Last year, 2013, was a great year for myeloma research.

We had a number of important discoveries that will impact diagnosis, moni­tor­ing, prognosis, and treatment of the disease. Some new findings provide us with a better understanding of myeloma biology and mecha­nisms of drug resistance, while others present information that immedi­ate­ly impacts how patients are man­aged.

Collectively, these discoveries represent a significant advance to­wards our goal of curing myeloma.

I present here my list of the top 10 most compelling scientific findings and discoveries of 2013 in the field of multiple myeloma.

I have tried to highlight the specific reason why each of these discoveries merits a place in this list. Some, especially the top five, have implications that I think extend beyond the actual finding, and I have provided this perspective as well.

This study conducted by the Southwest Oncology Group (SWOG) looked at 331 patients with monoclonal gammopathy of undetermined significance ^[2] (MGUS) or smoldering (asymptomatic) multiple myeloma ^[3] (SMM).  These are both diseases that can progress to multiple myeloma.

We have known for many years that there are several distinct subtypes of multiple myeloma that differ in terms of chromosomal abnormalities.  The major finding in this study was that the main genetic subtypes of myeloma were already present at the smoldering stage. Further, a gene expression profiling-based method of classifying these subtypes was also able to predict the risk of progression from smoldering myeloma to multiple myeloma.

Since we have started to look at ways to intervene early in the smoldering myeloma stage, the results of this study are timely and valuable.

The Spanish myeloma group is well known for their cutting-edge techniques in multi-color flow cytometry to analyze and profile myeloma cells. In this study, they applied these techniques to determine if circulating myeloma tumor cells in the blood differed from myeloma cells in the bone marrow.

They found that circulating myeloma cells represent a unique subgroup of bone marrow myeloma cells, and that, curiously, these myeloma cells preferred to escape the confines of the marrow to enter the circulating blood at night when the patient was asleep! The paper provides the specific features of these cells.

These findings will help us understand how myeloma evolves over time from a disease limited to bone and bone marrow to one that goes to other tissues and organs, and eventually even to leukemia in some pa­tients. They will also provide us with the information we need to detect these aberrant cells in the blood as we pursue eradication of minimal residual disease ^[5] (MRD).

SAR650984 ^[9] is an antibody that targets a protein called CD38 on multiple myeloma cells. Data from a Phase I multi-center trial of this agent in blood cancers was presented at the annual meeting of the American So­ciety of Hematology in December 2013.

Of the 39 patients treated, 34 had multiple myeloma. Among 24 patients with myeloma treated at a dose of 1 mg/kg or higher, 25 percent responded; and at a dose of 10 mg/kg or higher, 31 percent responded to treat­ment.

This is a remarkable finding because only a small number of drugs have shown “single-agent” activity in multiple myeloma – on their own without adding other drugs like steroids or Velcade ^[10] (bortezomib) or Rev­limid ^[11] (lenalidomide) to boost the response. In this regard, SAR650984 joins daratumumab ^[12], another CD38 antibody that has also shown single-agent activity.

Of note, other new drugs that have shown single-agent activity in myeloma include filanesib ^[13] (ARRY-520 ^[14], a kinesin spindle protein inhibitor), cyclin dependent kinase inhibitors (for example, dinaciclib ^[15]), indatuximab ravtansine ^[16] (BT062 ^[17], an antibody targeting CD138), and afuresertib ^[18] (GSK2110183, an oral Akt inhibitor).

One of the big frustrations in multiple myeloma is that resistance to treatment emerges right when things seem to be going just fine. This has been a major roadblock to finding a cure. In order to cure myeloma, we need to be able to understand how myeloma cells are able to find a way around some of our most capable drugs.

In this study, myeloma experts from the MD Anderson Cancer Center identified the protein CD44 as a me­di­a­tor for the development of resistance to Revlimid in myeloma. Resistant myeloma cells had higher than normal levels of CD44 on their surface, which then allowed them to bind to bone marrow stroma and avoid killing by Revlimid, a process called cell adhesion-mediated drug resistance (CAM-DR).

This study not only provides us with a mechanism for resistance to Revlimid, but suggests that we may be able to overcome this problem by using drugs that specifically target CD44.

As with Revlimid, resistance is also a major problem that emerges during therapy with Velcade.

In this multicenter study, researchers identified the presence of a subgroup of primitive cells in myeloma that are able to evade killing by proteasome inhibitors such as Velcade.  These included Xbp1s negative pre-plasmablasts and earlier stage CD20+ B cell progenitors that appear to survive despite therapeutic doses of Velcade. They found that Xbp1 was required for the maturation of precursor cells to mature myeloma cells that secrete monoclonal protein, and that its absence contributed to resistance to proteasome inhibition.

This study and the earlier one on Revlimid resistance are critical to our understanding of how and why resistance develops to our treatment regimens in myeloma, and they enable us to identify and overcome barriers to the goal of curing myeloma.

I have earlier written about the limitations of complete response as a treatment goal in myeloma (see my Beacon column ^[23] on the subject). For example, the monoclonal (M) protein that is detected in the blood of myeloma patients may come from both the true myeloma clone, as well as the precursor MGUS clone. Thus, some patients with residual M-protein after treatment may in fact have only residual MGUS cells remaining. They may technically not have achieved a complete response but yet have extremely long survival.

