Eur. J. Oncol. - Vol. 23 - Suppl. 1 - July 2018 | EuropEan ... · The European Journal of Oncology...

Mattioli 1885

EuropEan Journal of oncology

Eur. J. Oncol. - Vol. 23 - Suppl. 1 - July 2018 | ISSN 1128-6598

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La testata fruisce dei Contributi Statali diretti di cui alla legge 7 agosto 1990, n. 250

Contents

Volume 23 / Suppl. 1 July 2018

Case reports

5 Effect of Elotuzumab in combination with lenalidomide and dexamethasone as second line of treatment in a Bortezomib refractory multiple myeloma patient

Ilenia Manfra, Fabrizio Accardi, Benedetta Dalla Palma, Luca Pagliaro, Laura Notarfranchi, Federica De Luca, Nicola Giuliani

9 M-protein fluctuations in a case of elotuzumab treatment Elisabetta Antonioli, Michela Staderini

13 Rapid and progressive response to elotuzumab in combination with lenalidomide and dexamethasone in a first relapse multiple myeloma patient

Concetta Conticello, Luca Scalise, Giuseppe Sapienza, Francesco Di Raimondo

18 Elotuzumab plus lenalidomide and dexamethasone as rescue therapy for multiple myeloma failing bortezomib-based induction therapy

Giuseppe Mele, Domenico Pastore

22 Elotuzumab lenalidomide and dexamethasone efficacy and tolerability in a multiple myeloma patient in initial relapse: a case report

Marino Brunori, Luciano Mucci, Francesca Monaco, Rita Girolimetti, Pietro Sodani, Gabriele Frausini

26 Elotuzumab in combination with lenalidomide induces rapid response in a patient with relapsed multiple myeloma

Angela Bonalumi, Vittorio Meneghini, Mauro Krampera

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Autorizzazione del Tribunale di Parma n. 14/97 del 11/6/1997ISSN 1128-6598La testata fruisce dei ContributiStatali diretti di cui alla legge 7 agosto 1990, n. 250

Effect of Elotuzumab in combination with lenalidomide and dexamethasone as second line of treatment in a Bortezomib refractory multiple myeloma patient

Ilenia Manfra1,2, Fabrizio Accardi1,2, Benedetta Dalla Palma1,2, Luca Pagliaro1,2, Laura Notarfranchi1,2, Federica De Luca1, Nicola Giuliani1,2

1Department of Medicine and Surgery, University of Parma, Parma, Italy; 2Hematology and BMT Center, Azienda Ospeda-liero- Universitaria di Parma, Parma, Italy

Summary. Elotuzumab is a new humanized recombinant IgG1 monoclonal antibody targeting the signaling lymphocytic activation molecule family 7 (SLAMF7), highly expressed by multiple myeloma (MM) cells and by natural killer (NK) cells (1). Recently, it has been demonstrated that elotuzumab in combination with lena-lidomide and dexamethasone (EloRd) significantly improved the progression-free survival (PFS) in patients with relapsed or refractory MM as compared to lenalidomide dexamethasone (Rd), regardless of previous exposure and resistance to bortezomib (2). Here, we report and discuss the case of a 69 year-old male patient with primary bortezomib refractory lambda light chain MM, previously treated with melphalan, bortezomib and prednisone regimen. After the first line treatment, he progressed with anemia and started the treatment with EloRd triplet. He obtained a very good partial response (VGPR) after one cycle, maintaining a good quality hematological response in the subsequent months of treatment. This case supports the role of EloRd combination in bortezomib refractory MM patients.

