Redefining What It Means to Have Precursor Myeloma

A Conversation With C. Ola Landgren, MD, PhD

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Studies have shown that all patients diagnosed with multiple myeloma had a preceding asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or smoldering multiple myeloma. According to C. Ola Landgren, MD, PhD, Professor of Medicine and Chief Attending Physician of the Myeloma Service at Memorial Sloan Kettering Cancer Center, this clonal cell expansion process can begin in early adulthood and may lie dormant over a lifetime, never progressing to multiple myeloma, or transform into active disease decades later.

C. Ola Landgren, MD, PhD

C. Ola Landgren, MD, PhD

The question of determining the optimal time to treat multiple myeloma, either at the precursor stage before patients exhibit bone and other organ-damaging symptoms and when disease control and potentially cure is more likely or once the precursor condition progresses to multiple myeloma, has dogged clinicians for decades. Although the current standard of care for patients with precursor myeloma is watchful waiting, the influx of novel drugs that are effective and generally safe for patients with myeloma is again raising the dilemma of when and how to treat patients with precursor disease.

The results of a pair of new studies published by Dr. Landgren and his colleagues investigating prognostic models for risk stratification in the context of smoldering multiple myeloma1 and a targeted next-generation sequencing approach to capture the mechanisms of progression from monoclonal gammopathy of undetermined significance or smoldering myeloma to multiple myeloma2 may provide methods for better prognostic assessments to detect aggressive disease in its asymptomatic phase. In addition, these study findings may help to identify actionable mutations for targeted therapy in high-risk patients with a precursor condition.

The ASCO Post talked with Dr. Landgren about the results from his studies and how they may impact the way precursor myeloma is assessed and treated in the near future.

Identifying Patients With ­Asymptomatic Precursor Myeloma

Please talk about the results of your study examining a custom-capture next-generation sequencing panel, which is designed to identify rearrangements involving the immunoglobulin heavy chain (IgH) locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay, and how it may accurately identify patients with asymptomatic precursor myeloma.

The work to identify precursor stages of myeloma dates back to the 1960s, when early research was showing there were individuals with an abnormal monoclonal protein, or M protein, in their blood but no evidence of multiple myeloma. Back then, there was huge disagreement among investigators about what led to active myeloma. For example, Jan Waldenström, MD, who discovered Waldenström’s macroglobulinemia, was convinced that the premalignant clonal stage was a benign monoclonal gammopathy that is unrelated to multiple myeloma. Others were concerned that monoclonal gammopathy was related to multiple myeloma. The field did not reach agreement until 1978, when Robert Kyle, MD, a pioneer in multiple myeloma at the Mayo Clinic, introduced the term “monoclonal gammopathy of undetermined significance.”3

By proposing that the relationship between the precursor condition and multiple myeloma was undetermined, Dr. Kyle was able to link the two schools of thought together. In 2009, in collaboration with Dr. Kyle and his colleagues at the Mayo Clinic, we published a prospective study showing that, indeed, all people diagnosed with multiple myeloma had a preceding state of precursor disease. However, we were unable to provide biologic insights into the molecular underpinnings of disease progression vs nonprogression.4

This brief summary puts into context where the field has been and where it is going. Today, we have new technologies, such as next-generation sequencing, showing that myeloma is a complicated genomic cancer. There are somic mutations, IgH translocations, and gains and losses of certain chromosomes. With targeted sequencing assays, we will be able to further determine the mechanisms that are critical to disease progression.

One of those critical genetic features is MYC dysregulation. We and others have shown that the MAPK pathway is important to myeloma cell growth, and we also have shown that there are more mutations in the MAPK pathway that are important in the development of myeloma compared with precursor disease. So far, we have not been able to put the whole genomic puzzle together. This is where the focus of research will be over the next 5 or so years, and we will spend more time investigating next-generation whole-genome sequencing, as well as single-cell RNA sequencing, to identify changes in precursor cells and in the tumor microenvironment.

For example, at the 2019 American Society of Hematology Annual Meeting, Dr. Even Rustad showed fascinating results from his work designed to characterize the landscape of structural variants in myeloma pathogenesis and evolution, as well as their functional implications.5 These novel approaches will continue to guide the research field into the future.

