efficacy of thalidomide-based therapy following lenalidomide plus dexamethasone in patients with...
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Efficacy of thalidomide-based therapy following
lenalidomide plus dexamethasone in patients with
relapsed/refractory multiple myeloma
Immunomodulatory drugs (IMiDs), thalidomide and its derivative lenalido-
mide, have emerged as an effective treatment for relapsed/refractory
multiple myeloma (MM). Clinical studies have demonstrated that thalido-
mide and lenalidomide each have their own distinct toxicity and efficacy
[1–4] despite sharing an overlapping immunomodulatory profile [5,6]. It is
evident that patients previously refractory to the less potent IMiD thalido-
mide can still respond when treated with lenalidomide [7,8]. However, the
efficacy of thalidomide in patients refractory to lenalidomide is largely
unknown. Two recent studies have looked at the use of thalidomide as a
possible treatment regimen post-lenalidomide. Firstly, Guglielmelli et al. [9]
followed a diverse group of 20 patients with MM that relapsed while on a
reduced maintenance dosage of lenalidomide and treated these patients
with a thalidomide-based salvage regimen. Their results showed a 10%
overall response of equal or greater than partial response (� PR) and me-
dian response duration of 5 months. Secondly, Madan et al. [10] reported
an overall response rate of 25% in a subset of four patients with lenalido-
mide refractory MM subsequently treated with thalidomide.
We retrospectively studied 24 patients with advanced MM with relapsed
disease, refractory disease, or intolerance to full dose lenalidomide and
dexamethasone that were subsequently treated with a thalidomide-based
regimen. In our study, the median age of subjects at the start of thalidomide
therapy was 67 years (44–83) with 67% of patients being males. Monoclonal
types were IgG 54% (n 5 13), IgA 33% (n 5 8), and free light chains com-
prising 13% (n 5 3). Seven patients (29%) had a prior thalidomide exposure
pre-lenalidomide either as induction therapy pre-autologous stem cell trans-
plant (ASCT), post-ASCT maintenance or treatment in a relapsed setting.
Median time to re-exposure of thalidomide (post lenalidomide) from the end
of initial exposure (pre-lenalidomide) for the described seven patients was
2.9 years (1.2–4.0 years). The same seven patients that received thalido-
mide prior to lenalidomide when compared to the remaining 17 patients
exposed to thalidomide only post-lenalidomide had an expectedly reduced
median treatment duration and overall response to thalidomide regimen
given after lenalidomide (84 versus 103 days; 29 versus 35%). However,
these values were not statistically significant.
Table I summarizes the lenalidomide- and thalidomide-based regimen and
responses for all 24 patients. Nineteen of these patients tolerated and even-
tually progressed on lenalidomide having median treatment duration of 11.1
months, comparable with 11.3 months reported by the MM009 trial [2].
Overall, response to thalidomide-based regimen post-lenalidomide
resulted in nine patients (38%) achieving a very good partial response or
a partial response (VGPR 1 PR) and 13 patients (54%) achieving less
than a partial response, stable disease or progressive disease (SD 1 PD).
No complete responses (CR) were observed. Progression-free survival for
all 24 lenalidomide-treated patients receiving thalidomide-based treatment
was a median of 3.1 months (95% CI; 63–226 days) and overall survival
was a median of 9.6 months (95% CI; 255–444 days). In the thalidomide
containing responsive group (VGPR 1 PR), the median duration of thalido-
mide-based treatment was improved to 9.1 months (95% CI: 2.8–19.3)
A case of leptospirosis presenting as TTP
Dear Editor:
In their recent article, Booth et al. describe a number of cases of systemic
infection with reduced a disintegrin and metalloproteinase with a thrombo-
spondin type 1 motif, member 13 (ADAMTS13) activity, whose presenting
clinical features mimicked thrombotic thrombocytopenic purpura (TTP) [1]. In
the past, a small number of cases of leptospirosis have been reported to be
associated with TTP [2–4]. We describe a further such case of leptospirosis,
with presenting features suggestive of TTP and report, for the first time, an
associated reduction in ADAMTS activity.
