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1750 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1751

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One study examined single-agent bortezomib and a second THERAPY FOR THE
417
tested bortezomib combined with dexamethasone as initial therapy ; TRANSPLANTATION-INELIGIBLE PATIENT
in both studies, high frequency and extent of response were noted.
In the phase I/II trials, the safety and efficacy of the combination of The traditional age limit for auto-HSCT has been 65 years, although
lenalidomide, bortezomib, and dexamethasone (RVD) were demon- older patients should be considered for transplantation provided good
strated. The benefits of combination therapy with RVD as first-line organ function is present. Physiologic rather than chronologic age is
418
therapy were documented in two phase II trials—the IFM 2008 trial more suitable for determining transplantation eligibility (Chap. 14).
and the EVOLUTION trial. 419,420 The overall response rate (ORR) after Oral administration of melphalan and prednisone (MP) has
induction in the IFM trial was 97 percent (13 percent sCR, 16 percent been the standard of care for more than 5 decades in elderly myeloma
CR, and 54 percent very good partial response [VGPR] or better). The patients. This form of therapy produces objective response in 50 to 60
EVOLUTION trial was designed to compare RVD with cyclophos- percent of patients. The shortcomings of MP have stimulated investi-
phamide, bortezomib, and dexamethasone (CyBorD) in a randomized, gators to use many combinations of chemotherapeutic agents. Several
multicenter setting. The ORR for the RVD arm after primary treatment different combinations have been tested and two large overviews of
followed by maintenance with bortezomib for four 6-week cycles was 85 more than 10,000 patients have demonstrated that MP had equivalent
percent (24 percent CR, 51 percent VGPR or better). efficacy and survival to combination chemotherapy. 429,430 Consequently,
Carfilzomib is a second-generation proteosome inhibitor that MP remains a very reasonable treatment strategy for elderly myeloma
binds to the proteasome in a highly selective and irreversible fashion. patients. A number of new approaches promise to be improvements
Although the drug was initially approved only for relapsed or refractory over MP, however. Palumbo and colleagues have incorporated the use of
404
myeloma, carfilzomib is now being studied in the upfront setting. In thalidomide in combination with MP in newly diagnosed patients with
431
a dose-escalation study, the combination of carfilzomib, lenalidomide, myeloma who are older than age 65 years. The addition of thalidomide
and dexamethasone (CRD) has been evaluated at carfilzomib doses of resulted in a 76 percent complete or partial response rate compared to
20, 27, and 36 mg/m given on days 1, 2, 8, 9, 15, and 16 for eight cycles 47 percent in the MP arm. This translated into a doubling of the 2-year
2
followed by days 1, 2, 15, and 16 with subsequent cycles. Lenalidomide EFS to 54 percent from 27 percent. Based on these data, melphalan,
was given at a dose of 25 mg on days 1 to 21 and dexamethasone at 40 prednisone, and thalidomide (MPT) emerged as the standard of care
mg weekly for cycles one to four, then 20 mg weekly for cycles five to for transplantation-ineligible patients. However, all studies showed an
eight, with cycles of 28 days. After eight cycles, patients received the increase in adverse events in the MPT arm, including infections, neu-
421
regimen every other week for eight cycles. After 24 cycles, maintenance ropathy, and thromboembolism, suggesting that thromboprophylaxis
432
with lenalidomide was recommended off-study. After a median of 12 and antimicrobial prophylaxis is required. Melphalan, prednisone,
cycles, 62 percent achieved at least a near CR and 42 percent a sCR. The and lenalidomide (MPR) is another effective regimen in this popula-
24-month PFS was estimated to be 92 percent. The toxicity profile was tion. The GIMEMA–Italian Multiple Myeloma Network evaluated 54
acceptable and notable for limited peripheral neuropathy. patients with this combination. The maximum tolerated dose (MTD)
