Introduction

By William N. Hait, MD, PhD
Johnson & Johnson Pharmaceuticals Research & Development

Soon we will know our susceptibility to all diseases, but will have no idea what to do about it. Genotypic changes plus a life of environmental exposures may (or may not) lead to progression to serious disease. In certain instances, we can track progression and intervene appropriately. Oncologic diseases offer an important opportunity for potentially more effective approaches to therapy, i.e., the treatment of pre-malignances (“cancer interception,” a phrase coined by Dr. Elizabeth Blackburn of the University of California, San Franciso).

Multiple myeloma is a life-threatening disease characterized by end-organ damage, including intensely painful fractures of the bone (a feeling described by one of my patients as “stubbing your toe but it never goes away”). Pre-myelomas are identified by clonal expansion of plasma cells, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Dr. Robert Kyle’s excellent review describes the diagnosis and prognosis of these pre-malignant conditions and makes thoughtful recommendations regarding management.

Ideally, prevention of disease would entail minimal morbidity and would target those individuals at greatest risk. MGUS and SMM progress to MM at a predictable rate based on characteristics described by Dr. Kyle’s group that include the quantity of the M-spike and degree of marrow plasmacytosis.¹ Therefore, a group of patients at high risk for progressing to a fatal disease can be diagnosed and potentially treated. Might these patients have been spared the morbidity and mortality of multiple myeloma and its treatment by earlier therapeutic intervention?

There are reasons to suspect that early intervention, i.e., the treatment of pre-malignancies, will be more effective. For example, a BCR-ABL inhibitor such as imatinib is highly effective when used to treat chronic myelogenous leukemia (CML) in chronic phase.² However, as CML progresses to accelerated phase and on to blast crisis, this well-tolerated medication loses almost half of its efficacy.³

To make cancer interception a reality, much preparatory work needs to be done. Identification of practical regulatory endpoints, such as valid surrogates of clinical benefit and metrics for payor acceptance, remain important opportunities for further progress.

Dr. Kyle wisely opines that patients with SMM at low risk for progression should be carefully observed, and those who are at the highest risk should not be treated outside of a clinical trial. Preliminary studies with “imids” and dexamethasone are encouraging.^4,5 Recently, anti-interleukin 6 monoclonal antibodies (e.g., siltuximab) have been developed and are undergoing investigation in patients with high-risk SMM, tracked using a newly developed circulating myeloma cell kit.

Shakespeare wrote in Hamlet, “Disease desperate wrought by desperate measures are relieved or not at all.” In contrast, the predecessors to disease should require less desperation and greater concentration by the biomedical research community. Careful characterization of premalignant conditions exemplified by the work of Dr. Kyle’s group is essential if we are to make cancer interception a reality.

Dr. Hait, a medical oncologist, is Senior Vice President and Worldwide Therapeutic Area Head of Oncology at Johnson & Johnson Pharmaceuticals Research & Development, LLC. He currently serves on ASCO’s Cancer Research Committee.

References

1. Kyle RA, Remstein ED, Therneau TM, et al. N Engl J Med. 2007;356:2582-90.
2. Druker BJ, Talpaz M, Resta DJ, et al. New Engl J Med. 2001;344:1031-7.
3. Druker BJ, Sawyers CL, Kantarjian H, et al. N Engl J Med. 2001;344:1038-42.
4. Detweiler-Short K, Hayman S, Gertz MA, et al. Am J Hematol. 2010;85:737-40.
5. Mateos M-V, López-Corral L, Hernández M, et al. Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment. ASH Annual Meeting Abstracts. 2011:Abst 991.

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Insights into Smoldering (Asymptomatic) Multiple Myeloma (SMM)

By Robert A. Kyle, MD
Mayo Clinic

Smoldering (asymptomatic) multiple myeloma (SMM) is defined by the presence of a monoclonal (M) protein level ≥ 3 g/dL and/or ≥ 10% monoclonal plasma cells in the bone marrow, but no evidence of end-organ damage.¹ End-organ damage (“CRAB”) consists of hypercalcemia (C), renal insufficiency (R), anemia (A), or bone lesions (B) due to the plasma cell proliferative disorder. SMM must be differentiated from monoclonal gammopathy of undetermined significance (MGUS) because of its greater risk of progression to multiple myeloma (MM) or a related disorder. The risk of progression to symptomatic MM is approximately 10% per year for SMM compared to 1% per year for MGUS.