A previously well 49-year-old Caucasian male was hospitalized with
11-day history of general malaise and 5 days of increasingly severe lower
limb muscle pain. On physical examination, he was jaundiced and had gen-
eralized tenderness of his legs. He had low grade fevers with a maximum
temperature of 37.8�C. There was no history of headache or rigors. Com-
plete blood count (CBC) revealed hemoglobin of 12.9 g/dl with a white cell
count of 9.8 3 109/l and platelets 21 3 109/l. Both kidney and liver functions
were shown to be deranged, with urea of 35.5 mmol/l, creatinine of 698
mmol/l, bilirubin of 198 mmol/l, alanine aminotransferase of 244 IU/l, and
alkaline phosphatase of 180 IU/l, and hypoalbuminemia of 30 g/l.
Serum lactate dehydrogenase was 1,677 IU/l. Blood film examination
showed severe thrombocytopenia and fragmented red cells.
In light of this patient’s acute kidney injury, thrombocytopenia, and
anemia, a working diagnosis of TTP was made and subsequently daily
therapeutic plasma exchange (TPE) and high dose intravenous corticoste-
roids were commenced. Due to worsening renal function, with a serum cre-
atinine of 759 mmol/l, and the onset of oliguria on day 2 of admission,
hemodialysis was initiated. On day 3 of TPE and high dose IV corticoste-
roid treatment, a CBC revealed no improvement in the thrombocytopenia,
with a platelet count of 8 3109/l. There was still a marked transaminitis
which had not improved since admission. Closer questioning revealed that
the patient had potentially been exposed to vermin three weeks previously
while working outdoors. In light of this new information, leptospirosis serol-
ogy was undertaken and antibiotic treatment for the possible leptospiral
infection was commenced with a course of intravenous (IV) ceftriaxone.
Within the following 24 hr, the patient’s clinical condition and abnormal
blood test results began to improve, with CBC and renal indices returning to
normal values and markedly improved liver blood tests by day 16 of admis-
sion. Serological testing showed a positive microscopic agglutination test for
leptospira and ELISA-testing demonstrated the presence of anti-leptospira
IgM. Subsequently, a 14-day course of IV antibiotic treatment was completed,
hemodialysis was discontinued, and TPE was stopped after 5 days.
ADAMTS13 activity, sent on admission, was reduced at 43% (60–123%). This
patient presented with features suggestive of TTP but failed to respond to
plasma exchange. Once a diagnosis of leptospirosis was suspected and
appropriate antibiotics started, the patient made a rapid and complete recov-
ery. In retrospect, the disproportionally abnormal liver blood tests at presenta-
tion were atypical for TTP and might have triggered a more prompt
introduction of antibiotics for suspected leptospirosis. We certainly agree with
the conclusions of Booth et al. that, patients with systemic infection who pres-
ent with clinical features suggestive of TTP, timely detection and treatment of
such infections may avoid inappropriate continuation of plasma exchange.
DAIRE K. QUINN,1*
JOHN QUINN,1
PETER J. CONLON,2
PHILIP T. MURPHY1
1Department of Haematology/Oncology,
Beaumont Hospital, Dublin 9, Ireland2Department of Renal Medicine, Beaumont Hospital, Dublin 9, Ireland
*Correspondence to: Daire Kevin Quinn, Departments of Haematology and
Oncology, Beaumont Hospital, Dublin 9, Ireland
E-mail: dairequinn@gmail.com
DOI 10.1002/ajh.23394
References1. Booth KK, Terrell DR, Vesely SK, et al. Systemic infections mimicking
thrombotic thrombocytopenic purpura. Am J Hematol 2011;86:743–751.2. Hanvanich M, Moollaor P, Suwangool P, et al. Hemolytic uremic syndrome in
leptospirosis bataviae. Nephron 1985;40:230–231.3. Cserti CM, Landaw S, Uhl L. Do infections provoke exacerbations and
relapses of thrombotic thrombocytopenic purpura? J Clin Apher 2007;22:21–25.