Doublet, and especially triplet, regimens of novel drugs in combi- was 0.18 mg/kg melphalan, 2 mg/kg prednisone, and 10 mg lenalid-
nation with dexamethasone can induce complete remission rates com- omide. In this study, 81 percent of patients achieved at least a partial
parable to transplantation regimens. 413,422 Examples of modern regimens response, 47.6 percent a VGPR, and 23.8 percent a CR. One-year OS
433
include doublet combinations of lenalidomide and dexamethasone and was 100 percent. A subsequent study evaluated the efficacy and safety
bortezomib and dexamethasone, as well as, the triple combination of of induction therapy with MPR followed by lenalidomide maintenance
RVD, CyBorD, and CRD. therapy (MPR-R), as compared with MPR or MP without maintenance
Combinations that include alkylating agents should be avoided as therapy, in patients with newly diagnosed myeloma who were ineligible
damage to normal hematopoietic stem cells can be incurred, which may for transplantation. At a median followup of 30 months, the median PFS
423
render it impossible to collect stem cells for auto-HSCT. Lenalido- was 31 months for MPR-R versus 14 months for MPR and 13 months
mide may also hamper the collection of stem cells, although stem cell for MP. This benefit was observed in patients 65 to 75 years of age, but
mobilization with growth factors and chemotherapy may overcome the not in patients older than 75 years. Response rates were superior for the
myelosuppressive effects of lenalidomide. 424–427 The number of cycles of lenalidomide-containing regimen: 77 percent for MPR-R and 68 per-
treatment, especially with lenalidomide-containing regimens is limited cent for MPR versus 5 percent with MP. 434
to roughly four cycles before stem cell collection, as additional cycles Randomized trials of other novel agents, like bortezomib with MP,
may compromise stem cell harvesting. 424,428 have proven benefits as well. For example, the VISTA trial compared
Combination therapy with novel drugs achieves complete remission the regimen of bortezomib, melphalan, and prednisone (VMP) to MP
435
rates comparable to those obtained with auto-HSCT. This has led to the in patients who were not candidates for autologous SCT. Overall sur-
design of ongoing studies that compare novel agents followed by auto- vival was significantly improved in the VMP group versus MP group,
HSCT with novel agents followed by delayed auto-HSCT following disease with 3-year OS of 68.5 percent versus 54 percent, respectively. 436
relapse. Novel agents seem to be able to overcome some of the cytogenetic The FIRST trial, a randomized, phase III trial, compared continu-
adverse prognostic factors such as del 13, t(4;14), and del 17p. However, it ous lenalidomide with low-dose dexamethasone (Rd) against lenalido-
is premature to abandon auto-HSCT as the followup of clinical trials with mide with low-dose dexamethasone for 18 cycles (Rd18) and MPT for 12
437
new agents is too short to determine whether increased complete remis- cycles. Median PFS for continuous Rd was 25.5 months versus 20.7 for
sion rates will translate into durable remissions and EFS and OS. Complete Rd18 and 21.2 for MPT. The OS at 4 years was 59.4 percent for Rd versus
remission rates as a surrogate marker for eventual outcome may prove to be 55.7 percent for Rd18 and 51.4 percent for MPT. In the continuous Rd
inadequate. NCT01208662 is a phase III, multicenter randomized trial of arm, the ORR was 75.1 percent (15.1 percent CR, 28.4 percent VGPR)
RVD versus high-dose treatment with stem cell transplantation (SCT) for versus 73.4 in Rd18 (Cr 14.2 percent, VGPR 28.5 percent) and 32.3 per-
myeloma patients up to age 65 years, which was designed to address this cent MPT (CR 9.3 percent, VGPR 18.8 percent). The safety profile with
question of the role of autologous transplantation in the context of novel continuous Rd was manageable as hematologic and nonhematologic
drugs. It is likely that autologous transplantation will add to the benefits adverse events were as expected for Rd and MPT. Notably, the incidence
noted with new drugs. of hematologic second primary malignancies was lower with continuous

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