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\begin{document}

\title{A case of synchronous dual hematological malignancy: effects of multiple
myeloma therapy on essential thrombocythemia and vice versa}



\author[1]{Nupur Krishnan }%
\author[2]{Russell Price}%
\author[2]{Rouslan Kotchetkov}%
\affil[1]{University of Western Ontario Faculty of Science}%
\affil[2]{Royal Victoria Regional Health Centre}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
We present a case of synchronous dual hematological malignancies:
multiple myeloma (MM) and masked essential Thrombocythemia (ET).
Excessive thrombocytosis due to bone marrow recovery occurred during
anti-myeloma therapy. Treatment for MM had no effect on ET; concomitant
ET did not decrease the efficacy of anti-myeloma therapies in this frail
patient.%
\end{abstract}%



\sloppy


Case Report

A case of synchronous dual hematological malignancy: effects of multiple
myeloma therapy on essential thrombocythemia and vice versa

Nupur Krishnan\textsuperscript{1}, Russell Price\textsuperscript{2},
Rouslan Kotchetkov \textsuperscript{2*}

\textsuperscript{1} University of Western Ontario, 1151 Richmond St,
London, ON, N6A 3K7; Canada

\textsuperscript{2} Simcoe Muskoka Regional Cancer Program; Royal
Victoria Regional Health Centre, Barrie, ON, Canada, L4M 6M2

Short Title: Synchronous MM and ET

*Correspondence: KotchetkovR@rvh.on.ca

Rouslan Kotchetkov

Department of Oncology, Simcoe Muskoka Regional Cancer Program; Royal
Victoria Regional Health Centre, Barrie, ON, Canada, L4M 6M2

Tel: +1-705-728-9090

Number of Tables: 2

Number of Figures: 2

Word count: 1780

Keywords: Essential Thrombocythemia, Multiple Myeloma, Dual
Hematological Malignancies

\textbf{Abstract}

We present a case of synchronous dual hematological malignancies:
multiple myeloma (MM) and masked essential Thrombocythemia (ET).
Excessive thrombocytosis due to bone marrow recovery occurred during
anti-myeloma therapy. Treatment for MM had no effect on ET; concomitant
ET did not decrease the efficacy of anti-myeloma therapies in this frail
patient.

\textbf{Introduction}

Dual malignancies occurring in the same patient are reported in the
literature {[}1{]}; however, dual hematological malignancies (DHMs) are
recognized less frequently {[}2-5{]} and are likely underreported
{[}6{]}. DHMs can been classified as either synchronous (SDHMs), when
occurring within six months of diagnosis of the first malignancy, or
asynchronous when occurring later {[}1{]}. Using a more restrictive cut
off of one month, we had earlier reported a 1.5\% incidence of SDHMs in
patients referred to our cancer center {[}6{]}. The detection of DHMs
may be an incidental finding during routine bloodwork or during
investigation of discrepant clinical and laboratory findings {[}6{]}.
The observed underreporting, and potential under detection, of SDHMs may
be because of masking from the primary malignancy {[}6{]}. DHMs
involving essential thrombocythemia (ET) and multiple myeloma (MM) are
quite uncommon, and most cases report MM developing years after ET
diagnosis. The occurrence of these two malignancies synchronously is
extremely rare. We report a case of concurrent MM and ET in a frail
elderly patient. We review the literature, discuss possible mechanisms,
and present potential challenges in the management of such patients.

\textbf{Patient Information/} \textbf{Clinical Findings}

An 86-year-old female presented to the emergency in May 2016 with
confusion, hypercalcemia, and acute kidney injury. Her past medical
history included hypertension, hyperlipidemia, and osteoporosis. She was
brought to the clinic on a stretcher with an Eastern Cooperative
Oncology Group (ECOG) status of 4. On examination, she was disoriented
and had tenderness along her left rib cage. Investigations showed
hemoglobin (Hb) 82 g/L, macrocytosis (MCV 134), rouleaux, WBC 4.2
x10\textsuperscript{9} with normal differential, and platelets 226 x
10\textsuperscript{9}/L (shown in Fig. 1A). Chemistry showed total
protein 99 g/L, albumin 26 g/L, calcium 3.15 mmol/L, and creatinine
clearance 17 mL/min. Total IgG was elevated (45.9 g/L) with reciprocally
decreased IgA and IgM. Monoclonal Protein (MP) was 41.8 g/L. Free Light
Chain (FLC) lambda was elevated (9,050 mg/L). Skeletal survey showed
osteopenia and a T12 vertebral compression fracture. Bone marrow (BM)
examination showed infiltration by plasma cells comprising up to 90\% of
nucleated cells including occasional binuclear and atypical plasma cells
(PC) (shown in Fig. 1B). The PC were kappa restricted and had strong
cytoplasmic CD138+ expression (shown in Fig. 1C). Erythroid and
megakaryocytic maturation was reduced but normal morphologically.

\textbf{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 x10\textsuperscript{9}/L in July, 810 x10\textsuperscript{9}/L in
September, and to 1,518 x10\textsuperscript{9}/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
(300x10\textsuperscript{9}/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
x10\textsuperscript{9}/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
10\textsuperscript{9}/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
10\textsuperscript{9}/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 x10\textsuperscript{9}/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
x10\textsuperscript{9}/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
10\textsuperscript{9}/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.

\textbf{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 10\textsuperscript{9}/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 10\textsuperscript{9}/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.

\textbf{Statements}

\textbf{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. .

\textbf{Data Availability Statement}

All data that support the findings of this study are included in this
article

Supplementary Material The CARE Checklist has been completed by the
authors for this case report, attached as supplementary material

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\textbf{Figure Legends}

Fig. 1A. Peripheral blood film showing multiple rouleaux,
morphologically normal WBC and platelets. May-Giemsa, x100 objective.

Fig. 1B. Bone marrow aspirate with numerous plasma cells, comprising
over 90\% of bone marrow cells, reduced erythopoiesis, granulopoiesis
and thrombopoiesis. Plasma cells contain Dutcher bodies and Russell
bodies. H\&E, x200 objective.

Fig. 1C. Strong expression of CD138 on plasma cell surface. Clot
section, H\&E, x200 objective.

Fig. 2. Graphical changes over time in patient's, hemoglobin, platelet
counts, and affected free light chain over the course of disease and
anti-myeloma therapy. Hb, Hemoglobin (g/L); Plt, platelet count
(x10\textsuperscript{9}/L), FLC, serum free light chain (mg/L); MPV,
Melphalan, Prednisone, Velcade (Bortezomib); Ld, Lenalidomide and
dexamethasone; DVd, Daratumumab, Velcade (Bortezomib), dexamethasone;
PCd, Pomalidomide, Cyclophosphamide, dexamethasone; Id, Ixazomib,
dexamethasone.\selectlanguage{english}
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