4. Laing RW, Teh C, Toh CH. Thrombotic thrombocytopenic purpura (TTP) com-plicating leptospirosis: A previously undescribed association. J Clin Pathol1990;43:961–962.
Received for publication 15 November 2012; Revised 3 January 2013; Accepted8 January 2013
Published online 24 January 2013 in Wiley Online Library(wileyonlinelibrary.com)
DOI: 10.1002/ajh.23393
VC 2013 Wiley Periodicals, Inc.
American Journal of Hematology http://wileyonlinelibrary.com/cgi-bin/jhome/35105337
Correspondence
versus 2.4 months (95% CI: 1.4–2.9) in the non-response group
(P< 0.001).
In these advanced disease patients, low to medium level dosing of thali-
domide (100 mg–200 mg daily) was generally well tolerated. Only one
patient experienced grade 3 neuropathy and consequently discontinued tha-
lidomide treatment. Grade 1–2 neuropathy was noted in 13 patients. No
venous thromboembolisms were observed. Eight patients (72%) experi-
enced neutropenia of which seven patients (64%) were given Granulocyte
colony-stimulating factor (G-CSF) support. Six of the eight patients with neu-
tropenia were on a cyclophosphamide containing regimen.
Twelve patients treated with thalidomide in combination with cyclophos-
phamide showed an overall response rate of 54% and a median treatment
duration of 5.3 months (1.5–18.2 months) which was significantly longer
than the 2.9 months (2.0–9.1 months) median seen in patients treated with
thalidomide regimens without an alkylator (P 5 0.05). Synergism between al-
kylating agents and thalidomide with dexamethasone is reported to improve
overall response rates for relapsed/refractory myeloma (56%), higher than
thalidomide alone [11,12]. Our patients treated with thalidomide in combina-
tion with cyclophosphamide were not previously refractory to the alkylator
and therefore it is difficult to delineate whether the activity seen in this sub-
group is due to drug combination synergism or primarily due to cyclophos-
phamide. Further systematic studies are warranted to establish
cyclophosphamide as a beneficial synergistic agent with repeat IMiDs.
Analyzing 11 patients treated with thalidomide and steroids without cyclo-
phosphamide showed a PR in two patients (18%), SD in eight patients
(73%), and PD in one patient (9%). However, the two patients that
responded to this thalidomide regimen were not refractory to lenalidomide
and were only discontinued from lenalidomide due to toxicity reasons. Of
the remaining patients in this subset, seven patients were lenalidomide
refractory and showed a best response of only stable disease when subse-
quently treated with thalidomide and steroids. Nonetheless, two lenalidomide
refractory patients showed a clinical benefit (SD) on their thalidomide with
steroid regimen and remained on this treatment for more than 5 months
(5.9 and 8.3 months). These same two patients had a VGPR response to
lenalidomide with treatment durations of 8 and 27 months, respectively.
Considering all 24 patients, the level of response to lenalidomide-based
regimen was not indicative of the response to thalidomide-based treatment.
No significant relationship between the two responses was observed (P
value >0.99). However, duration of thalidomide-based treatment and dura-
tion of lenalidomide treatment were correlated with a Pearson correlation
coefficient of 0.584 and P value of 0.003. This may be describing a general
overall sensitivity to IMiDs.
In summary, results from this small subset of patients treated with repeat
IMiDs at our site suggests that patients able to tolerate longer lenalidomide
treatment durations also tend to show more benefit when later treated with
thalidomide-based regimen. These preliminary observations still need to be
evaluated via a larger prospective randomized study in order to define mo-
lecular biomarkers predictive of a clinical response for patients able to bene-
fit from multiple IMiD exposures.