EUR. J. ONCOL.; Vol. 23, Suppl. 1, pp. 5-8, 2018 © Mattioli 1885

Case report

PATIENT’S MEDICAL HISTORY

M 69 yrs

2016 diagnosis of MM

Comorbidity: cardiovascular problems

FIRST LINE THERAPY: Bortezomib, melphalan, prednisone (9 cycles)

- From the 5th cycles reduction of bortezomib dosage for peripheral neuropathy

- After 9th cycles, no significant hematological response

2018 SECOND LINE THERAPY: elotuzumab, lenalidomide, dexamethasone

- after 1st cycle, very good partial response

TREATMENT ACTuALLY ONgOINg: good tolerability, high compliance, very good partial response

I. Manfra, F. Accardi, B. Dalla Palma, et al.6

Legend:EloRd: elotuzumab, lenalidomide, dexamethasone; BJ: Bence Jones; VGPR: very good partial response

Introduction

A 69 year-old man was diagnosed on Decem-ber 2016 with light chain lambda multiple myeloma (MM). Patient was admitted to our hospital for hy-pogammaglobulinemia (gamma globulins 320 mg/dL) and the presence of urinary monoclonal component lambda (Bence Jones proteinuria of 4 gr/24 hrs). He had not anemia and/or renal insufficiency. Free light chains (FLC) lambda were 656 mg/L (normal range 5.71-26.3 mg/L) and serum FLC k/l ratio was 0.01 (normal range 0.26-1.65) while involved/uninvolved ratio was 137. Both bone marrow (BM) biopsy and as-pirate revealed a plasma cell infiltration of about 65%. Fluorescence in situ hybridization (FISH) analysis on purified CD138+ cells was negative for the presence of hyperdiploidy, del(13q), del(17p) and chromosome 14 rearrangements. 18FDG PET-CT failed to show lytic lesions or increased uptake areas and spine MRI depicted a diffuse heterogeneous salt-and-pepper pat-tern, but no focal lesions.

A diagnosis of active MM was done according to International Myeloma Working Group (IMWG) criteria (3), due to the presence of two out of three bio-markers of malignancy (BM plasmacytosis above 60% and the involve/ uninvolved FLC ratio >100). Both the International Scoring System (ISS) score and the revised ISS were intermediate (II). The patient was not judged transplant eligible because of age near 70 years and the presence of cardiovascular comorbidity. The first line therapy was the bortezomib, melphalan, pred-nisone (VMP) for 9 cycles according to the schedule of VISTA trial (4). After 6 cycles, the response as-sessment showed a stable disease (SD) according to IMWG criteria (5) with a Bence Jones proteinuria of 2.2 g/24 hrs. Bortezomib dose was reduced to 1 mg/m2 from the 5th cycle because of a related peripheral neuropathy. At the end of the 9th cycle a new hemato-logical evaluation confirmed a stable disease (SD) and the patient was considered a primary refractory to the bortezomib-based treatment due to the absence of a significant hematological response.

Case description

In March 2018 we observed a progressive lower-ing of hemoglobin value (Hb 9.5 gr/dl, normal range 13.5-17.5, with a normal Mean Cell Volume of 94/fL) and the onset of the fatigue. Therefore, a new disease evaluation was carried out. Serum protein electropho-resis showed a more severe hypogammaglobulinemia, with low levels of IgG (240 mg/dL, normal range 700-1600), IgA (8 mg/dl, normal range 70-400) and IgM (4 mg/dL, normal range 40-230). Serum and urine immunofixation revealed only the presence of lamb-da light chain band. Free light chains (FLC) lambda were 536 mg/L and serum FLC ratio was 0.01. Bence Jones proteinuria was 0.8 gr/24 hrs. A new BM biopsy revealed a persistent high plasma cell infiltration of about 50% of the entire cellularity.

Given the disease progression with anemia onset, the patient received a second line of treatment based on Elotuzumab, lenalidomide and dexamethasone (EloRd). After the first cycle the patient reached a very good partial response (VGPR) according to IMWG criteria (5), with BJ value <200 mg/24 hrs. Adopting the premedication protocol no infusion reactions dur-ing elotuzumab administration were observed.

