Until recently, patients with smoldering myeloma had no option but to watch and wait for the inevitable progression to malignancy. But now, two clinical trials of immunotherapy drugs offer patients with the precancerous condition a chance to delay disease progression and perhaps add years to their lives.
Smoldering myeloma has no symptoms and is diagnosed chiefly by levels of myeloma-produced proteins (e.g., monoclonal protein, free light chain proteins) in the serum and clonal plasma cells in the bone marrow. These levels help clinicians classify patients’ disease as low, intermediate, or high risk.
Because smoldering myeloma is expected to progress to multiple myeloma, a patient’s risk level indicates how soon this progression is likely to occur. Intermediate-risk smoldering myeloma, for example, indicates a 50%–74% chance of progression to multiple myeloma within 5 years. Patients’ risk levels help determine the frequency of clinic visits to monitor their disease.
Although observation is the standard management strategy for smoldering myeloma, several clinical trials have evaluated the use of approved multiple myeloma chemotherapy regimens to delay the progression of smoldering myeloma. One recent study, a multicenter phase II trial, evaluated a regimen of carfilzomib, lenalidomide, and dexamethasone in patients with high-risk smoldering myeloma. The results were promising; however, the regimen was arduous for patients.
“Patients in that trial had two infusions a week for 8 months, plus stem cell collection for transplant-eligible patients,” said Elisabet Manasanch, M.D., an assistant professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center and a co-investigator of that trial. “Patients who have smoldering myeloma usually are not feeling sick, so it’s difficult for them to accept a disruptive treatment.”
In search of less invasive treatments to delay the progression of smoldering myeloma, Dr. Manasanch and her colleagues turned to immunotherapy. She is the principal investigator of two ongoing clinical trials of different immunotherapy approaches.
Pembrolizumab, which inhibits the immune checkpoint protein PD-1 (programmed cell death protein 1), is approved by the U.S. Food and Drug Administration (FDA) for the treatment of several advanced cancers and has been studied against multiple myeloma. Promising results from an early trial of pembrolizumab plus low-dose chemotherapy drugs in patients with relapsed/refractory multiple myeloma led to a similar phase III trial (No. 2015-1037), which is ongoing but no longer recruiting patients. To see if the drug can slow the progression of smoldering myeloma, Dr. Manasanch is leading a phase I trial (No. 2015-0371) of pembrolizumab.
The phase I trial began enrolling patients with intermediate- or high-risk smoldering myeloma in 2016 and has nearly completed enrollment. Patients receive one intravenous infusion of pembrolizumab per 3-week cycle for up to 24 cycles. The trial’s primary outcome measure is the response rate; response is defined as decreased levels of myeloma-produced proteins in the serum and urine and/or decreased levels of clonal plasma cells in the bone marrow.
Dr. Manasanch is encouraged by the early results seen in the 12 patients who have begun treatment, and she plans to present these findings at the American Society of Hematology annual meeting in December 2017. “These results are a breakthrough,” she said.
CD38 is a glycoprotein that is found on the surface of many lymphocytes and overexpressed on myeloma cells. One drug that inhibits CD38, daratumumab, is approved by the FDA for the treatment of relapsed/refractory multiple myeloma. A phase II clinical trial (No. 2015-0148) of another CD38 inhibitor, isatuximab, is currently enrolling patients who have high-risk smoldering myeloma.
Patients in the trial receive isatuximab intravenously every week for the first 28-day cycle, then every other week for five cycles, and finally every 4 weeks for up to 24 more cycles. The primary outcome measure is the response rate. The safety and feasibility of the treatment will also be evaluated.
“Our goal is to achieve a 70% response rate after 6 months of treatment,” Dr. Manasanch said. She added that she hopes to have preliminary results ready to present in 2018.
For patients with intermediate- or high-risk smoldering myeloma who wish to pursue treatment, immunotherapy drugs—with their lower toxicity profiles—are an attractive alternative to traditional chemotherapy regimens. Dr. Manasanch believes her research will help determine not only which immunotherapy drugs can best delay the progression of smoldering myeloma but also when patients need to be treated (see “Observational Study May Uncover Indicators of Smoldering Myeloma Progression,” below).
“These are important studies, and we’re finding out important things already,” Dr. Manasanch said. “We’re making major steps toward treating this disease.”
For more information, contact Dr. Elisabet Manasanch at 713-745-5067 or firstname.lastname@example.org.
Lee HC, Patel K, Kongtim P, et al. Multiple myeloma and other plasma cell dyscrasias. In: The MD Anderson Manual of Medical Oncology. 3rd ed. Kantarjian HM, Wolff RA, Eds. New York: McGraw-Hill Education; 2016:229–253.
OncoLog, August 2017, Volume 62, Issue 8
Observational Study May Uncover Indicators of Smoldering Myeloma Progression
Smoldering myeloma begins as monoclonal gammopathy of undetermined significance (MGUS), which is characterized by low levels of myeloma-produced proteins in the serum. But the progression from MGUS to smoldering myeloma and then to multiple myeloma is not well understood.
“For some patients, it can take 20 years for their disease to progress; for others, it might be a couple of years or less,” Dr. Manasanch said.
Scales to stratify MGUS and smoldering myeloma have been developed by various groups, including the Mayo Clinic, Programa para el Tratamiento de Hemopatías Malignas, and SWOG; but these scales are not 100% accurate and are difficult to interpret. Furthermore, some of these scales rely on advanced flow cytometry and gene expression profiling, which are not commonly done outside large cancer centers.
To better understand the rate of disease progression and to identify molecular markers of such progression, Dr. Manasanch is enrolling patients with MGUS and smoldering myeloma in a 3-year observational study (No. PA150575). The patients’ disease is monitored by radiographic skeletal surveys at baseline and after 1, 2, and 3 years of follow-up; bone marrow aspiration and biopsies at baseline and after 3 years of follow-up; and standard blood and urine tests every 6 months. If signs of progression to multiple myeloma are seen, additional tests may be performed as clinically indicated.
“In the observational study and in our trials of pembrolizumab and isatuximab, we’re collecting data on the markers used to stratify MGUS and smoldering myeloma,” Dr. Manasanch said. “We hope this information will lead to a better scale for clinical use. We want to find markers that show when patients are going from a benign condition to something that can potentially be dangerous to their health.”