Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma

Abstract

Multiple myeloma (MM) is a heterogeneous disease with certain genetic features [e.g., t(4;14), del17p] associated with worse outcome. The introduction of thalidomide, lenalidomide, and bortezomib has dramatically improved the outlook for patients with MM, but their relative benefit (or harm) for different genetic patient subgroups remains unclear. Unfortunately, the small number of patients in each subgroup frequently limits the analysis of high-risk patients enrolled in clinical trials. Strategies that result in survival of high-risk genetic subgroups approximating that of patients lacking high-risk features are said to overcome the poor prognostic impact of these high-risk features. This outcome has been difficult to achieve, and studies in this regard have so far been limited by inadequate sample size. In contrast, strategies that compare the survival of high-risk genetic subgroups randomized to different treatment arms can identify approaches that improve survival. This type of analysis is clinically useful, even if the absolute gains do not improve outcomes to levels seen in patients without high-risk cytogenetics. Reviewing available data in high-risk MM from this perspective, it appears that bortezomib has frequently been associated with improved survival, whereas thalidomide maintenance has sometimes been associated with a shorter survival.

Figures

Figure 1

Genetic classifications of MM. The most commonly recognized high-risk genetic features are t(4;14) and del17p detected by FISH on either CD138-selected BM cells, or with the identification of clonally restricted plasma cells staining for cytoplasmic light chain immunoglobulin

Figure 2

Identification of regimens that overcome the poor prognostic impact of various genetic lesions in MM. xy plot of percent 3-year OS for patients with and without different genetic lesions treated with conventional, thalidomide or bortezomib-based therapies. Data from Table 3 for MM patients with (x-value) or without (y-value): t(4;14) (circles), del17p (triangles), unfavorable FISH (squares) treated with conventional (blue), thalidomide (light green), lenalidomide (dark green), or bortezomib (red) based regimens. The larger studies are represented with larger symbols. The regimens with data points closest to the dotted line have the most similar survival rates for patients with or without a given abnormality and are best at overcoming the implications of high-risk genetics. A conceptual example is given of the introduction of doxorubicin in the treatment of non-Hodgkin lymphomas. Diffuse large B-cell lymphoma, which had a shorter survival then other lymphomas, was suddenly found to have a better survival after the introduction of doxorubicin. None of the drugs in MM has such a dramatic effect on any genetic subtype of the disease. M indicates melphalan; P, prednisone; C, cyclophosphamide; V or O, vincristine; A or H, doxorubicin; D, dexamethasone; Da, attenuated-dose dexamethasone; Conv, conventional chemotherapy arm of GEM2005 for patients younger than 65 years (VBMCP/VBAD + Bz × 2 + ASCT × 1); T or Thal, thalidomide; Len, lenalidomide; Bz, bortezomib; and maint, maintenance.

Figure 3

Identification of novel agents that improve the survival of patients with high-risk MM. xy plot of percent OS for the 2 arms of randomized controlled clinical trials for patients with different genetic lesions. Data from Table 4 for MM patients with t(4;14) (circles), del17p (triangles), unfavorable FISH (squares) treated with thalidomide (red) or bortezomib (green) based regimens. The x-value is the survival for the arm with the novel agent, and the y-value for the survival of the control arm. The regimens with data points above the dotted line are better than control, whereas those below are worse. In this analysis, regimens that improve survival have points that fall in the upper left, whereas those that worsen survival fall in the lower left. One sees clearly that all of the bortezomib arms (red) fall in the upper left, whether bortezomib is being used in induction or maintenance and whether it is being compared with placebo, vincristine-adriamycin, or thalidomide. In contrast, the thalidomide arms (green) almost all fall in the lower right, whether thalidomide is being used for induction or maintenance and whether it is being compared with placebo, melphalan, or bortezomib. Abbreviations are as in Figure 2.