In line with the achievement of a good quality hematological response, a sustained improvement of hemoglobin value and a partial rise in immunoglobulin levels (best IgG value: 484 mg/dl), were noted. A tran-sient grade III lymphocytopenia (lymphocyte count 330/mmc, normal range 800-4.400), according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0), was recorded at the end of the first cycle and recovered during the subsequent weeks in the absence of significant infective episodes. The patient is currently undergoing the 4th cycle of therapy, with good tolerability and high compliance, and maintains a VGPR.

Discussion

Primary refractory myeloma is a therapeutic chal-lenge, conferring an adverse prognostic impact even in the era of the new drugs (6). A recent network me-ta-analysis of treatment outcomes in relapsed and/or refractory MM showed that triple-combination sav-

Elotuzumab in Bortezomid refractory myeloma 7

age regimen containing lenalidomide as a backbone ranked as the best results in terms of PFS and OS (7). The association of an IMiDs plus new anti-MM monoclonal antibodies offers the great advantage of combining a meaningful therapeutic effect with a very manageable safety profile. Consequently, an immuno-therapeutic strategy could improve both the negative prognosis and the intrinsic resistance to antineoplastic drugs directly targeting the cancer clone, that charac-terize this specific MM subset of patients. Elotuzumab Fab portion binds to the SLAMF7 receptor expressed on MM cells surface leading to a direct recognition of the tagged cells by NK lymphocytes, through the en-gagement of elotuzumab Fc portion with CD16 sur-face receptor. This interaction, enhanced by lenalido-mide immunomodulating effect, facilitates the killing of MM cells based on antibody-dependent cellular cy-totoxicity (ADCC) (8). Moreover, elotuzumab is able to induce NK cell activation, independently from Fc receptor, through direct engagement with SLAMF7

expressed on NK cells and the subsequent recruitment of intermediary EAT-2 protein, which in turn medi-ates downstream activation signaling (9). Finally, elo-tuzumab stabilizes SLAMF7-SLAMF7 interaction between effector NK cells and SLAMF7 positive tar-get cells (10). In a 3 year follow-up analysis of the Elo-quent-2 study, a phase III trial which compared EloRd versus Rd in relapsed/refractory MM patients a 43% reduction of the risk of progression or death (HR 0.57) was observed in the subgroup of patients refractory to previous treatment. Therefore, a great advantage of elo-tuzumab arm was demonstrated compared to control arm with a median PFS of 19.4 months versus 14.9 months (11). The PFS benefit was sustained through a longer follow-up of 5 years (minimum 60 months), and 27% reduction of the risk of progression or death (HR 0.73) and a sustained, durable clinically relevant rela-tive improvement of 50% in PFS rate (18 vs 12%) was observed. Pts with ≥very good partial response (ELd 36% vs Ld 30%) had the greatest reduction in risk of

Figure 1. Lymphocyte count and BJ proteinuria changes during EloRd treatment

I. Manfra, F. Accardi, B. Dalla Palma, et al.8

progression/death (HR 0.63). ORR was 79% (ELd) vs 66% (Ld) with minimal incremental number of AEs with ELd vs Ld. Higher rate of any-grade infection (84 vs 75%) and SPMs (17 vs 11%) compared with the previous follow up analyses, may reflect longer median duration of treatment with each agent of the ELd vs Ld regimens (E/L/d vs L/d: 17/17/17 vs 12/12 mo). Fewer deaths occurred with ELd than Ld (193 vs 208), mostly due to disease progression (12,13).

In our case, elotuzumab toxicity, observed dur-ing the patient treatment, was manageable, consist-ently with the results from Eloquent-2 study (2). We observed an early onset of lymphocytopenia on peripheral blood, probably induced by a lymphocyte trafficking as previously reported (13), subsequently we found an increase in the lymphocyte count until complete normalization after the first cycle, correlated with the hematological response as shown in the fig-ure 1. Interestingly, a partial recovery of IgG levels was also observed suggesting a possible dual effect of the antibody-based treatment with elotuzumab on NK ac-tivity and humoral immunity.

