A number of studies to be presented at this year’s American Society of Hema­tol­o­gy (ASH) meeting look at diseases that can progress to mul­ti­ple mye­lo­ma.

These 'myeloma precursor diseases,' as they are sometimes called, in­clude mono­clon­al gammopathy of undetermined significance (MGUS) and smoldering myeloma.

In today's ASH preview article, The Beacon turns its attention to myeloma pre­cursor diseases, reviewing the key studies about them that will be presented at ASH this weekend and early next week.

The results discussed in this article are those that have been published in the meeting abstracts.  Many of these results are likely to be updated during the presentations at the meeting.

The key studies related to smoldering myeloma examine the impact of actively treating the disease with different anti-myeloma therapies. There is likely to be substantial interest in these studies because active treatment of smoldering myeloma is currently a controversial practice.

In addition, a number of the key studies related to MGUS and smoldering myeloma investigate factors that may predict whether a patient with one of those diseases is particularly likely to progress to multiple myeloma.

Also, results of a French study will be presented indicating that certain infections may play a very important role in the development of myeloma precursor diseases and multiple myeloma itself.

Smoldering Myeloma

Smoldering myeloma is a precursor disease that can progress to multiple myeloma. The disease is char­acterized by an excess of monoclonal protein in the blood and urine, but, by definition, smoldering myeloma patients do not have any myeloma-related symptoms, such as elevated calcium levels, kidney damage, anemia, or bone lesions. A diagnosis of smoldering multiple myeloma is made when a patient’s mono­clon­al protein level (M-spike) is at least 3 g/dL or the proportion of plasma cells in the bone marrow is at least 10 percent.

The risk of progression from smoldering myeloma to symptomatic myeloma is estimated to be about 10 percent per year during each of the first five years after diagnosis, 3 percent per year for the following five years, and 1 percent per year thereafter.  This means that the median time to progression to active (symp­to­matic) disease for a newly diagnosed smoldering myeloma patient is about five years.

The current standard of care for smol­der­ing myeloma is a ‘watch and wait’ approach, which involves mon­i­tor­ing the patient regularly and beginning treatment only after the disease progresses to symptomatic mye­lo­ma.  This approach is based on research carried out a number of years ago, showing that active treatment of smoldering myeloma does not have an impact on overall survival, yet exposes patients to chemotherapy – and therefore side effects – for a longer period of time.

Recent results of an important Spanish study, however, suggest that treatment may delay disease pro­gres­sion and extend overall survival for certain smol­der­ing myeloma patients at high risk of progressing to symp­to­matic myeloma (see related Beacon news articles 1 and 2).

One of the presentations to be made at this year’s ASH meeting will summarize updated results from an on­going Phase 2 study of Kyprolis (carfilzomib) in combination with Revlimid (lenalidomide) and dexa­metha­sone (Decadron), followed by Revlimid extended dosing, in high-risk smoldering myeloma patients (ab­stract). Initial results of the study were presented at the International Myeloma Workshop in Japan earlier this year (see related Beacon news).

Thus far, the study includes 12 high-risk smoldering multiple myeloma patients. After a median of six treat­ment cycles, all of these patients have responded to treatment, with 58 percent achieving a complete re­sponse or stringent complete response, 17 percent a near complete response, and 25 percent a very good partial response. An additional 16 patients are currently being recruited to participate in the trial.

Another presentation will summarize initial results of a U.S. Phase 2/3 trial investigating the efficacy and safety of Revlimid treatment for high-risk smoldering myeloma (abstract).

The results of this trial are likely to attract particular attention because, superficially, the trial is similar to the Spanish study that has sparked debate about whether or not high-risk smoldering myeloma patients should be actively treated.

The U.S. trial differs from the Spanish trial, however, in that patients in the U.S. trial are being treated with Revlimid alone -- not Revlimid and dexamethasone.  In addition, the investigators conducting the U.S. trial note that the criteria used to select high-risk smoldering myeloma patients for their trial differ from the criteria used in the Spanish trial.

Investigators will report results from the Phase 2 portion of the U.S. trial at ASH.  That part of the trial enrolled 44 patients.  Among those patients, approximately 30 percent responded to treatment, and most of the rest had stable disease.  With a median follow-up time of 17 months, 5 percent of patients have progressed on therapy. Patients are currently being recruited for the Phase 3 portion of the trial, which will have two arms -- one in which patients are actively treated with Revlimid, and a second in which patients are not.

Also at the ASH meeting, researchers will present findings from a study investigating the effect of low-dose Velcade (bortezomib) on bone formation and disease progression in smoldering myeloma patients (ab­stract). The researchers found that bone density increased significantly in 46 percent of patients. In addi­tion, none of the patients in the study have progressed to symptomatic myeloma after a median follow-up time of 20 months.