VISHAL KUKRETI1*
ESTHER MASIH–KHAN1
TRIEU YOUNG1
CHIA–MIN CHU1
HAIYUN JIANG2
SUZANNE TRUDEL1
CHRISTINE CHEN1
VICTOR JIMENEZ–ZEPEDA1
DONNA E. REECE1
1Department of Medical Oncology and Hematology,
Princess Margaret Cancer Centre, Toronto, Ontario, Canada2Department of Biostatistics, Princess Margaret
Cancer Centre, Toronto, Ontario, Canada
*Correspondence to: Vishal Kukreti, MD, Princess Margaret Cancer Centre,
Department of Medical Oncology and Hematology, Suite 5-100, Toronto,
ON, Canada, M5G 2M9. E-mail: vishal.kukreti@uhn.ca
DOI 10.1002/ajh.23394
References1. Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple
myeloma. Mayo Clin Proc 2005;80:1549–1551.
2. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasonefor relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.
3. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone forrelapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.
4. Anderson KC. Lenalidomide and thalidomide: Mechanisms of action-similaritiesand differences. Semin Hematol 2005;42:S3–S8. Review.
5. Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immuno-modulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010;24:22–32.
6. Li S, Gill N, Lentzsch S. Recent advances of IMiDs in cancer therapy. CurrOpin Oncol 2010;22:579–585.
7. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone ismore effective than dexamethasone alone in patients with relapsed or refrac-tory multiple myeloma regardless of prior thalidomide exposure. Blood2008;112:4445–4451.
8. Guglielmelli T, Bringhen S, Rrodhe S, et al. Previous thalidomide therapy maynot affect lenalidomide response and outcome in relapse or refractory multiple
myeloma patients. Eur J Cancer 2011;47:814–818.
9. Guglielmelli T, Petrucci MT, Saglio G, et al. Thalidomide after lenalidomide: apossible treatment regimen in relapse refractory multiple myeloma patients. BrJ Haematol 2010;152:108–110.
10. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immu-nomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy ofnewly diagnosed multiple myeloma. Blood 2011;118:1763–1765.
11. Garc�ıa-Sanz R, Gonz�alez-Porras JR, Hern�andez JM, et al. The oral combi-nation of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) iseffective in relapsed/refractory multiple myeloma. Leukemia 2004;18:856–863.
12. Garc�ıa-Sanz R, Gonzalez-Fraile MI, Sierra M, et al. The combination of thali-domide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and
can be an option for relapsed/refractory multiple myeloma. Hematol J2002;3:43–48.
TABLE I. Summary of Thalidomide and Lenalidomide BasedTherapies (N 5 24)
Therapy type Value
LenalidomideDose—25 mg 24 (100%)
Lenalidomide regimenLen 1 Dex 24 (100%)
Duration of treatment all pts (median) 8.7 months (1–45 months)Best response on treatment
CR 4 (17%)VGPR 9 (37%)PR 6 (25%)SD 5 (21%)
Time duration from diagnosis (median) 35 months (18–143 months)Thalidomide
Dose
100 mg 5 (21%)150 mg 4 (16%)200 mg 15 (63%)
Thalidomide regimenTD/TP 11 (46%)TCD/TCP 10 (42%)DT-PACE 2 (8%)TM 1 (4%)
Duration of treatment all pts (median) 3.3 months (1.4–18 months)
Pts with duration of treatment � 5 months 9Pts with duration of treatment �12 months 2
Best response on treatmentVGPR 2 (8%)PR 7 (29%)SD 13 (54%)PD 2 (8%)
Time duration from diagnosis (median) 63.1 months (23–151 months)Time duration between two IMiD treatments 4.6 months (0–18 months)
T, thalidomide; M, melphalan; C, cyclophosphamide; D, dexamethasone; P,prednisone; DTPACE, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclo-phosphamide and etoposide; CR, complete response; VGPR, very good partialresponse; PR, partial response; SD, stable disease; PD, progressive disease.
Received for publication 18 June 2012; Revised 2 January 2013; Accepted8 January 2013
Published online 24 January 2013 in Wiley Online Library(wileyonlinelibrary.com)
DOI: 10.1002/ajh.23394
correspondence
338 American Journal of Hematology
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