In conclusion this case report indicate that EloRd combination induced both a consistent clinical re-sponse on a Bortezomib primary refractory disease, and an immunomodulating effect, partially revert-ing the detrimental immunosuppression status which characterizes refractory and/or relapsed MM patients.

References

1. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple my-eloma. Crit Rev Oncol Hematol 2013; 88(1): 168-177.

2. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373(7): 621-631.

3. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. Inter-national Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology 2014; 15(12): e538-e548.

4. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multi-ple myeloma. N Engl J Med 2008; 359(9): 906-917.

5. Kumar S, Paiva B, Anderson KC, et al. International My-eloma Working Group consensus criteria for response and

minimal residual disease assessment in multiple myeloma. The Lancet Oncology 2016; 17(8): e328-e346.

6. Majithia N, Vincent Rajkumar S, Lacy MQ, et al. Outcomes of primary refractory multiple myeloma and the impact of novel therapies. Am J Hematol 2015; 90(11): 981-985.

7. van Beurden-Tan CH, Franken MG, Blommestein HM, Uyl-de Groot CA, Sonneveld P. Systematic literature re-view and network meta-analysis of treatment outcomes in relapsed and/or refractory multiple myeloma. J Clin Oncol 2017; 35(12): 1312-1319.

8. Balasa B, Yun R, Belmar NA, et al. Elotuzumab enhanc-es natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Im-munol Immunother 2015; 64(1): 61-73.

9. Pazina T, James AM, MacFarlane IV AW, et al. The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and–independent mecha-nisms. OncoImmunology 2017; 6(9): e1339853.

10. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother 2013; 62(12): 1841-1849.

11. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refrac-tory multiple myeloma: Eloquent-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol 2017; 178(6): 896-905.

12. Weisel K, Dimopoulos MA, Lonial S, et al. Extended 5-years follow-up of phase 3 ELOQUENT-2 Study: Elo-tuzumab plus Lenalidomide/Dexamethasone versus Lena-lidomide/Dexamethasone in relapsed/refractory multiple myeloma. 23rd Congress EHA, 2018. PS1298.

13. Lonial S, Dimopoulos MA, Weisel K, et al. Extended 5-y follow-up (FU) of phase 3 ELOQUENT-2 study of elotu-zumab + lenalidomide/dexamethasone (ELd) vs Ld in re-lapsed/refractory multiple myeloma (RRMM). J Clin On-col 36, 2018 (suppl; abstr 8040).

14. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012; 120(3): 552-559.

Corrispondence: Nicola Giuliani, MD, PhDDepartment of Medicine and Surgery,University of ParmaVia Gramsci 14 - 43126 Parma, ItalyTel. +390521033299Fax +390521033264E-mail: [email protected]

M-protein fluctuations in a case of elotuzumab treatment

Elisabetta Antonioli1, Michela Staderini2

1 Division of Hematology, AOU Careggi, Florence Italy; 2 Division of Hematology, University of Florence Italy

Summary. We report a case of 66 yrs old male with IgA-lambda multiple myeloma relapsed after 2 lines of treatment based on bortezomib. Because of clinical and biological characteristics of “non-aggressive multiple myeloma” the patient was treated with elotuzumab and lenalidomide regimen (Elo-RD). The patient had good tolerance to the treatment and achieved a VGPR. Nevertheless atypical FLC and BJP fluctuations were observed during therapy although the patient remained completely asymptomatic, other lab tests were normal and IgA level rapidly decreased. Different actions on immune system and on myeloma subclones exerted by the Elo-RD combination therapy were supposed. The detection of a single altered determination should not be interpreted as a lack of response.