MGUS

MGUS is another myeloma precursor disease, characterized by an elevated level of monoclonal (M) protein in the blood. MGUS is clinically defined as having less than 10 percent plasma cells in the bone marrow and an M-spike less than 3 g/dL.

The current standard of care for MGUS is also the ‘watch and wait’ approach, in which patients are moni­tored and not treated unless they progress to symptomatic myeloma.  People with MGUS typically pro­gress to symptomatic myeloma at a rate of 1 percent per year.

A French study to be presented at ASH will show that certain infections may play a key role in the devel­op­ment of MGUS and multiple myeloma (abstract). The study, which draws on data from 101 patients, finds that 21 percent of the patients with MGUS and 24 percent of the patients with multiple myeloma had M-proteins at diagnosis that were specific for an antigen from the hepatitis C virus, the Epstein-Barr virus, or H. pylori bacteria.

Another presentation will summarize findings from a study that sought to identify early predictors for pro­gression from MGUS to symptomatic multiple myeloma (abstract).  Previous studies have shown that the M-protein concentration – the ratio of M-protein to total protein – and an abnormal serum free light chain ratio are predictors for progression of MGUS to symptomatic myeloma.  The investigators of the current study found that the number of polyclonal gamma globulins suppressed, the degree of polyclonal suppression, and IgM gamma globulin suppression were also associated with an increased risk of progression to symp­to­matic myeloma.

Results of a large retrospective analysis will be presented showing that MGUS patients with an abnormal free light chain ratio are at an increased risk of developing kidney disease (abstract). M-proteins are made up of light chains and heavy chains. When light chains – of which there are two types (kappa and lambda) – enter the blood stream unattached to the heavy chains, they are then referred to as free light chains and can impair kidney function.

The results of the current study show, in particular, that MGUS patients with a kappa-to-lambda light chain ratio outside the normal range are significantly more likely to develop kidney disease.  In addition, among MGUS patients who have an abnormal free light chain ration, those with free light chain levels above 100 mg/L were particularly likely to develop kidney disease.

Another study, which was conducted at the Mayo Clinic and will be presented at ASH, investigated the de­vel­opment of solid tumor cancers in MGUS patients (abstract). The results suggest that MGUS patients are at a higher risk of having respiratory cancers, but not any other type of solid tumor cancer, compared to the general population. However, when the researchers looked only at cancers discovered in MGUS patients after their MGUS diagnosis, the patients did not have a higher-than-normal risk of developing respiratory cancers -- or, for that matter, any other solid tumor cancer.

Studies Involving Both MGUS And Smoldering Myeloma Patients

A couple of studies will be presented at this year’s ASH meeting that involve both MGUS and smoldering myeloma patients.

One presentation will summarize results of a Spanish study that investigated the prognostic impact of heavy/light chain pairs in both MGUS and smoldering myeloma patients (abstract).

Patients with multiple myeloma or one of its precursor diseases MGUS or smoldering myeloma over­pro­duce a single type of antibody, known as monoclonal or M-protein. Each M-protein is comprised of heavy chains and light chains. A person’s myeloma cells produce M-proteins with IgG, IgA, IgM, IgD, or IgE heavy and light chains.

The results of the Spanish study show that normal or lower than normal heavy/light chain ratios for IgG and IgM monoclonal proteins in patients with MGUS or smoldering myeloma were associated with longer time to progression to symptomatic disease than higher values of these ratios.  The result is intriguing, in that an earlier study found that higher heavy/light chain ratios are associated with longer survival in myeloma pa­tients who have achieved a complete response after stem cell transplantation (see related Beacon news).

Another presentation will summarize the results of a study focusing on the chromosomal features of MGUS and smoldering myeloma patients (abstract), specifically translocations involving chromosome 14 that in turn affect the heavy chain portion of monoclonal proteins. The investigators found that 42 percent of MGUS and smoldering myeloma patients had chromosome 14 translocations, which is similar to the rate seen in myeloma patients.  However, t(14;16) was twice as common in people with a precursor disease, while t(4;14) was more common in people who had myeloma.  The researchers also found that translocations that affect the FGFR3 gene, a gain of the chromosomal region 1q21, and deletion of the TP53 gene were present in smoldering myeloma but not in MGUS.

Finally, researchers will present a proposed new method of classifying MGUS and smoldering myeloma patients by risk of progression to symptomatic multiple myeloma (abstract). The researchers identified eight factors – including IgM monoclonal protein, progesterone levels, hemoglobin, age, and levels of several additional proteins – that together appropriately classified 86 percent of patients as having either a low or high risk of pro­gressing.

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For information about additional studies that will be presented at ASH, see a list of all myeloma-related ASH abstracts, all abstracts about new treatments under development for myeloma, clinical trial results for new treatments, and preclinical research about new treatments.