Researchers from the U.S. National Institutes of Health (NIH) recently pub­lished what they describe as a "curative blueprint" for myeloma.

The "blueprint" outlines key issues the researchers believe need to be ad­dressed if medical science is to achieve a cure for myeloma.

A crucial question that needs to be answered, the researchers argue, is whether treating "early myeloma" is more advantageous than waiting until the disease has progressed to the symptomatic, or active, stage.

The NIH researchers define "early myeloma" as symptomatic myeloma with limited organ damage, or smol­dering multiple myeloma with the highest risk of progression.

The researcher's first question, related to the treatment of "early myeloma," leads to a second issue, which the authors also highlight.  It is the need to identify which patients with the myeloma precursor diseases smoldering multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) are most likely to pro­gress to symptomatic disease.

A third issue, according to the authors, is whether treatment with three- or four-drug combination therapies leads to better treatment outcomes than simpler therapies using fewer agents.

And the final issue, the researchers contend, is whether monitoring patients for minimal residual disease, and perhaps treating myeloma to achieve the absence of minimize residual disease, is a more effective approach to treating myeloma.

“One of the major obstacles [in curing myeloma] is our own mindset. If we believe it is incurable, it will al­ways remain incurable. If we try to cure, we may be able to cure,” said Dr. Ola Landgren, one of the NIH re­search­ers who authored the "blueprint" article.

“Today’s drugs are more effective than drugs we have had access to in the past; they also have fewer toxi­ci­ties. We have indications that tumors get genetically more complex as they get more advanced clinically – suggesting that earlier initiation of therapy would make sense. And we have access to better monitoring tools (flow cytometry, molecular monitoring, functional imaging, etc) to study eradication of tumor cells (mini­mal residual disease negativity). Taken together, I think the development of ‘early myeloma’ therapy trials should be encouraged,” explained Dr. Landgren.

Dr. Landgren acknowledged that more research is needed to determine if a cure to myeloma is feasible. “Of course we do not know if we will be able to cure with our current drugs/tools – that has to be assessed in well-designed treatment trials. By working hard to find minimal residual disease, to characterize such re­sid­u­al clones molecularly, and seek ways to remove them by rational therapies – in my opinion, could be a way to define an established therapy to cure myeloma.”

Background

The NIH researchers begin the discussion of their "blueprint" by noting that there currently are two com­mon, but opposing, views among myeloma specialists about the best way to treat multiple myeloma. The two views are often thumbnailed as "cure" and "control."

Proponents of the ‘cure’ approach believe it best to aggressively treat myeloma from the outset, with the intention of eliminating as much of the disease at as early a stage as possible.

Proponents of the ‘control’ approach, on the other hand, believe it better to take a long-term management approach to myeloma, controlling the disease while allowing the patient to maintain a good quality of life.

However, according to the NIH researchers, components of both approaches will probably need to be in­cor­porated into an eventual cure for multiple myeloma.

To explain why they believe this, the researchers go on to explain the issues they believe need to be ad­dressed to develop a curative therapy for myeloma.

Treatment Of Early Myeloma

The key issue that needs to be investigated in greater depth, the authors argue, is whether myeloma should be treated, and hopefully eradicated, in its earliest stages.

The importance of this issue has been highlighted, the NIH researchers note, by the results of a clinical trial being conducted in Spain, which has demonstrated a trend toward improved survival with early treatment of high-risk smoldering myeloma (see related Beacon news).

The authors also point to recent evidence that patients with asymptomatic, smoldering disease often show signs of active disease.

Furthermore, the genetic and chromosomal abnormalities in patients’ plasma cells, which often predict disease aggressiveness, progressively get more complex and pervasive with disease progression.

Part of the problem, however, lies in the ambiguity of the term “early myeloma.”  Not all patients with the myeloma precursor disease progress to active disease, which makes it hard to define “early myeloma” and therefore difficult to determine who should be treated.

Dr. Landgren acknowledges that treatment of early myeloma, despite its curative potential, might have several disadvantages. “Downsides could be that it does not work (always an option for anything). And of course, even if it works, side effects/quality of life have to be factored in. Keep in mind, current therapy for multiple myeloma at many places around the world includes transplants; toxicities are not trivial and the risk of dying is maybe 1 to 2 percent due to the therapy. I think if there is a therapy that can cure early myeloma, patients are going to take certain risks. This is not different from any other cancer/non-cancer we treat.”

Identification Of High-Risk Smoldering Patients

Dr. Landgren and his co-authors go on in their article to suggest that, if investigating the value of treating "early myeloma" is a critical step to curing the disease, then it is also important to determine which bio­markers identify patients with high-risk smoldering disease. These patients would be most likely to pro­gress to symp­tomatic disease, and could therefore be considered to have “early myeloma.”

Although two retrospective studies have recently identified variables associated with high-risk smoldering disease, they were unable to definitively predict which individuals would progress to symptomatic disease (see related Beacon news).

Biomarkers that conclusively identify patients with high-risk smoldering disease would serve multiple pur­poses. They would help define “early myeloma” and thereby determine which patients should receive early treatment. In addition, by not treating patients with lower-risk smoldering disease, the use of un­nec­es­sary therapies, which are generally accompanied by side effects, could be reduced.

Treatment With Combination Therapy

The next question that future research should address, the NIH investigators argue, is whether combination therapy with three or more drugs is more likely to lead to curative outcomes than treatment with simpler reg­i­mens.

The authors believe this may be the case.

Cancer is caused by unregulated cell growth, which eventually forms a tumor of genetically identical cells. Over time, some of the cells in the tumor may develop mutations that render them resistant to certain or all types of treatment.

The major potential benefit of combination therapy is that it is more likely to suppress most, if not all, cancer cell mutations in a patient's body.

Furthermore, if combination therapy is used in the very early stages of cancer – when mutations are less pervasive and varied – it may have the greatest chance of suppressing or eliminating the cancer.

Early indications of the potential benefit of combination therapy in "early myeloma" can be seen, the authors write, in initial results reported for a trial being conducted at the NIH.  In that trial, 78 percent of high-risk smoldering myeloma patients achieved a near complete response or complete response with a com­bi­na­tion of Kyprolis (carfilzomib), Revlimid (lenalidomide), and dexamethasone (Decadron) (see related Beacon news). Another previous study showed similar findings for the same combination in newly diag­nosed, symptomatic myeloma patients (see related Beacon news).

However, the researchers point out that, despite the potential benefits of combination therapy, the use of multiple drugs may lead to increased rates of side effects, which must be considered when treating a­symp­tomatic patients.

Monitoring Of Minimal Residual Disease

A final step that needs to be taken to develop curative approaches to myeloma, the authors argue, is as­sess­ing whether measures of minimal residual disease should regularly be used to assess and drive treatment decisions.

The authors note that there already is evidence that measures of minimal residual disease can predict im­portant treat­ment out­comes.

Two recent studies, for example, showed that the absence of minimal residual disease was associated with longer progression-free survival and, in some patients, longer overall survival (see related Beacon news).

By monitoring minimal residual disease, researchers could measure molecular responses to therapy to determine, for example, if treatment should be continued, stopped, or perhaps restarted. Furthermore, mea­sures of minimal residual disease could be used to categorize patients into different risk groups after initial therapy.

Taken as a whole, these steps could lead to a higher proportion of myeloma patients actually being cured.  In addition, the research could improve outcomes for patients who do not respond fully to existing therapies.

For more information, please refer to the authors' paper in the journal Blood (abstract).