hematology

1. Impact of Comorbidities in Decision Making
in Multiple Myeloma Management
By
Assistant.Prof. Rasha Ibrahim Madena
Ain Shams University

2.  Multiple myeloma (MM) is the second most common
hematologic malignancy, with an estimated incidence
rate of 5- 6.5 per 100,000 men and women annually
(Siegel et al .,2016).
 MM rarely presents before age 40, with a median age at
diagnosis of 70 years.
 The prevalence is expected to increase in developed
countries in concert with increasing life expectancy.
Siegel, R.L., Miller KD, and Jemal A, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.

3.  There have been outstanding improvements over the past
decade in the area of initial therapy of newly diagnosed
multiple myeloma.

4. Despite today's novel therapeutic options, multiple
myeloma (MM) remains an incurable disease in the
majority of patients with highly variable outcome,
depending on various risk factors.
 The classification of MM is based on Salmon and
Durie (S&D) and International Staging System,
including primarily disease-related risk ;
Nevertheless, patient-related factors, like
comorbidities and abnormal organ function,
describing additional hazards on outcome, are not
as yet integrated in prognostic models

5.  Comorbidities have been demonstrated to affect
progression-free survival (PFS) and overall survival
(OS), although their impact in multiple myeloma
(MM) patients is as yet unsettled.
 Definition of comorbidity is the concurrent presence
of 2 medically diagnosed diseases in the same
person.
 Assessment of Comorbidity Charlson comorbidity
index (CCI) and Cumulative index rating scale-
geriatric(CIRS-G)

6. With aging, the incidence of comorbid conditions
increases markedly, because the frequency of
individual chronic conditions rises with age.
As a result, 35% of men and 45% of women aged
60-69 years have 2 comorbid conditions; this
percentage increases dramatically to 53% of men
and 70% of women by age 80 years.

8.  Many factors should govern the choice of initial
therapy for MM. The patient’s age, performance
status, eligibility for stem cell therapy, and most
importantly the presence of disease-related
complications as well as other comorbid conditions
.

10. MM and Renal Failure

12. Management
Dehydration and hypercalcaemia must be
carefully avoided
 Infections must be promptly treated.
Nephrotoxic drugs should not be administered
All the pharmacokinetic properties of each drug
must be evaluated to perform dose reduction with
respect to creatinine clearance.
For dialysis-dependent patients, the timing of
administration of each drug must be evaluated to
avoid under or over-exposition of the patient to
the drug.

15. Since the prevalence of type 2 diabetes is
increasing worldwide, an increase in the
diagnosis of MM with concomitant DM is
expected.
Therefore, physicians treating such patients
should be fully aware of the potential effect of
MM treatment on glucose metabolism in this
population

16. Is there evidence about a causal
relationship?
Although results in the literature are contradictory, in a study
conducted by Khan et al. there was no association between self
reported diabetes and multiple myeloma, whereas the highest
level of postload glucose was associated with risk of mortality
from multiple myeloma (HR, 3.06; 95% CI, 1.05–8.93) in another
study by Chiu et al.
Khan AE, Gallo V, Linseisen J et al., “Diabetes and the risk of non-Hodgkin’s lymphoma and multiple
myeloma in the European Prospective Investigation into Cancer and Nutrition,” Haematologica, vol. 93, no.
6, pp. 842–850, 2008.
Chiu BC, Gapstur SM, Greenland P, Wang R, and Dyer A, “Body mass index, abnormal glucose
metabolism, and mortality from hematopoietic cancer,” Cancer pidemiology Biomarkers and Prevention,
vol. 15, no. 12, pp. 2348–2354,2006.

17.  Dexamethasone- and prednisone-based regimens are
part of the conventional and new methods to treat
newly diagnosed or recurrent/multiple myeloma.
 These medications raise blood glucose through
 increased insulin resistance,
 gluconeogenesis,
 glycogenolysis,
 and decreased insulin production and secretion

18. Corticosteroids
Generally for MM, mega doses of
corticosteroids, such as 40 mg for 4 days/4
days off, are no longer used.
 The more acceptable dose is 40 mg once
weekly, but this dose can sometimes be
excessive for patients with diabetes ,so you
may reduce the dose to 20 mg, 10 mg, or lower,
or even eliminate the corticosteroids altogether,
especially in a patient who has had a good
response to the initial few cycles of treatment

19. Dexamethasone was shown to be more harmful
to the diabetes profile in a study by Facon et al.
where the investigators compared
dexamethasone and Prednisone-based
regimens with standard melphalan in newly
diagnosed MM patients ineligible for high-dose
therapy.
The morbidity associated with dexamethasone-
based regimens was significantly higher than
with melphalan prednisone including severe
diabetes
Facon T, Mary JY, P´egourie B et al., “Dexamethasone-based regimens versus melphalan-
prednisone for elderly multiple myeloma patients ineligible for high-dose therapy,” Blood, vol.
107, no. 4, pp. 1292–1298, 2006.

