Deciding on the therapy of multiple myeloma using genetic risk stratification

In this issue of Leukemia and Lymphoma, Karlin and colleagues describe 102 consecutive patients who carry the t(4;14) translocation in multiple myeloma. Despite high response rates, both progression-free survival after induction therapy and progression-free survival after salvage therapy and overall survival fall far short of expectations, compared with patients lacking this translocation [1]. The immunoglobulin heavy chain locus is located on chromosome 14. It comes as no surprise, therefore, that translocations involving this chromosome with partner chromosomes on 4, 11, and 16 are quite common. These genetic changes are not specific for symptomatic multiple myeloma since they are found in the presence of monoclonal gammopathy of undetermined significance and do not predict evolution into multiple myeloma. The sole presence of these genetic abnormalities never constitutes an indication for the initiation of chemotherapy [2].

Once symptomatic multiple myeloma does develop and therapy is required, the presence of specific genetic abnormalities is highly predictive of outcomes and is more sensitive than conventional metaphase cytogenetics for recognizing chromosomal changes. Using fluorescence in situ hybridization (FISH), the deletion of chromosome 13, in the absence of other genetic abnormalities, does not constitute an adverse prognostic factor as it does when seen with metaphase cytogenetics. The most commonly found genetic abnormalities are t(11;14), t(4;14), and −17(p13.1). Time to progression and overall survival are not affected adversely by t(11;14). Time to progression and overall survival are significantly shorter for patients with t(4;14) and those with −17(p13.1). In multivariable analysis, both −17 (p13.1) and t(4;14) continue to have clinical importance for estimating time to progression and overall survival.

Following high-dose chemotherapy with stem cell transplant, the relapse-free survival in the subset of patients with t(4;14), approximately 15% of the total population with myeloma, is only 8.2 months, suggesting minimal benefit from autologous stem cell transplant [3]. The presence of t(4;14) in heavily pretreated patients with relapsed or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone gave lower overall response rates and shorter median progression-free survival and overall survival compared with patients who did not have these abnormalities [4]. In a series of 507 patients with newly diagnosed multiple myeloma who received induction with four cycles of bortezomib–dexamethasone, the presence of t(4;14) and −17p remained significant prognostic factors. However, bortezomib significantly improved the prognosis in terms of both event-free and overall survival in patients with t(4;14). In contrast, patients who received induction with vincristine, doxorubicin, and dexamethasone had inferior outcomes with the t(4;14) abnormality. Both groups showed no improvement with −17p, suggesting that novel agents are incapable of improving outcomes in the approximately 5% of patients presenting with this genetic abnormality [5].

Other groups have confirmed that patients with t(4;14) and −17p had a significantly shorter survival than patients without these abnormalities. However, in one report, the presence of −17p, without other abnormalities by FISH, had a similar outcome to that in patients without genetic changes. The worst prognosis in patients treated with high-dose chemotherapy was in the t(4;14) subgroup [6].

The recognition of the importance of these genetic changes led the International Myeloma Working Group to propose a molecular classification of multiple myeloma. These include immunoglobulin heavy chain translocations associated with more aggressive clinical features including t(4;14) and t(14;16). Trisomies representing a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified, including abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell proliferation have also been identified, such as nuclear factor-κB (NFκB)-activating mutations and deregulation for the cyclin-dependent pathway regulators [7]. Current data suggest that novel agents can overcome the initial adverse prognosis of deletion 13q and t(4;14), but probably not that of −17p [8].

These findings led the group at the Mayo Clinic to propose a risk-adapted therapeutic strategy, which can be found at the website http://msmart.org/, where patients are classified into low, intermediate and high risk. Patients with genetically defined high risk in this schema are recommended to have induction using 4–6 cycles of a bortezomib-containing regimen followed by the collection of stem cells. If patients do not achieve a complete response, autologous stem cell transplant is to be considered. All patients receive maintenance with lenalidomide-based therapy until progression. These risk-adapted recommendations have not been prospectively validated but are based on evidence from subgroup analysis and retrospective studies, although it is an effort to develop a set of consensus guidelines to manage patients with newly diagnosed disease. Multiple myeloma represents one of the first disorders whereby genetics are used to risk-stratify and this risk is used to guide the specifics of therapy. The development of agents that are capable of overcoming the adverse prognostic implications of these genetic changes is sorely needed.