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Chapter 86 Plasma Cell Neoplasms 1403

study and were noted to have equivalent antimyeloma activity.
BOX 86.1 Treatment of Newly Diagnosed Multiple Myeloma
Cyclophosphamide is less stem cell toxic than melphalan. Cyclophos-
2
2
• Confirm patient has symptomatic myeloma. Patients with phamide in high doses (2 g/m up to 6 g/m ) followed by filgrastim
monoclonal gammopathy of unknown significance or smoldering has been used for stem cell mobilization, whereas high doses of
2
multiple myeloma are not treated outside a clinical trial. melphalan (200 mg/m ) are routinely used as the conditioning
• Evaluate for risk stratification using International Staging System regimen in conjunction with an autologous stem cell transplant.
staging, fluorescence in situ hybridization/cytogenetic and There is a higher incidence of secondary leukemia associated with
biochemical testing to test renal function, and lactate chronic melphalan therapy (up to 17% at 50 months), leading to
dehydrogenase to develop long-term treatment plan as well as abandonment of melphalan as maintenance therapy and limiting the
prognosis. Although initial treatment is not affected by risk exposure to 1 year or less.
category, a later consideration of more aggressive consolidation or
use of allogeneic stem cell transplant in eligible patients can be
considered in high-risk younger patients.
• Induction: Both transplant-eligible and transplant-ineligible Immunomodulatory Drugs
patients can be treated with a triple-drug regimen (bortezomib
and dexamethasone with lenalidomide [RVD], with thalidomide Currently, thalidomide, lenalidomide, and pomalidomide are the
[VTD] or cyclophosphamide [VCD], OR other proteasome inhibitor three IMiDs available for the treatment of MM. Recently, insights
(carfilzomib or ixazomib) in place of bortezomib, into the mechanism of action of IMiDs has been gained with the
cyclophosphamide, thalidomide, dexamethasone [CTD]) for three discovery of thalidomide-binding protein cereblon (CRBN). Human
to six cycles pretransplant or 9–12 months for transplant- CRBN was originally identified as a candidate gene for an autosomal
ineligible patients. For transplant-ineligible patients, additional recessive form of mild mental retardation and is located on chromo-
options include a two-drug regimen (dexamethsone with
lenalidomide [RD], with bortezomib [VD] OR with thalidomide some 3 at 3p26.2. CRBN is the substrate receptor of CUL4-RBX1-
CRBN
[TD]) OR melphalan-containing regimens, which include DDB1-CRBN also known as CRL4 E3 ubiquitin ligase. IMiDs
CRBN
melphalan with prednisone (MP) in combination with any of the bind CRBN and inhibit ubiquitination of endogenous CRL4
newer agents, MPT, MPV, or MPR. substrates, but unexpectedly IMiDs also repurpose the ligase to target
• Selection of therapy should be influenced by patient new proteins for degradation. IMiDs induce degradation of the
characteristics. lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3)
• Renal dysfunction: agents that can be considered for use are and casein kinase 1α (CK1α). Degradation of Ikaros and Aiolos
bortezomib, carfilzomib, cyclophosphamide, thalidomide, and contributes to clinical efficacy in the treatment of MM, whereas
dexamethasone (VCD or VTD) degradation of CK1α is responsible for IMiD activity in 5q-associated
• Neuropathy: agents that can be considered for use are
lenalidomide, carfilzomib cyclophosphamide, and myelodysplastic syndrome. Downregulation of Ikaros and Aiolos lead
dexamethasone. to specific and sequential downregulation of c-Myc followed by IRF4
• Older-age patients: consider dose or schedule attenuation. and subsequent growth inhibition and apoptosis of myeloma cells.
• Convenience: use of oral versus intravenous agent regimen. Drug resistance to IMiDs is associated with depletion of CRBN.
• Transplant-eligible patients can undergo a single autologous Aiolos and Ikaros are transcriptional repressors of IL-2 in T cells.
transplant with melphalan, with a second autologous transplant Thus IMiDs are able to increase the number of T cells and NK cells;
being optional, depending upon the overall response or on there is polyfunctional T-cell activation with increased cytokine
protocol participation. production by CD4 and CD8 T cells and reduction of the suppressive
• Maintenance: Following transplant or optimal induction therapy effects of Tregs on T-effector cells. There is increased expression
(to best response), patients can receive maintenance with
thalidomide, lenalidomide, or bortezomib. For high-risk patients of cytolysis genes granzyme B and perforin by CD8 T cells and
only, both bortezomib and lenalidomide or a thalidomide NK cells.
combination may be used. Selection can be influenced on the
basis of the induction regimen.
• Improving complete response rates is a key goal of current trials, Thalidomide
but patients can live a long time with residual paraprotein.
An international, randomized phase III trial has shown that thalido-
mide with dexamethasone (TD) is superior to dexamethasone alone
for ORR (63% vs. 46%) and PFS (14.9 months vs. 6.5 months).
substantial improvement in the PFS and OS has been observed. Hair There was no difference in efficacy between TD versus VAD as a
loss and the need for catheter placement to administer these vesicant pretransplant induction regimen. TD had a slightly inferior survival
agents are important limitations and require acceptance by the outcome compared with MP as first-line therapy in elderly patients.
patient. It is also possible to administer the daily dose of vincristine Thalidomide does not overcome poor prognostic genetic features.
and adriamycin as an intravenous push without loss of efficacy or TD is no longer considered optimal treatment for newly diagnosed
increased toxicity. patients with MM. Thalidomide is generally prescribed at 200 mg
daily. No maximally tolerated dose (MTD) has been defined; doses
as high as 800 mg daily has been used. Major side effects of thalido-
Chemotherapy With Alkylating Agents mide include irreversible peripheral neuropathy that develops after
exposure for a period of 6 months or longer. Other serious side effects
Alkylating agents melphalan and cyclophosphamide were introduced include DVT and pulmonary embolism when combined with dexa-
in the management of MM in the early 1960s. Since the time of methasone but does require thromboprophylaxis for patients without
introduction, they have continued to play a vital role in the treatment additional risk factors for developing DVT. Prophylaxis with a low-
of myeloma. MP has been the gold standard of treatment. All new dose aspirin (81–100 mg) daily is adequate. Other clinically signifi-
combinations are benchmarked against MP. MP has been given in cant side effects include severe constipation, severe bradycardia, and
different doses and schedules for a minimum of 9–18 months. Other skin rash. Results with thalidomide combinations in relapsed and
agents such as cyclophosphamide, carmustine (BCNU), vincristine, newly diagnosed patients are summarized in Tables 86.12 and 86.13.
and/or Adriamycin, have been successfully combined with MP (e.g., Thalidomide has been used in combination with other drugs in
VBMCP, VBAP). Combination therapies improved the response rate newly diagnosed patients with MM. Six large randomized clinical
but did not change the OS outcomes. MP has a response rate of 50% trials have been conducted combining melphalan and prednisone
to 60%, a PFS of 18 months, and an OS of 30–36 months. with or without thalidomide. Metaanalysis of these six large studies
In the 1960s, single-agent oral cyclophosphamide and oral mel- has shown MPT to be superior to MP alone: The ORR improved by
phalan were compared head to head in a randomized, double-blind 22% (59% vs. 37%); PFS improved by 5 months (20 months vs. 15