Our study compared conventional chromosome analysis, including multiple myeloma–targeted fluorescence in situ hybridization (FISH) panels and single-nucleotide polymorphism (SNP) microarrays, with our custom-capture next-generation assay called myTYPE. We designed this assay to detect the most common and relevant genomic aberrations in myeloma. We found that this assay had a very high sensitivity and specificity in capturing the recurrent genomic aberrations in multiple myeloma compared with FISH and SNP.2

In the future, based on new emerging insights from discovery science, there will be updated versions of myTYPE and other similar custom-capture next-generation assays. I think that, over the next 5 years, a multiple myeloma–designed, custom-­capture, next-generation sequencing assay will replace standard-of-care prognostic bone marrow assays with a single test.

“Myeloma is a complicated genomic cancer…With targeted sequencing assays, we will be able to further determine the mechanisms that are critical to disease progression.”
— C. Ola Landgren, MD, PhD

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Determining Evolution of Disease

Do all patients with myeloma first have precursor monoclonal gammopathy of undetermined significance, which then progresses to smoldering myeloma, or do the conditions independently progress to active disease?

Generally, patients with either precursor condition share some genomic aberrations with multiple myeloma, confirming the existence of a chronologic order of acquisition of cytogenetic aberrations potentially involved in clonal progression from monoclonal gammopathy to smoldering myeloma and from smoldering to multiple myeloma.

From a clinical perspective, my prediction is that, 5 years from now, we will have a better understanding of how the genomics actually evolve over time. We also will be able to show that when certain somatic markers or certain genomic signatures become active, it is an indicator that the precursor condition is evolving to active myeloma. In my opinion, the endgame will be become one precursor condition, monoclonal gammopathy, and we will get rid of the rest of the term “of undetermined significance.” We also will no longer use the term “smoldering multiple myeloma,” because smoldering myeloma really does not exist. So, patients either have monoclonal gammopathy or multiple myeloma.

Developing New Protocols for Early Treatment of Myeloma

Is watchful waiting still the best approach for precursor myeloma?

The current practice is to monitor patients closely until they progress to active disease. The U.S. Food and Drug Administration has not approved any therapy for so-called smoldering multiple myeloma or monoclonal gammopathy, so drugs should not be given to patients who do not have myeloma.

In my opinion—and I’ve been going back and forth thinking about what to do in this case—there are many ultra-high–risk patients who are asymptomatic and do not fulfill the textbook criteria for myeloma, but genomically they have active disease and could potentially benefit from treatment. A phase III study published in 2013 by Mateos et al randomly assigned patients with high-risk smoldering myeloma to a watch-and-wait approach or treatment with lenalidomide plus dexamethasone for nine cycles, followed by a fixed 2-year maintenance regimen.6 The study found that the treatment-based group had a significant delay in progression to symptomatic myeloma, and this delay translated into a significant overall survival benefit, with 94% of the patients alive at 3 years vs 80% in the observation arm.6

Putting high-risk patients in a clinical trial investigating a weaker regimen, such as melphalan/prednisone or bisphosphonates, than we would use to treat myeloma makes no sense to me. In that scenario, I think the patient could potentially benefit from conventional myeloma therapies. I would be more prone to follow the patient closely, and once the patient fulfills the criteria for active disease, start highly effective combination therapy earlier rather than later.

We should have more definitive answers regarding the timing of treatment within the next 5 years. That will be the next big step in the management of multiple myeloma. 

DISCLOSURE: Dr. Landgren has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Medscape, and Onyx; has served as a consultant or advisor to Bristol-Myers Squibb, Celgene, and Onyx; has received research funding from Amgen, Celgene, Janssen, and Takeda; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Millennium, and Onyx.


1. Maura F, Bolli N, Rustad EH, et al: Moving from cancer burden to cancer genomics for smoldering myeloma: A review. JAMA Oncol. December 12, 2019 (early release online).

2. Yellapantula V, Hultcrantz M, Rustad EH, et al: Comprehensive detection of recurring genomic abnormalities: A targeted sequencing approach for multiple myeloma. Blood Cancer J 9:101, 2019.

3. Discovery’s Edge: Robert Kyle, MD: Multiple myeloma pioneer. Mayo Clinic Research Magazine. Available at Accessed January 29, 2020.

4. Landgren O, Kyle RA, Pfeiffer RM, et al: Monoclonal gammopathy of undetermined significance consistently precedes multiple myeloma: A prospective study. Blood 113:5412-5417, 2009.

5. Rustad EH, Yellapantula V, Glodzik D, et al: Revealing the impact of recurrent and rare structural variations in multiple myeloma. Blood 134(suppl 1):Abstract 576, 2019.

6. Mateos M-V, Hernández M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.