Clarithromycin appears to have immunomodulatory ef-
fects and direct antineoplastic properties, Dr. Puig noted
in her presentation, and previous non-randomized stud-
ies have shown that adding clarithromycin to standard Rd
treatment for patients with MM who are not eligible for
autologous hematopoietic cell transplantation is safe and
enhances response.
To build a larger evidence base examining clarithro-
mycin plus Rd, Dr. Puig and researchers conducted the
open-label, randomized, phase III GEM-Claridex trial,
which included 286 patients with previously untreated
MM. Patients were randomized 1:1 to receive Rd (lena-
lidomide 25 mg daily plus dexamethasone 40 mg on days
1, 8, 15, and 22) with or without clarithromycin 500 mg
twice daily. Treatment continued until disease progres-
sion or unacceptable toxicity.
Participants’ median age was 76 years (range = 65-93).
About one-third of patients (36.8%) had ISS stage III dis-
ease, and 15.6% had high-risk cytogenetic abnormalities.
During a median follow-up of 16 months (range = 1-47),
patients received a median of 10 treatment cycles (range
= 1-40) in the Rd group and 8 cycles (range = 1-40) in the
clarithromycin group. All patients experienced at least
one adverse event (AE), and most experienced at least one
grade ≥3 treatment-emergent AE: 82.5% (n=118) in the
Rd group and 81.8% (n=117) in the clarithromycin group.
There were no significant differences in rates of hemato-
logic AEs, except for anemia, which was more frequently
reported in the Rd arm (17.4% vs. 14.6%; p=0.04).
A substantial number of patients discontinued treat-
ment: 66 (46.2%) in the Rd group and 91 (63.2%) in the
clarithromycin group. “Importantly, the percentage of
treatment discontinuations was significantly higher in
the clarithromycin arm, due to a higher percentage of
toxicity-related death,” Dr. Puig reported. “In contrast,
the percentage of patients discontinuing due to disease
progression was significantly higher in the Rd arm.”
Reasons for treatment discontinuation were as follows:
• disease progression: 31 (47%) in the Rd arm and 26
(28.6%) in the clarithromycin group
• AE: 12 (18.2%) and 16 (17.6%)
• treatment-related deaths: 8 (12.1%) and 21 (23.1%)
• other reasons: 15 (22.7%) and 28 (24.2%)
The higher number of treatment-related deaths in the clar-
ithromycin group points to the failure of clarithromycin to
improve progression-free survival (PFS), the study’s primary
endpoint. While clarithromycin was associated with higher
objective response and complete response rates, there were
no significant differences in median PFS: 23 months with
Rd versus not reached for clarithromycin (p=0.12). Most of
these deaths were related to infections, the authors noted,
and mainly affected the group of patients older than 75.
In the 129 patients <75 years, though, 61% and 60% of
patients in the Rd and clarithromycin group, respectively,
were alive and free from progressive disease at 20 months. Of
those ≥75 years, there was a significant benefit for PFS in the
Rd arm: 28 months vs. 19 months (hazard ratio = 1.5; p=0.07).
Overall survival also was not reached and not signifi-
cantly different between the two treatment arms.
Given that the higher efficacy of clarithromycin plus
Rd was not associated with a better PFS, particularly in
older patients, Dr. Puig concluded, “Clarithromycin could
be added to Rd in patients with newly diagnosed MM who
are younger than 75 years and not candidates for trans-
plant, but dose reductions and anti-infectious prophy-
laxis should be considered.” Although the trial was not
designed to determine why the addition of clarithromycin
failed to prolong survival, she added that the interaction
between steroids and clarithromycin could potentially
explain these results.
Study authors report relationships with Celgene, the
manufacturer of lenalidomide.
Reference
Puig N, Hernández MT, Dachs LR, et al. Randomized trial of lenalidomide and dexamethasone ver-
sus clarithromycin, lenalidomide and dexamethasone as first line treatment in patients with
multiple myeloma not candidates for autologous stem cell transplantation: results of the
GEM-Claridex clinical trial. Abstract #694. Presented at the 2019 American Society of Hematology
Annual Meeting, December 9, 2019; Orlando, FL.
Early-Phase Study Shows
Promising Response Rates
With Venetoclax Plus
Navitoclax in ALL
Nearly half of patients with relapsed/refractory acute lymphocytic
leukemia (ALL) had a complete response (CR) after treatment
with a combination of venetoclax and navitoclax, according to
findings from a phase I study presented at the 2019 ASH Annual
Meeting. While nearly all patients experienced at least one grade
3/4 adverse event (AE), the investigators, led by Norman Lacayo,
MD, from Stanford University and Lucile Packard Children’s Hos-
pital in Palo Alto, California, noted that there was no unexpected
toxicity with this combination.
“Venetoclax is a highly selective BCL2 inhibitor, and navi-
toclax is also a BCL2 inhibitor, but also inhibits BCLX L and
BCLW,” Dr. Lacayo explained. “BCL2 and BCLX L inhibitors
March 2020
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