Diagnostic Assessment/Therapeutic Intervention
At that stage the patient was presenting with the classical picture of
FLC lambda and IgG lambda multiple myeloma (MM), standard risk.
Fluorescence in situ hybridization (FISH) was positive for monosomy
13/13q deletion and no high risk abnormalities, like del(17p) or t(4;14)
and/or t(14;16), were found. Revised International Staging System was
II. Since her platelet count was normal, no work up for
myeloproliferative neoplasms was done.
She started MPV (Melphalan–Prednisone–Bortezomib) treatment with
Darbopoietin support in June 2016. By October 2016, her Hb improved to
132 g/L and FLC decreased to 9.7 mg/L. She reached stringent complete
remission (CR) with no MP detected on serum protein electrophoresis
(SPEP) or immunofixation (IFE). We noticed her platelet counts increase
to 514 x109/L in July, 810 x109/L in
September, and to 1,518 x109/L in October.
Due to the appearance of unexpected thrombocytosis, we first ruled out
infections and iron deficiency. The platelet count was unusually high
for secondary causes for thrombocytosis, thus we initiated work up for
myeloproliferative neoplasms. JAK2 mutation was negative, but she was
found to have a mutation in exon 9 of Calreticulin (CALR). We concluded
that she had concomitant CALR-positive ET. Based on an International
Prognostic Score for Essential Thrombocytopenia score of 4, she had high
risk ET. Due to classical ET presentation and the patient’s preference,
we omitted repeated bone marrow examination. Aspirin and Hydroxyurea
(HU) were added to MPV, stabilizing her platelet counts
(300x109/L). As this second diagnosis occurred within
5 months of diagnosis of the first malignancy, we updated her diagnosis
to a synchronous dual hematological malignancy (SDHM): MM and ET,
initially masked by marrow infiltration by PC.
She finished MPV in April 2017. By August 2018, her platelets were 388
x109/L; she relapsed, with FLC climbing to 1,130 mg/L,
MP 23.9 g/L, and Hb dropping to 104 g/L. HU was held and she was started
on second-line Lenalidomide-Dexamethasone (Ld) treatment for MM. Upon
achieving a second CR, her platelet count increased to 500 x
109/L and HU was restarted. In March 2019, her MM
progressed again with FLC increasing over 600 mg/L, and MP 17.0 g/L. She
developed new anemia (Hb 114 g/L) and thrombocytopenia (platelets 118 x
109/L). Once again, HU was held. She was started on
third-line anti-myeloma therapy with DVd
(Daratumumab-Bortezomib-Dexamethasone) in April 2019. FLC decreased to
11.5 mg/L, MP was down to 0.2 g/L, Hb increased to 120 g/L, and
platelets increased (580 x109/L). She attained third
remission and we re-started HU. After the 7th cycle with DVd, however,
her FLC increased again to 255 mg/L, MP was 6.9 g/L, and Hb decreased to
110 g/L. HU was put on hold and platelets remained low-normal (154
x109/L). In October 2019 she started fourth-line
therapy with PCd (Pomalidomide-Cyclophosphamide-Dexamethasone), and she
reached CR with no measurable MP and normalization of FLC kappa (6.6
mg/L) in December 2019. Platelet count was 247 x
109/L. She was in remission until June 2020 when she
progressed to PC leukemia and passed away. FLC and platelet counts
dynamics over the course of disease and treatment is shown in Figure 2.
Discussion/Conclusion
SDHMs are suspected if certain clinical, hematological, or biochemical
features cannot be explained by the primary malignancy alone. These
cases can be challenging to diagnose and treat and warrant additional
attention and investigation. Table 1 summarizes case reports of
synchronous ET and MM [7-12]. The median patient age was 59 years,
with equal gender distribution (five males and three females). The
median platelet count was 835 x 109/L. Plasma cells in
bone marrow ranged from 11.5% to 90%, as well as one patient who had
only 6% PCs but presented with a plasmacytoma. Molecular markers were
only reported for three cases and were all JAK2 positive. ET and MM were
diagnosed concomitantly in all except one, in which ET diagnosis
preceded that of MM by one month.
