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1754 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1755

12 months versus 8.1 months (p <0.0001) for patients treated with the combined with thalidomide and dexamethasone, bendamustine with
triple therapy. ORR was 61 percent versus 55 percent and duration of prednisone and thalidomide, and lenalidomide with doxorubicin and
response of 13.1 months versus 10.9 months. OS data is not yet mature. dexamethasone. 478–482 There are currently many new drugs in develop-
Common side effects included myelosuppression and diarrhea. ACY- ment that target novel pathways. For example, filanesib, a kinesin spin-
467
1215, a selective HDAC 6 inhibitor, is another well-tolerated HDAC dle protein inhibitor, has demonstrated activity in combination with
inhibitor that is being studied in combination with both lenalidomide lenalidomide and bortezomib. 483,484 Several other classes of novel drugs
and bortezomib plus dexamethasone. The ORR in combination with are currently under investigation including the bromodomain inhibi-
lenalidomide and dexamethasone was 69 percent even though 13 of 16 tors, CDK inhibitors, and inhibitors of the ubiquitin pathway. Data gen-
patients had received prior lenalidomide and three of six were refrac- erated from these early studies will provide a better understanding of
468
tory to lenalidomide. In combination with bortezomib and dex- how these new drugs will be incorporated into the continuum of mye-
amethasone, the ORR was 60 percent. 469 loma care. 485–487
Another area of interest and therapy development is the blockade
of interactions between the tumor cells and immune cells. PD-1 and
Monoclonal Antibodies PD-L1 are two targets of interest. PD-1 is a molecule present on T cells
Several monoclonal antibodies have demonstrated activity in myeloma, that interacts with PD-L1 expressed on tumor cells. There are ongoing
including novel drugs targeting CD38, CS1, and BAFF. Daratumumab, clinical trials exploring PD-1 blockade in combination with a dendritic
a monoclonal anti-CD38 antibody, was granted Fast Track Designation cell/myeloma fusion vaccine in myeloma. 488
and Breakthrough Therapy Designation by the FDA based on results The choice of therapy for relapsed or refractory patients depends on
of a phase I/II trial that demonstrated single-agent activity in relapsed, a number of factors, including time since last therapy, prior exposure to
refractory myeloma. In the 4 mg or more/kg groups (n = 12), five PRs novel agents, alone or in combination, and drug-induced comorbidities,
and three MRs were observed. Median PFS had not been reached by for example, neuropathy, renal malfunction, and loss of patient physio-
a data cutoff of 3.8 months. Daratumumab is now being studied in logic reserve. In the past decade, there has been a dramatic increase in
470
combination with lenalidomide and dexamethasone in relapsed or the number of therapies available to patients with relapsed or refractory
refractory disease. SAR650984, another anti-CD38 antibody, had an myeloma. This is a very dynamic area within oncology and will continue
ORR of 30.8 percent as a single agent in the dose-escalation study in to evolve as more new therapies enter trials and gain approval.
relapsed or refractory (RR) patients at the MTD. 471
Elotuzumab, a humanized monoclonal IgG antibody directed
1
against human CS1 (also known as CD2 subset-1, SLAMF7, CRACC, ALLOGENEIC HEMATOPOIETIC STEM CELL
and CD319), a cell-surface antigen glycoprotein that is highly expressed TRANSPLANTATION
on myeloma cells and normal plasma cells, has also been granted Break- Allogeneic transplantation was seen as an attractive option to treat mye-
through Therapy Designation by the FDA. In a phase I study, no objec- loma because it has the potential to be curative, provides a donor graft
tive responses were seen, although 26.5 percent had stable disease by that is not contaminated with myeloma stem cells, and may establish
European Bone Marrow Transplant Group (EBMT) myeloma response a graft-versus-myeloma (GVM) effect that could eradicate any sur-
criteria. In combination with lenalidomide and dexamethasone, viving myeloma cells. 489,490 Furthermore, molecular remissions have
472
objective responses were obtained in 82 percent (23 of 28) of treated been observed, which predict for longer survival. 491,492 However, the
patients. After a median followup of 16.4 months, the median time to early experience with myeloablative allogeneic transplantation has not
progression was not reached for patients in the 20 mg/kg cohort who been encouraging as a result of a high mortality, varying from 30 to
were treated until disease progression. An ORR of 92 percent and a 50 percent, despite improvements in patient selection and supportive
median PFS of 33 months was observed after a median followup of 20.8 care. 493–500
months at the 10 mg/kg dose which was the dose chosen for the phase Studies from Seattle 494,501 and the EBMT have reported that some
502
473
III trial. Phase I results of elotuzumab in combination with borte- patients remain progression-free at long intervals after hematopoietic
zomib and dexamethasone are also favorable. Phase I results demon- stem cell transplantation (HSCT). The EBMT has reported that actuar-
strate a PR or better in 48 percent of 27 evaluable patients with relapsed ial OS was 32 percent at 4 years, and 28 percent at 7 years for the 72 (44
or refractory disease. 474 percent) patients who achieved CR after allografting. 496,497,503 However,
Tabalumab, is a fully human monoclonal antibody designed to overall PFS was 34 percent at 6 years, and few patients remain in con-
have neutralizing activity against both membrane-bound and soluble tinuing CR for more than 4 years post allograft. Favorable pre–marrow
BAFF, has been combined with bortezomib and dexamethasone. In the transplantation prognostic factors for both response and survival after
phase I/II study, the ORR was 45.8 percent. A phase II trials of this marrow transplantation were female sex, IgA isotype, low serum β M,
475
combination has been completed but results have not yet been reported. 2
stage I disease at diagnosis, one line of previous treatment, and being in
CR prior to marrow transplantation. Of major concern is the early 40
Other Treatments percent transplant-related mortality (50 percent in males) in the EBMT
Bendamustine as a single-agent or in combination with lenalidomide report, which has subsequently been reduced to 20 to 30 percent as a
495
and dexamethasone is another option for patients with relapsed or consequence of better patient selection, early transplantation, and less
refractory myeloma. The combination of bendamustine, lenalidomide, pretransplantation treatment. The actuarial probabilities of survival
503
and dexamethasone was evaluated in a phase I/II trial. The median PFS and progression-free survival were 0.50 +/– 0.21 and 0.43 +/– 0.17 at
476
was 6.1 months, PR rate 52 percent, and VGPR rate 24 percent. The 4.5 years. Adverse prognostic factors included: transplantation more
2
MTD of bendamustine was 75 mg/m as compared with prior studies than 1 year after diagnosis; serum β M higher than 2.5 mg/dL at time of
2
using 100 mg/m . Toxicity was mainly hematologic arguing in favor of transplantation; female patients transplanted from male donors; having
2
the lower dose, particularly in light of the fact that this population is received more than eight cycles of chemotherapy; and Salmon-Durie
heavily pretreated. 477 stage III disease at presentation (see Table 107–5). Toxicity was sub-
Other regimens that have been explored include bortezomib stantial, with 35 (44 percent) patients dying of transplant-related causes
and pegylated doxorubicin with or without thalidomide, bortezomib within 100 days of marrow transplantation. 494,501

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