The clinical entity of multiple myeloma (MM) exhibits great heterogeneity. Some patients present with advanced, bulky, or rapidly evolving disease, whereas others have indolent, asymptomatic disease (eg, smoldering multiple myeloma) and require no treatment for a considerable period of time.1,2 At the time of diagnosis, clinicians must first identify which patients need immediate treatment, and then tailor management strategies based on several factors that influence post-treatment outcomes. These include patient-specific factors, such as age, comorbidities, and performance status, as well as biologic features of the plasma cell clone, including chromosomal abnormalities, plasma cell labeling index, and measures of disease stage.
Over the past 10 years, we have witnessed a dramatic shift in the paradigm of care for MM, and today’s front-line regimens typically include at least 1 novel biologic agent (eg, thalidomide, lenalidomide, or bortezomib). These newer combinations have led to im proved response rates and survival. In some cases, outcomes have been similar to those observed with autologous stem cell transplant (ASCT) in clinical trials.3 However, there are still significant differences in responses following treatment, and as discussed in the accompanying article, the presence of cytogenetic abnormalities has emerged as an important independent prognostic variable.4,5 As with any biomarker, the correlation of cytogenetics with specific therapeutic implications is the Holy Grail, with the hope of providing predictive value.
Given these latest developments, we must now ask the question: “Where does genetic evaluation of the plasma cell clone fit into the current treatment algorithm for MM?” According to recent guidelines, management of the disease should be stratified by eligibility for stem cell transplant and high-risk features. Patients are considered “high risk” if fluorescence in situ hybridization (FISH) detects translocations t(4;14), t(14;16), or deletion 17p, or if conventional karyotyping detects hypodiploidy or deletion 13q (del[13q]).4,5 Using these criteria, approximately 25% of the myeloma population falls into the high-risk category.5 Since these patients tend to experience poorer outcomes with conventional treatment (including ASCT), and have a median survival of only 2 years,5 treatment with novel agents is warranted.
Recent studies have shown that introducing bortezomib early in treatment abrogates some high-risk genetic aberrations, including translocations involving chromosome 14 and del(13).6,7 Whether bortezomib-based induction therapy followed by early ASCT is superior to bortezomib-based therapy alone for high-risk MM has yet to be determined. In an upcoming international phase 3 trial conducted by the Intergroupe Francophone du Myélome and Dana-Farber Cancer Institute, investigators will be comparing a bortezomib-based regimen with and without ASCT in both standard- and high-risk patients. Both arms of this trial will receive lenalidomide as maintenance. The use of lenalidomide following ASCT has been shown in 2 randomized trials to prolong time to progression.8,9 However, longer followup is needed to determine if there is a survival benefit with this approach, and no risk stratification has been reported. We anxiously await more data from these trials.
Another important question that needs to be addressed is: “How are recent clinical findings on cytogenetics impacting the practicing community?” To date, there are no data available on the penetration of these studies in the evaluation of newly diagnosed patients in the community setting. However, in my informal and anecdotal experience, I have observed the majority of community oncologists utilizing cytogenetic testing, particularly with the support of myeloma stem cell investigators who are promoting risk stratification in the consideration of treatment paradigms. From a cost standpoint, routine bone marrow processing and interpretation charges (including flow cytometry) total approximately $3000. A FISH panel for myeloma adds another $1000 in charges, and the cost for bone marrow cytogenetics is approximately $1400 (of course, reimbursement varies widely depending on contractual and other discounts). Taking into account the cost of body imaging (individual magnetic resonance imaging examina tions exceed $3000) and stem cell transplant ($50,000-$100,000), the added cost for cytogenetic studies do not appear to be excessive or inappropriate.
This is an exciting time in the management of myeloma. Not only do we have highly effective treatments to offer our patients, but with genetic studies of the plasma cell clone, we now have biomarkers that provide valuable prognostic and predictive information, moving us closer to truly individualized therapy. It is my belief that as more evidence becomes available, cytogenetic testing will evolve into an even more useful tool, both for decision-making and assessing response to novel therapies.
- Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347.
- He Y, Wheatley K, Clark O, et al. Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev. 2003; CD004023.
- Palumbo AP, Cavallo F, Di Raimondo F, et al. A phase III trial of melphalan/ prednisone/lenalidomide (MPR) versus melphalan (200 mg/m2) and autologous transplantation (MEL200) in newly diagnosed myeloma patients. J Clin Oncol. 2010;28:577s. Abstract 8015.
- Dispenzieri A, Rajkumar SV, Gertz ME, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82:323-341.
- Stewart AK, Bergsagel PL, Greipp PR, et al. A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia. 2007;21:529-534.
- Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21:151-157.
- Avet-Loiseau H, Leleu X, Rouissel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients t(4;14) myeloma but not outcomes of patients with del(17p). J Clin Oncol. 2010;28:4630-4634.
- Attal M, Cristini C, Marit G, et al. Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol. 2010;28:577s. Abstract 8018.
- McCarthy PL, Owzar K, Anderson K, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: CALGB 100104. J Clin Oncol. 2010;28:577s. Abstract 8017.