Case report


M 66 yrs

2012 September diagnosis of MM

Comorbidity: artherial hypertension

FIRST LINE THERAPY: Bortezomib, Thalidomide, dexamethasone (5 cycles)

- PartialResponse

2013Novembersingleautologoustransplantation

- Verygoodpartialresponceuntil2016May

2016 September: bortezomib +dexamethasone (6 cycles)

- Verygoodpartialresponse,withouttherapyfor5months

2017JuneSECONDLINETHERAPYelotuzumab,lenalidomide,dexamethasonewithpre-infusiontherapy (10 cycles)

- Prophylaxis: Acyclovir , aspirin

- Noinfusionrelatedreactions

TREATMENTACTUALLYONGOING:Verygoodpartialresponse

E. Antonioli, M. Staderini10

Elotuzumab is a humanized IgG1 monoclonal antibody directed against signaling lymphocytic ac-tivation molecule F7 (SLAMF7), a glycoprotein ex-pressed mainly on normal plasmacells, NK cells and also on malignant plasma cells. Preclinical studies demonstrated elotuzumab significant anti-myeloma activity; its mechanisms of action include mediating antibody-dependent cellular cytotoxicity, enhancing cytotoxicity of NK cells and inhibiting multiple mye-loma (MM) cell interaction with bone marrow stromal cells (1-2). Lenalidomide and dexamethasone signifi-cantly increase the effect of elotuzumab making MM cells more vulnerable to NK lysis (3). Furthermore Elotuzumab exhibits response kinetics that involves induction of a cellular immune response.

Herein we report a case of relapsed/refractory MM (RRMM) treated with Elotuzumab displaying atypical FLC and BJP fluctuations, despite a good re-sponse to treatment.

A 66-year-old male, with a history of arterial hy-pertension, was diagnosed in September 2012 with IgA lambda multiple myeloma. At diagnosis he had ISS I (beta2microglobulin 2.1 mg/dl), normal LDH, normal renal function and absence of hypercalcemia. His blood count showed mild anaemia (Hb 11.0 g/dL), platelets 179,000/mm3 and WBC 3000/mm3. No lytic bone lesions were detected.

Myeloma markers revealed hypergammaglobu-linemia (43.5%), an IgA monoclonal spike of 51.5 g/L, lambda 878 mg/dL, FLC ratio >100, Bence Jones 1413 mg/24h. A bone marrow biopsy showed clonal lambda plasma cells (65% of cellularity), FISH was negative for del17p and t(4;14). The patient was treated with 5 courses of bortezomib (1.3 mg/sqm), thalidomide (200 mg/die) and dexamethasone (160mg/week) (VTD), obtaining a partial response (PR) and then underwent single autologous transplantation (conditioning regi-men with melphalan 200 mg/sqm) in November 2013. After transplant he maintained a VGPR until May 2016 when he experienced a biochemical relapse.

In September 2016 he was re-treated with bort-ezomib (1.3 mg/sqm) twice weekly and dexametha-sone (160 mg/week) (VD) for 6 cycles. Therapy was well tolerated except for a peripheral venous throm-bosis of his left inferior limb completely resolved after LMWH treatment for 3 months. After treatment the

patient obtained a VGPR and was off-therapy for 5 months.

In June 2017 he experienced his second biochemical relapse. In August 2017 myeloma markers further wors-ened with serum total IgA 11.3 g/L, BJP 327 mg/24h, λFLC 201 mg/L, creatinine clearance 70 ml/min, while CBC kept normal. Treatment with elotuzumab in com-bination with lenalidomide and dexamethasone (Elo-RD) was initiated in September 2017. Elotuzumab was infused weekly at 10 mg/kg during cycles 1 and 2 (28-day cycles), and every 15 days during subsequent cycles. Infusion rate was progressively increased, starting with 0.5 ml/min on the first infusion and reaching a maxi-mum of 5 mL/min (about 1 hour duration) on cycle 1 day 15 which was the final maximum infusion rate for all subsequent doses. Standard pre-infusion therapy in-cluded paracetamol 1000 mg orally, ranitidine 150 mg orally and cetirizine 10 mg orally; dexamethasone 8 mg i.v. + 28 mg from 3 to 24 hours before the infusion, with additional 40 mg given on weeks without elotuzumab starting with cycle 3.

