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