MGUS and disease progression
MGUS is found in 3% of the white population age 50 or older. It is more common in men (4.0%) than in women (2.7%). The prevalence increases to 5% in persons age 70 or older and to 7.5% among those age 85 or older. The size of the M protein is modest, with more than 60% having an M protein < 1.0 g/dL. Uninvolved immunoglobulins are reduced in less than one-third of patients.² The prevalence of MGUS in black patients is approximately twice that of the white population, and the prevalence in Japanese patients is approximately two-thirds that of the white population.^3,4 This was confirmed in patients from Ghana, where the prevalence was 5.8% in 917 men age 50 years or older.⁵ In contrast, the prevalence of MGUS in Nagasaki, Japan, was 2.4% in patients age 50 older.⁶ It should be pointed out that MGUS precedes virtually all cases of MM.⁷

It is impossible to know whether a patient with MGUS will remain stable or progress to a plasma cell malignancy such as MM, Waldenström macroglobulinemia, or AL amyloidosis. Predictors of progression include the size of the serum M protein at the time of recognition of MGUS. The risk of progression 10 years after the recognition of MGUS was 6% for those with an M-protein level of 0.5 g/dL or less in contrast to 24% for those with an M protein of 2.5 g/dL. At 20 years, the risk of progression in a patient with an M protein of 1.5 g/dL was 1.9 times the risk of progression with an initial value of ≤ 0.5 g/dL, while the risk of progression with an M protein of 2 g/dL initially was 4.6 times the risk of progression with an initial value of 0.5 g/dL. Patients with an IgM or an IgA monoclonal protein have an increased risk of progression compared to those with an IgG protein. The number of bone marrow plasma cells in the bone marrow is also an important factor. The presence of an abnormal serum free light chain ratio (FLC) is found in about one-third of patients with MGUS. The risk of progression in these patients was higher than in patients with a normal FLC ratio (hazard ratio = 3.5). This was independent of the level and type of serum M protein.⁸

Risk factors consisting of an elevated serum M protein ≥ 1.5 g/dL, an IgA or an IgM monoclonal protein, and an abnormal FLC ratio had a risk of progression at 20 years of 58% (high risk), compared with only 5% when none of these risk factors were present. It must be kept in mind that death from cardiovascular disease, cerebrovascular events, non-plasma cell malignancies or other causes unrelated to the plasma-cell proliferative process are much more common than death from a plasma cell disorder during long-term follow-up.

Patients with MGUS should not be treated but should be tested again in four to six months to exclude the possibility of an evolving MM. I believe that patients with low-risk MGUS may be reevaluated every two years, whereas those with high-risk MGUS should be followed annually or until they develop an unrelated condition that significantly limits life expectancy.

Distinguishing SMM from MM requiring therapy
SMM is a more advanced premalignant stage than MGUS. Just as in MGUS, there is no evidence of CRAB (no end-organ damage) related to the plasma-cell proliferative process. However, patients with SMM may fulfill the usual diagnostic criteria of MM such as a serum M spike ≥ 3 g/dL, 10% or more plasma cells in the bone marrow, reduction of uninvolved immunoglobulins in the serum, and monoclonal light chains in the urine. Thus, SMM must be distinguished from MM requiring therapy. Approximately 10% to 20% of patients with newly diagnosed MM actually have SMM.

In a group of 276 patients who fulfilled the criteria for SMM, the median age of 64 (with only 3% younger than 40) and 62% male were similar to that in MM.¹ The serum M protein at diagnosis ranged from 0.5 to 5.4 g/dL with 11% of the patients having an M spike of ≥ 4 g/dL. IgG was the most common (74%), while 22.5% had IgA, 0.5% had an IgD monoclonal protein and biclonal gammopathies were found in 3%. Kappa was the most common light chain at 67%, with lambda in the remaining 33%. Reduction of uninvolved immunoglobulins occurred in 83%. A monoclonal light chain was found in the urine in 53% but was < 0.1 g/24h in 84%. The most common proportion of bone marrow plasma cells was in the 15% to 19% category. Only 10% had fewer than 10% plasma cells in the bone marrow, while 10% had 50% or more bone marrow plasma cells.

During follow-up, 85% of patients with SMM died. During this period, symptomatic MM developed in 57%, while AL amyloidosis was recognized in 2%. The median time to progression (TTP) was 4.8 years. The median survival of the patients who developed MM was 3.4 years, which was similar to that of MM during the same period.

Deaths from non-myeloma disorders, including cardiovascular and cerebrovascular disease as well as non-plasma cell cancers, were 18% at five years, 26% at 10 years, 30% at 15 years, and 35% at 20 years. The overall survival of SMM was 60% at five years, 34% at 10 years, and 20% at 15 years (median, 6.3 years).