There are more reports of asynchronous MM and ET, as summarized in Table
2 [13-24]. The median patient age was 67 years, with 9 males and 5
females. The median platelet count was 1,065 x 109/L.
Bone marrow PCs ranged from 24% to 100%. Molecular markers were only
reported for five of the cases: three were JAK2 positive while two were
JAK2 negative. In all cases, ET preceded MM with a median of 4.5 years
between diagnoses.
Reports prior to 2011 did not describe JAK2 status or calreticulin
mutations. Additionally, none of the previous reports of synchronous MM
and ET had simultaneous treatment for both malignancies, as was required
in our case. Although the exact mechanism of such SDHMs is not clearly
understood, there are several possible reasons. Firstly, a common
trigger at the stem cell level may lead to their differentiation into
myeloid (ET) and lymphoid (MM) cells [12]. Secondly, the two
malignancies may arise from separate malignant clones at different
differentiation levels [16]. Alternatively, therapy for one
malignancy may cause or trigger development of the second malignancy
[25], however, this is unlikely to be the case in SDHMs, as in our
patient. Additionally, it has been suggested that Interleukin-6 may
cause reactive thrombocytosis via stimulation of thrombopoietin, and may
precipitate synchronous development of ET [26]. It is also possible,
however, that the occurrence of the two malignancies was purely
coincidental. MM is a slowly progressing malignancy, with an average
time gap of 163 days from symptom onset to diagnosis [27], so it may
have been present subclinically for some time in our patient before its
diagnosis meaning that these malignancies may not necessarily have been
synchronous. Due to the concomitant development of ET and MM in our
patient, it is likely that BM infiltration by PC suppressed excessive
megakaryopoiesis and thus masked ET. With restoration of hematopoiesis
by anti-myeloma therapy, the patient developed thrombocytosis. In such
cases when clinical or biochemical parameters cannot be explained by the
primary malignancy alone, it is important to consider DHMs.
In managing such patients, one needs to treat the malignancy that has a
more aggressive, life-threatening course or the potential to transform
into acute leukemia. In our case, we first treated for MM. Unexpected
extreme thrombocytosis prompted addition of cytoreductive therapy for
ET. Additionally, therapy for DHMs needs to balance disease control, the
patient’s condition, and BM capacity. We did not observe any effect of
treatment for MPV, Ld or Daratumumab on ET. With the fourth-line PCd,
the patient had normalization of platelets, but not to the level of
thrombocytosis; possibly due to “tired bone marrow” with decreased
capacity to produce excess platelets or due to anti-platelet effects of
PCd. Similarly, therapy with HU for ET did not have any effect on the
course of MM. Duration of response with all therapies in our patient was
comparable to that of previously reported patients with MM alone.
Despite our patient’s age, comorbidities, and combination of treatments,
she tolerated multiple lines of treatment well for both malignancies and
achieved CR.
In conclusion, synchronous MM and ET is rare. BM suppression by MM can
mask thrombocytosis at diagnosis. Restoration of hematopoiesis due to
anti-myeloma therapy may uncover ET. Therapy of MM does not affect ET,
except probably use of PCd. Frequent monitoring of both malignancies is
important, as drops in blood counts could be a result of either
cytoreductive therapy or MM relapse. Presence of concomitant ET did not
decrease efficacy of sequential anti-myeloma therapies in our elderly
and frail patient.
Statements
Statement of Ethics Ethical approval is not required
for this study in accordance with our local guidelines. The research was
conducted ethically in accordance with the World Medical Association
Declaration of Helsinki. Written informed Consent for Publication was
obtained from the patient’s daughter (next-of-kin) for publication of
the details of their medical case and any accompanying images.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No Research support for this study.
Author Contributions
N.K., R.P., and R.K. wrote and reviewed the manuscript. All authors
approved the final version to be published and agreed to act as
guarantors of the work. .