In this study, the Spanish myeloma group examined 698 patients with newly diagnosed myeloma. They found using sophisticated multicolor flow cytometry ^[24] that 8 percent of patients had an MGUS-like profile at baseline. These patients had excellent survival; about 65 percent were alive at 10 years, higher than other myeloma patients. Further the survival was similar whether or not they achieved a complete response.

The study identifies one subset of patients with myeloma who have excellent outcomes regardless of wheth­er or not they achieve complete response.  Further, in my opinion, the study strengthens the argument that the real goal of myeloma therapy should be to try and eradicate residual clonal malignant cells; trying to eradicate residual clonal premalignant (MGUS) cells may not only be unnecessary but also places patients at the risk of needless toxicity.

Two studies occupy the top 4 spot. They have strikingly similar conclusions: The risk of progression in smoldering multiple myeloma is significantly different based on the underlying cytogenetic subtype of the disease. The highest risk of progression was seen with smoldering multiple myeloma and either t(4;14) or del(17p) abnormalities, while smoldering multiple myeloma with trisomies had intermediate risk.

On the surface, the studies are important in the specific prognostic value they provide based on the under­ly­ing chromosomal abnormalities ^[29]. But on a higher level, they provide additional supporting data that what we call myeloma is not one disease, but a collection of cytogenetically distinct entities. We previously knew that the clinical presentation, response to therapy, and outcome are affected by the underlying cyto­ge­net­ic sub­type, and we now know that the risk of progression from premalignancy to malignancy is also different.

The Phase 3 PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial  compared panobinostat ^[31] (LBH589) in combination with Velcade and dexa­meth­a­sone ^[32] (Decadron) versus Velcade and dexa­meth­a­sone alone in patients with relapsed or relapsed and refractory multiple myeloma.

The study found that the addition of panobinostat significantly prolonged progression-free survival compared to Velcade and dexamethasone alone. Although specific data are not yet available, this is of major im­por­tance to the field since it identifies a new class of anti-myeloma therapy.

I have been quite skeptical that drugs with zero to minimal single-agent activity are of value in myeloma. If the results hold out, this trial will disprove my assumption. It opens up the possibility that there may be drugs without meaningful single-agent activity that nevertheless prove to be of clinical benefit when combined with other active drugs.  In that sense, this is indeed remarkable news.

Treatment has not been recommended for patients with smoldering multiple myeloma because these pa­tients are asymptomatic and there was concern that therapy would do more harm than good. Earlier ran­dom­ized trials failed to show a survival benefit.

However, it is time to reexamine this paradigm. First, we have better drugs; second, we are able to identify patients with smoldering multiple myeloma who are at higher risk of progression.

Employing these two strategies, the Spanish myeloma group studied 119 patients with high-risk smoldering multiple myeloma. Patients were randomly assigned to treatment with Revlimid plus low-dose dexa­meth­a­sone versus observation. They found that the time to progression to myeloma was significantly longer in patients treated with Revlimid-dexamethasone. More importantly, overall survival was also sig­nif­i­cant­ly longer with Revlimid-dexamethasone.

This study shows that early treatment of patients with high-risk smoldering multiple myeloma may be an effective intervention that can prolong overall survival. It is a landmark finding in that it is the first time we have found that early intervention can prolong life in myeloma, and it changes the existing paradigm. There are caveats though, including identifying which patients need therapy, and we still encourage most patients with high-risk smoldering multiple myeloma to consider enrollment in clinical trials such as the ECOG E3A06 ^[35] trial of Revlimid versus observation.

Melphalan ^[38] (Alkeran) has always been the mainstay of treatment of elderly patients with multiple myeloma who are not candidates for stem cell transplantation. Despite being one of the most active agents in this disease, melphalan does have drawbacks including its effect on stem cells and that it increases a patient’s risk of developing myelodysplastic syndrome or secondary leukemia.

Revlimid plus low-dose dexamethasone (Rd) has been shown to be a well-tolerated regimen and is widely used as a doublet or in combination with other drugs in regimens such as VRd (with Velcade) or KRd (with Kyprolis ^[39] (carfilzomib)).

In this study, one of the largest randomized trials in myeloma, 1,623 patients were randomized to MPT (mel­phalan, prednisone ^[40], and thalidomide ^[41] (Thalomid)) for 18 months, Revlimid-dexamethasone for 18 months, or Revlimid-dexamethasone until progression.  The results of the study were presented in the plenary ses­sion of the annual meeting of the American Society of Hematology in December 2013.

The study found that overall survival was significantly longer with Rd given until progression compared with MPT; no significant difference in survival was apparent as of now between the two Rd arms. There was no increase in risk of second cancers. Besides the compelling result that a well-tolerated doublet can prolong survival in elderly patients with myeloma, the study shows that when there is effective therapy, overall survival improvement can still be demonstrated in myeloma. It also provides support to numerous ongoing trials that have used the Rd backbone in other combinations in the frontline setting, anticipating this result at least in part.

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As with any list compiled in this fashion, there will be articles that others will feel that I should have included instead of the ones I picked. And I am sure there can be disagreement on the order of the top 10. Despite these considerations, I feel that this is a worthwhile exercise, since it brings hope to those of us in the field and informs the patients we serve of the progress that is being made by a truly global team of researchers.

Dr. S. Vincent Rajkumar is a professor of medicine and chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.