Most of the 15,000 people per year in the United States who develop multiple myeloma (MM)1 require some form of treatment at the time of diagnosis. Combination regimens incorporating alkylating agents, corticosteroids, and/or anthracyclines have been used for decades, with little overall progress during that time in terms of survival or cure rate.2' 3 High-dose chemotherapy with autologous stem cell support (HDC/ASCS), shown in some studies to offer a modest survival benefit, is nonetheless noncurative (summarized below, and in greater detail in Chapter 90). Thalidomide plus dex-amethasone (TD) has recently emerged as the most widely used front-line regimens in the United States, and other thalidomide-containing combinations, as well as ones incorporating bortezomib (Velcade; PS-341) or lenalidomide (Revlimid; CC-5013), are currently being studied. New regimens are often difficult to compare to more established therapies for a variety of reasons. The most important endpoint of therapy, survival, is not known for many newer regimens. Additionally, with the exception of Melpahlan-Prednisone-Thalidomide (MPT), newer combinations have not been compared in a randomized fashion to standards like Melphalan-Prednisone (MP) or Vincristine-Doxorubicin (Adriamycin)-Dexamethasone (VAD) (described in detail below, Tables 83.1 and 83.2). Increasingly, surrogate endpoints are being used to assess new agents and combinations, with some debate as to the best indicator of clinical efficacy. Though it is widely held that complete response (CR) rate is the best predictor of long-term survival,4, 5 some investigators have shown other endpoints such as time to disease progression may correlate more strongly.6 There is the least amount of data to support the use of partial reduction in serum or urine M-protein concentration as a surrogate efficacy endpoint, but it is often used in Phase II studies where the goal is often to determine if a regimen has enough "promise" to warrant larger-scale Phase III trials. For further discussion regarding response assessment, please refer to Chapter 91.

When treatment for a patient with newly diagnosed MM is being considered, the first question the clinician must ask is, "Does the patient require any treatment right now?" Definite indications for therapy include bone pain or the presence of multiple lytic skeletal lesions, cytopenias or renal dysfunction without other identifiable causes, hypercalcemia, or a high serum or urine M-protein level. Less common manifestations, such as amyloidosis or paraprotein-related hyperviscosity, also represent indications to initiate systemic therapy. Recently published management guidelines emphasize that asymptomatic newly diagnosed myeloma (formerly termed indolent or smoldering myeloma) should not be treated with cytotoxic therapy.7 It is clear that many of these patients can be followed for an extended period of time without intervention or complications.8 At least two randomized studies have addressed this point. In the first, a group of Swedish investigators randomized 50 patients with asymptomatic MM to either immediate or deferred therapy with MP.9 There were no differences in response rate, response duration, or survival, despite the fact that therapy was started on average a year later in the deferred-therapy arm. Riccardi et al. also found no differences in response rate or overall survival (OS) amongst 145 patients enrolled on a prospective study with a similar design.10 In contrast to the Swedish experience, patients treated at the time of disease progression had a shorter duration of response. Thalidomide, 200-800 mg/day, has been investigated as treatment of asymptomatic MM in a group of 29 patients at the Mayo Clinic.11 Although the majority of patients exhibited reduction in M-protein levels, 37% of patients progressed to symptomatic myeloma by 2 years, and 28% experienced grade 3-4 drug toxic-ity. It is thus premature to recommend the use of thalidomide in this setting outside of a clinical trial designed to assess whether it retards the time to progression to overt disease compared to observation alone. Initiation of bisphosphonates in patients with asymptomatic MM in an effort to prevent the development of symptomatic skeletal disease is also being able 83.1 Combination chemotherapy regimens for multiple myeloma

Regimen Drugs Doses Frequency able 83.1 Combination chemotherapy regimens for multiple myeloma

Regimen Drugs Doses Frequency

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