20. Thalidomide-Induced Hyperglycemia
 In a study by Iqbal et al., thalidomide 150 mg or placebo
was administered for 3 weeks in a crossover design to 6
patients with diabetes.
Insulin resistance was increased by 31% and glycogen
synthesis was decreased by 48%.
 In 2001, Figg et al. showed that decreasing the dose of
thalidomide improved hyperglycemia.
 In 2003, a case report on thalidomide induced severe
hyperglycemia was published by Pathak et al.
 Overall, larger studies are needed to assess this risk and
its implications on diabetes and multiple myeloma
outcome.
Iqbal N, Zayed M, and. Boden G, “Thalidomide impairs insulin action on glucose uptake and glycogen
synthesis in patients with type 2 diabetes,” Diabetes Care, vol. 23, no. 8,pp. 1172–1176, 2000.
Figg WD, Arlen P, Gulley J et al., “A randomized phase II trial of docetaxel (taxotere) plus thalidomide
in androgen independent prostate cancer,” Seminars in Oncology, vol. 28,no. 4, supplement 15, pp.
62–66, 2001.
-. Pathak RD, Jayaraj K, and Blonde L, “Thalidomide associated hyperglycemia and diabetes: case
report and review of literature,” Diabetes Care, vol. 26, no. 4, pp. 1322–1323,2003.
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21.  Diabetics with multiple myeloma constitute a challenging
specific population to physicians.
 Multiple myeloma by itself and its related treatments can
complicate the microvascular and macrovascular
complications of diabetes. The treating physician has to
recognize the treatment-related complications and closely
follow up diabetic patients for the emergence or the
worsening of hyperglycemia, neuropathy,nephropathy, or
retinopathy in addition to Cardiovasculardiseases.
 In addition, maintaining adequate blood glucose
levels reduces the risk of infection in patients with multiple
myeloma and decreases the risk and severity of diabetic
microvascular complications, thus, minimizing the
increased morbidity of multiple myeloma

22. Managing Patient with Peripheral
Neuropathy and MM

25.  Bortezomib-induced peripheral neuropathy
is more likely to occur in the first few cycles.it is
mainly sensory,it may be less evident with SC
rout (6-24% versus 16-41% in IV rout) The highest
risk and grade of bortezomib neurotoxicity was
observed in patients who had baseline peripheral
neuropathy and diabetes mellitus
 Thalidomide-induced peripheral neuropathy
is characterized by being mainly distal sensory
and less commonly motor. Its incidence varies
from 25% to 75% .The major predictors to
thalidomide-induced peripheral neuropathy seem
duration of treatment and possibly baseline
neuropathy

26. Guidelines for managing bortezomib-induced PN
 Patients should be asked about PN symptoms prior to
every dose of bortezomib
 Educate patients about AEs.
 With appropriate dose modifications the neuropathy may
be reversible
 We often will also intervene with other measures, such as
the use of gabapentin, pregabalin, TCA, and drugs of the
selective serotonin reuptake inhibitors (SSRI) and
serotonin and norepinephrine reuptake inhibitors (SNRI)
classes.
 Neuropathy is reversed or reduced in the majority of
patients Some patients will have lifelong residual
neuropathy

27. For patients who have baseline neuropathy,
you may be inclined to use carfilzomib,
lenalidomide, and dexamethasone, which
appears to have a superior depth of response
without the rates of PN

29.  Compared to the general population,
individuals with cancer are at 4 to 7 times
higher risk of developing a venous
thromboembolism (VTE) as malignancy
induces a prothrombotic state
 Multiple myeloma (MM) has one of the highest
risks of thrombosis among all cancers due to
disease-related pathological changes and
treatment.

31.  Thalidomide and lenalidomide (IMIDs) are well
known to be associated with increased risk of
thrombosis ,especially when combined with high-
dose steroids and other chemotherapy, with
incidence approaching 25% in some studies .
 Preliminary data with the next-generation PI
carfilzomib suggest that it is associated with a low
incidence of VTE (2% this increase to 6% if used in
combination with DEXA or REV+DEXA ).

36.  The peak incidence of MM is in the
6th and 7th decades of life. This
combined with the high prevalence of
CV disease .
 Men have higher rates of both MM
and CV risk factors

37. Cardiovascular complications of pharmacology MM therapies
AGENT CARDIOVASCULAR MANIFESTATION
CARFILZOMIB LV dysfunction, CHF, myocardial ischemia, pulmonary
hypertension
BORTEZOMIB LV dysfunction, CHF, myocardial ischemia, pulmonary
hypertension, autonomic dysfunction, hypotension, AVt
blocks, prolonged QTc
LENALIDOMIDE Thromboembolism, arrhythmias
POMALIDOMIDE Thromboembolism, arrhythmias, autonomic dysfunction,
hypotension
CYCLOPHOSPHAMI
DE
LV dysfunction, CHF, pericardial effusions, hemorrhagic
myopericarditis* *high dose
DEXAMETHASONE CHF, arterial hypertension
PANOBINOSTAT Prolonged QTc, ventricular arrhythmias
MELPHALAN LV dysfunction, arrhythmias

41. Conclusion
You should start treatment of patient with
comorbidities after careful risk-benefit assessment as
Attention to detail in ALL aspects of the patient’s care
is likely to produce the best outcome