Lenalidomide (25 mg/day) was administered on Days 1-21 of each cycle.

Acyclovir 400 mg BID, Bactrim two tabs twice weekly and aspirin 100 mg daily were also added as prophylaxis.

Patient had good tolerance to the treatment. No elotuzumab infusion-related reactions were observed. Elotuzumab and lenalidomide were not reduced or interrupted because of toxicity. Only a G1 thrombo-cytopenia occurred on Cycle 8. The patient has cur-rently completed 10 courses of Elo-RD. During treatment, serum IgA progressively decreased; on the contrary FLC e BJP showed several fluctuations. On Cycle 3 a doubling of BJP and an increase of about 25% of λFLC were observed whereas on cycle 4 both parameters were lower than previously reported on cy-cle 2. Equally on cycle 6 the patient experienced a fur-ther doubling of BJP and λFLC. During these fluctua-tions the patient remained completely asymptomatic and other lab tests were normal. The trend of myeloma markers while on Elo-Rd is represented on Figure 1.

At last observation (May 2018) the patient pre-sented total serum IgA 2.46 gr/L, lambda FLC were 26 mg/l, BJP was 92 mg/24 h; accordingly the patient achieved a VGPR.

M-protein in ELO-RD 11

Discussion

Monoclonal antibodies are very effective thera-pies acting through different mechanisms including an immune modulating function. Although MM is an immunogenic tumor, it is associated with a profound immune dysfunction. Nevertheless NK cells have demonstrated an important role in controlling myelo-ma cells and represent a key target for immunotherapy. Lenalidomide seems to be the ideal partner for these

drugs since it is able to enhance their activity and the association has a favorable toxicity profile.

Eloquent-2 phase 3 study demonstrated substan-tial and durable benefits in terms of overall response rate, progression free survival (PFS), overall survival and time to next treatment in patients treated with Elo-RD compared with RD (4); on this basis this regi-men received Italian Drug Agency (AIFA) approval for MM treatment after 1 previous line of therapy in April 2017. A subgroup analysis of Eloquent-2 showed the

Figure 1. Myeloma markers during Elo-Rd treatment

E. Antonioli, M. Staderini12

greatest benefit in terms of PFS for patients with a his-tory of disease longer than median from the diagnosis.

Our patient presented a myeloma history of 5 years and a hematologic remission after autologous bone marrow transplant lasting almost 3 years. He had a biochemical relapse without organ damage and no significant residual toxicities from previous treat-ments, thus he was considered the ideal candidate for Elo-RD combination. The patient did not experience any relevant adverse event during treatment. The pa-tient achieved a rapid disease control in terms of IgA, however we observed several fluctuations in serum λFLC and BJP that raised some doubts about its ef-ficacy. Even if we cannot demonstrate a specific effect of elotuzumab and/or lenalidomide, we might hypoth-esize different actions on immune system and on my-eloma subclones exerted by the combination therapy. The trend of MM markers in our case suggests that the evidence of a higher FLC or BJP value at a single time-points should not be immediately interpreted as a lack of response. Rather it may be reasonable to as-sess response later on in order to solve between actual chemoresistant cases and patients possibly benefiting from treatment continuation.

References

1. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple my-eloma. Clin Cancer Res 2008; 14: 2775-84.

2. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function com-plementing ADCC. Cancer Immunol Immunother 2013; 62(12): 1841-9

3. Lional S, Vij R, Harousseau JL, et al. Elotuzumab in com-bination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. JCo 2012; 30 (16): 1953-1959.