Risk of progression
The risk of progression of SMM to MM was 10% per year for the first five years, 3% per year for the next five years, and then 1% to 2% per year for the next decade (Figure 1).¹ This is in contrast to MGUS, which has a risk of progression of approximately 1% per year following recognition throughout more than 25 years of follow-up.⁹

The risk of progression to active MM or AL amyloidosis at 10 years was 55% for patients with an initial plasma cell level of 10% to 14%, compared to progression in 70% of the patients who had more than 50% plasma cell infiltration of the bone marrow. At 10 years, the risk of progression to active MM or AL amyloidosis was 57% in patients with an initial M protein of 2 g/dL and 70% in those with an M protein of 5 g/dL. On multivariate analysis, the size of the serum M protein and the number of bone marrow plasma cells were the most significant independent risk factors for progression. The cumulative probability of progression at 15 years was 87% in patients with ≥ 10% plasma cells and ≥ 3 g/dL of M protein compared to 70% for those with ≥ 10% plasma cells and < 3 g/dL of M protein, and only 39% for the patients with < 10% plasma cells and ≥ 3 g/dL of M protein. The median TTP was two years in the first group, eight years in the second group, and 19 years in those with fewer than 10% bone marrow plasma cells and ≥ 3 g/dL of monoclonal protein. At five years of follow-up, 66% of patients with IgA experienced disease progression, compared to 46% with IgG. At 10 years, 77% of patients with IgA experienced disease progression, compared to 62% with IgG. In addition to the size of the M protein and number of bone marrow plasma cells, an FLC ratio of ≤ 0.125 or ≥ 8 was an independent risk factor for progression. Incorporating the FLC ratio into the risk model, the five-year progression rates in those with bone marrow plasma cells ≥ 10% and a serum M protein ≥ 3 g/dL was 76%, while those with bone marrow plasma cells ≥ 10% but a serum M protein < 3 g/dL was 51%. The risk of progression was only 25% for those with a serum M protein ≥ 3 g/dL, bone marrow plasma cells < 10%, and an FLC ratio of > 0.125 to < 8.¹⁰

Treatment of patients with SMM
I believe that patients with SMM should be observed for evidence of progression and not treated unless they are part of a clinical trial. The blood tests should be repeated two to three months after the initial recognition to exclude the possibility of an evolving MM. It has been suggested that there are two types of SMM—an evolving SMM characterized by progressive increase of the serum M protein until symptomatic MM develops and a non-evolving SMM in which the M protein is stable and then abruptly increases when symptomatic MM develops.¹¹ If stable, testing should be repeated every four to six months for the first year and if still stable, reevaluate at six- to 12-month intervals.

Efforts to treat patients with SMM have been reported. In a series of 29 eligible patients with SMM, 34% had a partial response to thalidomide. The median TTP to symptomatic myeloma was 35 months. The median TTP was 61 months for those achieving a partial response, 39 months for those with a minimal response (MR), and nine months for those whose disease failed to respond.¹² Mateos et al. reported that 118 patients with SMM at high risk of progression were randomly assigned to lenalidomide and dexamethasone or no treatment. Four patients experienced disease progression in the lenalidomide/dexamethasone regimen, compared to 28 of 61 (46%) in the placebo arm. The three-year overall survival was 98% in the treated patients, compared to 82% for placebo.¹³

In my opinion, the key is to recognize the patients with SMM at the highest risk for progression and then treat them in a clinical trial with a regimen active for multiple myeloma and with as few side effects as possible. One would like to identify those patients who are at a 90% risk of progression at two years and treat them in a randomized clinical trial.

Dr. Kyle is a Professor of Medicine, Laboratory Medicine, and Pathology at Mayo Clinic and has been an ASCO member since 1968. An internationally recognized expert in hematologic malignancies, he was the first to describe monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. In 2007, Dr. Kyle was presented with the David A. Karnofsky Memorial Award, ASCO’s highest scientific honor.

References

1. Kyle RA, Remstein ED, Therneau TM, et al. N Engl J Med. 2007;356:2582-90.
2. Kyle RA, Therneau TM, Rajkumar SV, et al. N Engl J Med. 2006;354:1362-9.
3. Cohen HJ, Crawford J, Rao MK, et al. Am J Med. 1998;104:439-44. [Erratum. Am J Med. 1998;105:362.]
4. Landgren O, Gridley G, Turesson I, et al. Blood. 2006;107:904-6.
5. Landgren O, Katzmann JA, Hsing AW, et al. Mayo Clin Proc. 2007;82:1468-73.
6. Iwanaga M, Tagawa M, Tsukasaki K, et al. Mayo Clin Proc. 2007;82:1474-9.
7. Landgren O, Kyle RA, Pfeiffer RM, et al. Blood. 2009;113:5412-7.
8. Rajkumar SV, Kyle RA, Therneau TM, et al. Blood. 2005;106:812-7.
9. Kyle RA, Therneau TM, Rajkumar SV, et al. Mayo Clinic Proc. 2004;79:859-66.
10. Dispenzieri A, Kyle RA, Katzmann JA, et al. Blood. 2008;111:785-9.
11. Rosiñol L, Bladé J, Esteve J, et al. Br J Haematol. 2003;123:631-6.
12. Detweiler-Short K, Hayman S, Gertz MA, et al. Am J Hematol.2010;85:737-40.
13. Mateos M-V, López-Corral L, Hernández M, e tal. Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment. ASH Annual Meeting Abstracts. 2011;Abst 991.