Page 1588 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 86 Plasma Cell Neoplasms 1415

at 1 year (after a median follow-up of 24.5 months) in the ERd group administration alone has also been shown to produce responses or
was 68%, as compared with 57% in the Rd group. Moreover, at 2 delays in disease progression in occasional patients. Bisphosphonates
years, there was a 41% PFS advantage in the ERd group compared have multiple actions, including suppression of OC number and
with 27% in the Rd group. The median PFS was 19.4 months in the function, inhibition of IL-6 production by stromal cells, inhibition
ERd group versus 14.9 months in the Rd group (hazard ratio for of farnesyl and geranyl-geranyl transferase activity, and immune
progression or death in the elotuzumab group, 0.70; p < .001). ORRs effects via γ/δ T cells.
varied between the two groups: 79% in the ERd group and 66% in Two potential side effects of bisphosphonates have limited their
the Rd group. Prespecified interim analysis for OS indicated a strong very long-term use in the recent past; effects on renal function and
trend (p = .0257) in favor of the ERd arm compared with the Rd development of osteonecrosis of the jaw (ONJ). ONJ is observed in
arm with early separation sustained over time (43.7 months vs. 39.6 patients with dental infections or procedures following its longer-
months, respectively; hazard ratio, 0.77). Of the patients in the ERd term use. The frequency of these adverse events has been between
group, 10% had infusion reactions. Other grade 3/4 adverse events 3% and 5%. In one study, 11 (3.8%) of 292 patients with MM
in the ERd arm were lymphocytopenia and fatigue. developed ONJ. Patients receiving bisphosphonates require a thor-
Daratumumab is a human anti-CD38 IgGκ monoclonal antibody ough dental checkup before starting therapy and should have frequent
that has recently been approved for patients who have had more than dental follow-up with careful and conservative use of dental proce-
three relapses or refractory myeloma. Daratumumab binds CD38- dures. With these precautions, the frequency of ONJ has been
expressing malignant plasma cells with high affinity and induces reduced. Similarly, the measurement of renal function before each
tumor cell death through diverse mechanisms of action, which bisphosphonate dose and the adjustment of dose based on renal
include complement-dependent cytotoxicity; antibody–dependent, function also make use of bisphosphonates safer. A slower administra-
cell-mediated cytotoxicity; antibody-dependent cellular phagocytosis; tion of bisphosphonates prevents or protects against the development
and induction of apoptosis. Moreover, daratumumab suppresses Tregs of renal dysfunction. Most recently, the recommended duration of
and the actor enzyme activity-driven suppression of T cells via the bisphosphonate has been 2 years, with reduction in frequency after
adenosine signaling pathway. The ORR was 29% among 106 patients that if patients enjoy a good remission. However, in the light of the
treated with daratumumab at 16 mg/kg; the median response dura- recent MRC-IX study, this recommendation will require revision
tion was 7.4 months, PFS was 3.7 months, and OS was 17.5 months. with the possible benefits of long-term use. Additional bone-directed
Daratumumab was well tolerated; fatigue and anemia were the most targets and agents are in development that have the ability to further
common adverse events. inhibit OC function (denosumab) and also to improve OB activity
The POLLUX trial was a phase III study comparing daratu- and with bone anabolic effects (DKK-1 - BHQ-880 and activin A
mumab, lenalidomide, and dexamethasone (DRd; 286 patients) with -ACE-011). These agents are currently under clinical investigation in
lenalidomide and dexamethasone (Rd; 283 patients) in patients with patients with MM.
relapsed/refractory myeloma. After a median follow-up of 13.5
months, the estimated median PFS was not reached in the DRd
group compared with 18 months in the lenalidomide and dexametha- FUTURE DIRECTIONS
sone group.
Other promising targets, agents, and stages of their clinical Significant advances have occurred in the understanding of the
development are listed in Table 86.25. The optimal treatment of a pathobiology of MM, which have translated to development of novel
relapsed patient requires ensuring that the patient’s relapse requires therapeutics. Predictive in vitro and in vivo models have been devel-
intervention. The approach to therapy is dictated by whether the oped to study growth and survival characteristics of MM cells in the
patient had a prior transplant or is a transplant candidate, and the context of the bone marrow microenvironment, but, more important,
selection of a possible drug depends on the prior therapy received. to preclinically evaluate efficacy of novel targeted agents. Similarly,
Additional selection criteria should consider patient characteristics there has been an explosion of genomic data covering various genomic
such as age, risk factors, existing comorbidities such as renal failure, correlates including expression profile, CNA, alternate splicing,
previous toxicities such as neuropathy, and patient convenience. miRNA, and now whole-genome and RNA sequencing with muta-
Improving CR rates is a key goal of current trials in relapsed patients tional analysis of expressed genes as well as noncoding regions.
as well. Understanding of mutational landscape, molecular drivers of the
disease and patterns, and surrogates of genomic evolution are provid-
ing newer clues to the disease biology as well as novel therapeutic
Bisphosphonates approaches. Evolving understanding of the epigenomic alterations
that affect cell growth, survival, and development of drug resistance
Aminobisphosphonates, pamidronate, and zoledronate have been is providing clues for novel interventions. For example, there is
investigated in patients with myeloma and bone disease and have already an HDAC inhibitor approved for therapy of relapsed
been shown to reduce skeletal complications and bone pain. Research- myeloma. Moreover, MM cell proliferation is now considered to be
ers in a number of older randomized studies looked at their efficacy dependent on the bromodomain and extraterminal (or “BET”)
in patients with existing bone lesions and evaluated the development domain family of bromodomain-containing proteins (BRD2, BRD3,
of new skeletal-related events. In this regard, pamidronate 90 mg and and BRD4), which are novel therapeutic targets.
zoledronic acid 4 mg are equipotent in reducing bone-related prob- These model systems and improved understanding have led to
lems in MM; the infusion time for zoledronic acid is 15 minutes as new drug development, with 10 new agents approved for myeloma
compared with 1 to 2 hours for pamidronate. In a recent large study, in the last 12 years and over 15 other novel agents in phase I or II
MRC IX, investigators evaluated the efficacy of zoledronic acid in a studies. The genomic information is being integrated to develop more
randomized comparison with clodronate. This study included 1960 accurate risk stratification models and to develop personalized medi-
patients and confirmed the efficacy and superiority of zoledronic acid cine to optimize response while avoiding toxicities. With these
in preventing new skeletal-related events in patients both with and advances and use of combination of agents, there is a significant
without existing bone lesions (Table 86.26), and it provided evidence improvement in the achievement of CR, over 60% to 70% in some
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that its continued use beyond 2 years was beneficial ; importantly, studies. This has led to validation of molecular MRD as an important
the study also suggested that zoledronic acid compared with clodro- new endpoint in myeloma with its incorporation into all clinical
nate, a first-generation bisphosphonate, improves OS, providing for studies as well as exploration as an ultimate endpoint to achieve cure.
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the first time some evidence of its antimyeloma activity (Fig. 86.17). Finally, because of these advances, the median survival of patients
A similar survival advantage has also been reported with pamidronate with MM has increased from 3 years to over 8–10 years, and in a
(21 vs. 14 months; p = .041) in patients receiving salvage chemo- number of individuals, it becomes a chronic disease with curative
therapy and pamidronate versus chemotherapy alone. Pamidronate outcome predicted in a proportion of patients in the near future.