4. Lional S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed and refractory multiple myeloma. NEJM 2015; 373: 621-31

Corrispondenza: Elisabetta Antonioli Division of Hematology, AOU Careggi Largo Brambilla 3 - 50134 Firenze, ItalyTel. +39 055 7947958Fax +39 055/7947343E-mail: [email protected]

Rapid and progressive response to elotuzumab in combination with lenalidomide and dexamethasone in a first relapse multiple myeloma patientConcetta Conticello, Luca Scalise, Giuseppe Sapienza, Francesco Di Raimondo1Division of Hematology, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Catania, Italy

Summary. We discuss the case of a young male patient whose MM diagnosis in January 2009 had been preceded 4 years earlier by a diagnosis of monoclonal gammopathy of undetermined significance (MGUS). He underwent autologous stem cell transplantation (protocol RV-MM-PI-209) relapsed in a nonaggressive way 8 years later. He was treated in second line with the EloRd regimen: elotuzumab in combination with lenalidomide and dexamethasone, which provided a rapid improvement that improved progressively from a partial response (PR) after one month to a very good partial response (VGPR) at three months. This has been maintained with gradual improvements up to the ongoing seventh cycle. Conclusions: This case illustrates a real life experience with Elotuzumab for a nonaggressive first relapse of MM in a patient with a history of MGUS. The EloRd regimen resulted in a continuous and progressively deepening response and good long-term tolerability.


Case report


M 53 yrs

- IgG Kappa MGUS diagnosis in2005

- MM diagnosis in 2009

2009 FIRST LINE THERAPY: lenalidomide and prednisone induction (four cycles), followed by autologous stem cell transplantation.

- durable very good partial response until 2017

- slight gradual increase in monoclonal component starting in 2014.

- relapse with small vertebral lesions in 2017

2017 SECOND LINE THERAPY: elotuzumab, lenalidomide, dexamethasone; recommended prophylaxis

- partial response after the 1 cycle; very good partial response after 3 cycles.

TREATMENT ACTUALLY ONGOING: very good partial response; no adverse events of any grade.

C. Conticello, L. Scalise, G. Sapienza, F. Di Raimondo14

Introduction

Several new therapies for relapsed or refractory multiple myeloma (RRMM) have been approved re-cently, based on their performance in controlled clini-cal trials (1). Subgroup analyses have sought to iden-tify patients most likely to benefit from these novel therapies; however, published real life experiences are still scarce. Here we discuss the case of a first relapse in a patient with multiple myeloma (MM) who obtained a rapid response with elotuzumab in combination with lenalidomide and dexamethasone.

Case presentation

Patient details

The patient is a 53-year-old man diagnosed in 2005 with IgG Kappa monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition that can progress to MM or other lym-phoproliferative disorders. MGUS is defined by evi-

dence of serum monoclonal protein (M-protein <3 g/dl), clonal bone marrow plasma cells (<10%) and the absence of end-organ damage, namely CRAB symp-toms (hyperCalcemia, Renal failure, Anaemia, patho-logic Bone fractures).

Assessment

In January of 2008, four years after the diagnosis of MGUS, the patient presented in our centre for a standard follow-up evaluation, referring pelvic bone pain. Bone marrow, MRI and CT suggested that MGUS had progressed into MM (Durie and Salmon stage IIIA, International Staging System (ISS) stage II). In particular, MRI revealed an osteolytic lesion in the right iliac crest with bone swelling and isodense tissue in the same 12-cm region. Laboratory exams showed haemoglobin level below the normal range (10.6 g/dl), and the presence of two serum IgG-Kappa spikes with beta 2 and gamma mode, that were 2.4 g/dl and 1.37 g/dl, respectively. Fluorescence in situ hy-bridization (FISH) was performed but unfortunately failed to provide useful results.

Figure 1. Clinical course of the patient.

