 clinical trial, researchers from across Spain investigated whether treatment with Revlimid plus dexa­methasone would prolong the time it took for high-risk smoldering multiple myeloma patients to progress to symptomatic multiple myeloma. A total of 119 high-risk smoldering myeloma patients recruited between 2007 and 2010 were randomly assigned to receive early treatment (57 patients) or to be observed until progression (62 patients). The two groups of patients had median ages of 63 years and 69 years, respectively. The criteria for being considered high-risk were plasma-cell bone marrow infiltration of at least 10 percent and a monoclonal component (defined as an IgG level of at least 30 g/L, an IgA level of at least 20 g/L, or a urinary Bence Jones protein level of more than 1 g per 24 hours). Alternatively, the patients could have only one of the two criteria described above, plus at least 95 percent abnormal plasma cells in the bone marrow, with reductions in one or two uninvolved immunoglobulins of more than 25 percent compared to normal values. Patients in the treatment arm received an initial therapy consisting of nine four-week cycles of Revlimid plus dexamethasone. During each cycle, they received 25 mg of Revlimid daily on days 1 to 21 and 20 mg of dexamethasone daily on days 1 to 4 and 12 to 15. They then received maintenance therapy consisting of 10 mg of Revlimid on days 1 to 21 every four weeks until disease progression or two years of treatment. Patients in the non-treatment arm did not receive any form of treatment until progression to symptomatic multiple myeloma. The median follow-up time was 40 months. Results After initial treatment with Revlimid plus dexamethasone, 79 percent of high-risk smoldering myeloma patients responded, with 7 percent achieving a stringent complete re­sponse, 7 percent a complete re­sponse, 11 percent a very good partial response, and 54 percent a partial response. In total, 88 percent of the treated patients completed initial therapy and started maintenance therapy. Among those patients, the overall response rate was 90 percent. In addition, 24 percent of patients experienced improvements in their quality of response during the maintenance phase of treatment. Treatment of high-risk smoldering myeloma significantly delayed time to progression. Specifically, the medi­an time to progression was not yet reached for patients who received treatment, compared to 21 months for those who were observed. Three years after entering the study, the progression-free survival rate was 77 percent for patients who re­ceived treat­ment and 30 percent for those who did not. Click on image to view a larger version of it. In addition, patients who received treatment had significantly longer overall survival. Five years after di­agnosis, the overall survival rate was 94 percent for those who received treatment compared to 78 percent for those who were not treated. (Click here or on the image to the right to see a larger graph of the key overall survival results.) The investigators found that the time from di­ag­nosis to the time the patient started the clinical trial did not influence their time to pro­gres­sion to multiple myeloma. Severe side effects during the initial Revlimid-dexamethasone therapy phase were more common among the patients who received treatment (12 percent) compared to those who were observed (3 percent). No patients experienced severe side effects during maintenance therapy. The most common severe side effects during the initial treatment phase were infections (6 percent of pa­tients), weakness (6 percent), low white blood cell counts (5 percent), and rash (3 percent). The research­ers noted that infections were equally common among patients who received treatment and those who did not. One patient died from a respiratory infection that was identified as a side effect of treatment. A total of 6 percent of treated patients and 2 percent of those who were not treated reported developing secondary cancers. The researchers stated that 75 percent of these patients had early signs of a second cancer at the time they started the study. For more information, see the study in the New England Journal of Medicine (abstract), the related Celgene press release, and a presentation from the 2013 International Myeloma Workshop which summarizes some of the study results (courtesy of Dr. Mateos).