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HSP90 inhibitors
A phase 2 clinical trial looked at the HSP90 inhibitor tanespimycin in combination with bortezomib in
[184]
patients with relapsed and/or refractory MM . All patients enrolled in the study experienced at least
one side effect, with most common grade 3/4 toxicities being fatigue, thrombocytopenia, neutropenia, and
abdominal pain. Four patients had significant liver toxicity with higher doses of tanespimycin, however
2
this was manageable and reversible. The best responses observed to treatment were 1 MR in the 340 mg/m
2
group, and 2 PRs in the 175 mg/m group. An additional 10 patients across all treatment groups had stable
disease. A later phase 3 study evaluating tanespimycin and bortezomib has been completed, however
results are not yet available.

KW-278 is a novel, non-anisomycin, non-purine based HSP90 inhibitor that has a more favorable
[185]
pharmacokinetic and safety profile compared to tanespimycin . A phase 1 trial examined the safety and
[186]
efficacy of KW-278 in B-cell malignancies, including 22 MM patients . The most common side effects
included diarrhea, headache, rhinitis, and fatigue. Ten patients experienced grade 3 and 4 toxicities such
as lethargy, syncope, QT prolongation, and neutropenia. Six patients experienced eye disorders (decreased
visual acuity, blurry vision, dry eyes) that were deemed related to KW-278. All of the eye disorders
were reversible with the exception of dry eyes. Two patients died during the trial and both deaths were
determined to be unrelated to the study medication. Of the 21 MM patients evaluated, 20 patients (95%)
had stable disease, and 1 patient had progressive disease.

A subsequent phase 1/2 study evaluated KW-278 with bortezomib in patients with relapsed or refractory
MM who had failed at least 1 previous treatment . The most common side effects were fatigue and
[187]
gastrointestinal toxicity, while the most common grade 3-4 side toxicities were cytopenias. There was
no sign of significant ophthalmologic side effects in the 95 patients enrolled in this study. There were 28
serious treatment-related adverse events such as lung infections, GI toxicity, anemia, hematuria, syndrome
of inappropriate diuretic hormone, pancreatitis, and transient ischemic attack. Efficacy of the treatment
2
was based on a KW-278 dose of 175 mg/m with bortezomib at the standard concentration. The ORR
was 39%, the CBR was 92%. Median progression-free survival was 6.8 months, and median duration of
response was 5.6 months. Patients who were lenalidomide-naïve had an ORR of 45.5 as compared to 25%
for patients previously exposed to lenalidomide. Bortezomib-naïve patients had an ORR of 44% vs. 33% in
patients previously exposed to bortezomib. These findings suggest a potential therapeutic benefit of KW-278
with bortezomib in the treatment of relapsed or refractory MM.

PI3K-AKT-mTOR inhibitors
The PI3K-AKT-mTOR inhibitor everolimus was tested as a single agent in a phase 1 trial in patients with
[188]
relapsed and/or refractory MM . Most side effects were mild to moderate with gastrointestinal upset,
elevated muscle and liver enzymes, and cytopenias being the most common. One patient developed an
atypical pneumonia that was thought to be drug-related. Of the 15 patients assessed, 10 (67%) experienced
clinical benefit with one patient achieving a partial remission after 4 cycles.

A phase I trial assessed the safety and efficacy of everolimus in combination with lenalidomide in patients
with relapsed or refractory MM [189] . Most common side effects were fatigue, cytopenia, diarrhea and
neuropathy. One patient discontinued treatment due to non-infectious pneumonitis that was related to
everolimus, and another discontinued due to grade 3 myalgia. Of the 23 patients that completed 2 cycles
of treatment, the CBR was 74% with 1 CR and 4 PR. In patients who were lenalidomide-naïve, the ORR
was 90%, compared to 37.5% for patients who had previously received lenalidomide. Median progression-
free survival was 5.5 months, and median overall survival was 29.5 months. Promising results from these
studies demonstrate the potential for mTOR inhibitors to be used the treatment of relapsed or refractory
MM. A clinical trial looking at the role of mTOR inhibitors in combination with pomalidomide and
dexamethasone is currently enrolling (NCT03657420).