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Emerging Therapies for Multiple Myeloma

Emerging Therapies for Multiple Myeloma

ABSTRACT:   Abstract In the past decade, the therapeutic landscape for myeloma has changed dramatically with the advent of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib). These agents alone have activity against myeloma with even better responses when combined with additional agents such as steroids and chemotherapy. Initially introduced for relapsed/refractory disease, these agents are being increasingly tested in the upfront setting with improvement in response rates and prolongation of responses. We review the key findings from recently completed and ongoing studies that evaluate the effect of the novel therapies, both in newly diagnosed myeloma and in relapsed disease. The use of these agents in specific settings is also discussed.

Developments in the understanding of multiple myeloma biology have revolutionized our approach to therapy, leading to meaningful improvements in survival.[1] It is becoming increasingly clear that like all tumors, myeloma is a heterogeneous disorder, with different cytogenetic abnormalities, disease kinetics, response to therapy, and prognosis.[2,3] Therefore, a “one size fits all” approach to therapy is no longer tenable for this disease.[4,5] In parallel with this novel understanding of disease biology has been the discovery of novel classes of agents such as the immunomodulatory agents (IMiDs)[6,7] and proteasome inhibitors (eg, bortezomib [Velcade])[8] that alone have significant activity against the disease and more so when used in combination with other agents. With the availability of this expanded therapeutic armamentarium, when faced with a new diagnosis of multiple myeloma, we have to address early on whether the patient is a potential candidate for autologous hematopoietic stem cell transplantation (ASCT). If the answer is in the affirmative, every effort must be made to treat such patients with agents that do not compromise hematopoietic stem/progenitor cell collection. In such a setting, a few cycles of induction therapy followed by early collection of progenitor cells is the current approach.

Diagnostic Evaluation and Prognosis

In our opinion, the diagnostic evaluation of multiple myeloma is incomplete without metaphase cytogenetic studies, interphase fluorescent in situ hybridization (FISH), and an assessment of the proliferative fraction of tumor cells either by flow cytometry or with the plasma cell labeling index (PCLI) (Table 1).[4,5] Many studies now provide incontrovertible evidence that kinetically active myeloma (PCLI > 3%) or the presence of specific cytogenetic abnormalities (del13q, t[4;14], t[14;16], 17p-, hypodiploidy, or a complex karyotype) are associated with high-risk disease.[9,10] In contrast, other cytogenetic abnormalities and a low PCLI imply a good prognosis and considered ”standard-risk” disease.

While patients with “good-risk” disease benefit from stem cell transplantation, patients with high-risk disease do not experience long-term benefit.[11,12] Although high-risk patients respond to transplantation (and even achieve a complete response [CR]), response duration is usually in the region of a few months.[12] These patients (about 25% of all those with newly diagnosed multiple myeloma) should probably not undergo routine front-line transplantation but are best enrolled in clinical trials testing combinations of novel agents with chemotherapy.

Treatment Endpoints

There has been considerable discussion about the importance of a CR or very good partial response (VGPR) in myeloma, and for a long time, achieving higher CR rates was considered an important endpoint of therapy—perhaps even a benchmark by which regimens are compared.[13,14] If there were curative therapy available for multiple myeloma, then achieving a CR would be a necessary but insufficient step in the path to eradication since, all else being equal, the disease would become undetectable before it is cured. However, CR must be sustained, and here lies the problem, since many patients with high-risk disease achieve CR only to relapse rapidly.[12]

The depth of response implied by CR or VGPR inherently also implies that the myeloma cells behave in a homogeneous fashion and neglects the fact that even in the same patient some cells may secrete a great deal of paraprotein while others, little or none at all.[15] The latter cells contribute to the tumor burden (and presumably to morbidity and mortality), yet are undetectable with the technology noted above.

Finally, all of us have seen multiple myeloma patients with stable disease for long periods without therapy even if they achieve less than a CR or VGPR with the best available therapy. Therefore, while a response is essential for improvement in survival and quality of life, it remains unclear that the depth of response by itself is a good guide to improved survival.[16-18]

Initial Therapy for Transplant-Eligible Patients

The best induction regimen for transplant-eligible multiple myeloma patients is not known. Superiority is often determined by the response rate, although as mentioned, the depth of response prior to transplant does not seem to have a major impact on the outcome after ASCT. The combination of vincristine, doxorubicin, and dexamethasone (VAD) had long been the mainstay of induction therapy, but in head-to-head comparisons with TD (thalidomide [Thalomid] and dexamethasone), the latter proved superior. Cavo et al performed a well-matched retrospective analysis involving 100 patients per treatment cohort: TD was associated with superior responses (partial response [PR] or better, 76% vs 52%, P < .001), although the incidence of venous thromboembolism was higher in the TD-treated group.[19] TD had no impact on progenitor cell collection.

These results were confirmed in a large, randomized international phase III trial, which demonstrated improvement in the time to disease progression.[20] In a phase III trial by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and German GMMG-HD3 group, patients with newly diagnosed myeloma were randomized to either three cycles of VAD or TAD (with thalidomide replacing vincristine).[21] Each arm had 201 patients, and both groups were well balanced. Patients treated with TAD had a higher overall response rate before transplantation ( VGPR = 33% vs 15%, P < .001). Posttransplantation, the respective responses improved to 49% and 32% (P < .001).[21] Long-term follow-up from this study is eagerly awaited.

Perhaps the other conclusion from this study is that vincristine does not confer much benefit to myeloma patients. Although it is difficult to compare across studies, dexamethasone alone seems to produce equivalent tumor control compared to VAD,[19,22] with less toxicity, suggesting that the anthracycline has little to offer in combination with dexamethasone (this may change with new combinations), while TD is clearly superior to dexamethasone alone.[22] Moreover, TD is an oral regimen that causes minimal myelosuppression, although it is associated with its own toxicity including a significant risk of deep venous thrombosis and peripheral neuropathy. The current consensus for the prevention of IMiD-induced deep venous thrombosis was recently published.[23]

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