Barbara Jones

In the treatment of multiple myeloma (MM), following decades of little progress, the last 10 years have been characterized by more clinical advancements than for any other cancer.

One recent achievement includes encouraging results from a small pilot study of patients with high-risk smoldering multiple myeloma (HR-SMM),

or minimal residual disease (MRD). Another study demonstrated the first evidence of prolonged survival in this population of patients.

In fact, much current research focuses on the myeloma precursor statemonoclonal gammopathy of uncertain significance (MGUS)/SMM&mdash;and how integrating novel biologic markers (still under development), very sensitive molecular imaging, and clinical monitoring could result in the development of successful early treatment strategies that forestall progression from precursor disease to full-blown MM.

Ola Landgren, MD, PhD, is head of the Multiple Myeloma Section, Metabolism Branch, at the NCI, and lead author at the December 2013 meeting of the American Society of Hematology (ASH) of a pilot study in a dozen patients with HR-SMM. In that study, with a 3-drug combination, (carfilzomib, lenalidomide, and dexamethasone [CRd]), 9 patients obtained complete response (CR), 1 patient obtained a stringent complete response (sCR), and 2 patients obtained near CR.2

Landgren called these results a &ldquo;very powerful finding,&rdquo; which he considered even more striking by confirmation via high-quality assays, including multicolor flow cytometry capable of analysis of &ge;3 x 106 events, with a sensitivity detection rate of q x 10-5. Next steps include an expansion of the cohort (initially by 16 more patients), and ongoing monitoring to ensure that patients continue to be MRD negative.

Landgren authored a chapter of the ASH annual Educational Program book,

, in which he further examined this type of state-of-the-art MM research and offered current strategies in patient care.

The following are some research and clinical pearls from that chapter: &ldquo;Monoclonal gammopathy of undetermined significance and smoldering multiple: biological insights and early treatment strategies.&rdquo;

The Molecular Composition of Myeloma Precursor Disease Versus Multiple Myeloma

&ldquo;Based on current standard technologies (eg, fluorescence in situ hybridization [FISH]), the molecular makeup of myeloma precursor disease states and multiple myeloma are strikingly similar, and no defining molecular features unique to multiple myeloma have been identified.&rdquo;

&ldquo;Currently, the serum-free light chain (sFLC) ratio is one of the most promising clinical biomarkers in asymptomatic myeloma. The sFLC ratio has been used as a prognostic indicator both in patients with MGUS and SMM.&rdquo;

&ldquo;&hellip;There is a consensus that bone marrow plasma cell (BMPC) levels &ge;10%, serum M protein levels &ge;3 g/dL, and abnormal sFLC ratios (&le;.125 or &ge;8) increase the probability that SMM will develop into multiple myeloma.&rdquo;

A Note on Current Clinical Management Strategies

&ldquo;In 2013-2014, the cornerstone of managing MGUS/SMM involves a prudent &lsquo;watch and wait&rsquo; strategy. Outside of trials, there are no current standardized treatment options for MGUS or SMM.&rdquo;

&ldquo;Although current evidence does not support the treatment of SMM outside of clinical studies, it seems reasonable to support the development of early treatment trials that integrate molecular monitoring.&rdquo;

On Tools and Technology to Detect End- Organ Damage: From X-ray to Molecular Imaging

&ldquo;According to the most recent consensus guidelines of the International Myeloma Working Group (IMWG), updated in 2011, radiological skeletal survey is still the gold standard for the initial workup of patients with multiple myeloma.&rdquo;

&ldquo;However, conventional x-ray has some important drawbacks.&rdquo;

&ldquo;&hellip;The occurrence of bone destruction is a relatively late event.&rdquo;

&ldquo;Magnetic resonance imaging (MRI) is able to assess the disease in the [bone marrow] BM itself independently from the growth pattern, and therefore can provide information on the actual tumor burden.&rdquo;

&ldquo;&hellip;Dynamic contrast-enhanced MRI and diffusion-weighted imaging MRI comprise the possibility of gaining information regarding disease activity.&rdquo;

&ldquo;&hellip;In SMM or high-risk MGUS patients highly suspicious of harboring bone disease, imaging evaluation may be better served by obtaining MRI or positron emission tomography (PET) rather than skeletal surveys.&rdquo;

In a recent interview, Landgren discussed the major questions that challenge myeloma clinical researchers, questions that are critical to advancing treatments and improving outcomes in patients with MM.

First, he said, knowing &ldquo;when is the right time to start therapy,&rdquo; instead of waiting for a patient to get sick, is a key challenge. What is needed is for researchers to &ldquo;find something that would drive the initiation of therapy.&rdquo;

Second, although the availability of effective drugs, and more effective new drugs, is important, he said, even more important is to have tests that predict which therapies will work. &ldquo;I am not saying that we should stop developing drugs, but we need to have a balance. Tools have been left behind.&rdquo;

The last question that Landgren raised is how to &ldquo;test in a more sophisticated way how well a given therapy is working,&rdquo; and measuring the depth of (patient) response using molecular tools. Now, according to Landgren, the way to evaluate therapy is old and very crude.

Clinicians with a focus on &ldquo;better characterization&rdquo; imaging to determine who is and is not responding to drugs will be able to help patients to a much greater degree, according to Landgren. &ldquo;This may take time,&rdquo; he said, but is likely to have a large impact on patient outcomes.

On the practical side of patient care, Landgren advocates a sharper focus on elderly patients. Myeloma has an average age of 70 years, he said, but &ldquo;People above the age of 70 have been treated with quite inferior drugs.&rdquo;

In studies, Landgren noted, &ldquo;&hellip;all of the driving (advances) in multiple myeloma have involved people up to age 70.&rdquo; But it has been shown that people above age 70 years can have good results, and this is about half of the MM population.

&ldquo;We have treated patients (similarly) in their upper 80s and their 40s,&rdquo; a wide range of ages, with &ldquo;very effective therapy&rdquo; and no age-related differences.

&ldquo;Just by doing this, you could improve survival,&rdquo; he said.

Landgren O. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies. American Society of Hematology.

. 2013:478-487. http://asheducationbook.hematologylibrary .org/

Landgren O, Mailankody S, Kwok M, et al. Clinical and correlative pilot study of carfilzomab, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRdR) in high-risk smoldering multiple myeloma.

Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.

Barbara Jones | Authors

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Insights on Multiple Myeloma From Ola Landgren, MD, PhD