Rapid and progressive response to elotuzumab in combination with lenalidomide and dexamethasone 15

Treatments

In February 2009, the patient was enrolled in a phase III clinical trial (NCT00551928) that compared the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) versus melphalan (200 mg/m2) and autologous transplantation (MEL200) in newly diagnosed MM patients. Following the study pro-tocol, induction with lenalidomide and prednisone (four cycles) was followed by mobilization and au-tologous stem cell transplantation (September 2009) and achieved a durable very good partial response (VGPR). In follow-up, the patient had monthly i.v. zoledronic acid for the first two years, and every 3-4 months thereafter. He stopped zoledronic acid therapy in 2014 after developing osteonecrosis of the jaw that required surgical resection, but continued clinical and laboratory follow-up. In May 2017, the patient report-ed severe pain in the pelvis and spine. MRI revealed small osteolitic lesions in L1, T10 and T11 vertebra. This was accompanied by a slight but progressive in-crease in the monoclonal component over the course of 7 years (from 0.2 g/dl after autologous transplanta-tion to 1.2 g/dl).

First relapse was diagnosed in November 2017 at the age of 52 years, 8 years after the initial MM diag-

nosis. Relapse was Durie and Salmon stage IIIA, ISS stage I, and stage I also according to the revised ISS (R-ISS), because FISH analysis did not reveal high risk alterations. The nonaggressive nature was con-firmed also by the absence of extramedullary lesions, normal lactate dehydrogenase levels and long doubling time of the monoclonal component.

We started second-line treatment with elotuzum-ab (1100 mg i.v. with standard premedication, on days 1, 8, 15 and 22 of the first four 28-day cycles, then on days 1 and 15 of subsequent cycles) in combina-tion with lenalidomide (25 mg orally, on days 1 to 21) and dexamethasone (40 mg weekly orally). Although monoclonal antibodies (elotuzumab and daratumum-ab) may induce respiratory/non-respiratory infusion-related reactions (IRRs) (2), the appropriate pre- and post-infusion medication strategies were applied and the patient did not experience IRRs or adverse events of any grade.

A partial response (PR) was achieved after the first cycle. A VGPR was re-established after the third cycle and has been maintained with progressive im-provement. The patient is currently receiving the sev-enth cycle. Response to treatment closely resembled the 2.8-month median time to best response reported in the ELOQUENT-2 trial (3,4).

Figure 2. Response duration by treatment regimen.

C. Conticello, L. Scalise, G. Sapienza, F. Di Raimondo16

Conclusion

Eight years after initial diagnosis of MM, the pa-tient had a first relapse. The elapse was indolent with a progressive and continuous increase in the monoclo-nal component leading to the appearance of small os-teolytic lesions on MRI. Based on this nonaggressive disease with a low ISS and R-ISS staging, we decided to initiate second-line treatment with Elotuzumab in combination with lenalidomide and dexamethasone (EloRd). We based the treatment choice also on the long progression-free survival (PFS) achieved with first iMDs-based treatment.

Discussion

The EloRd regimen was approved for relapsed/refractory MM (RRMM) by the European Medicines Agency (EMA) in 2016. Approval was based mainly on evidence from the phase III ELOQUENT-2 trial, which demonstrated that the EloRd regimen provides responses in patients previously exposed to 1 to 3 lines of therapy (3). Elotuzumab is approved for continuous administration until disease progression or unaccep-table toxicity. When tolerated, elotuzumab combined with IMiDs is effective, particularly in terms of mini-mal residual disease, as maintenance for newly diag-nosed multiple myeloma (NDMM) and recently also for RRMM (5). Moreover, 5-year follow-up data from the ELOQUENT-2 study support that the EloLd reg-imen provides a long-term clinically relevant improve-ment in efficacy. It reduced the risk of progression or death by 27% and provided a 50% improvement in the 5-year PFS rate (18% v.s. 12%), with minimal incre-mental toxicity compared to lenalidomide and dexa-methasone (6).

MM prognosis is worse in patients with cytoge-netic abnormalities such as t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). All novel approved therapies (carfilzomib, daratumumab, elotu-zumab, ixazomib, panobinostat) improve PFS in such high-risk patients, but none of the trials has provided clear statistical evidence that they overcame high-risk status (7). Subgroup analyses of PFS in the ELO-QUENT-2 trial showed an advantage in all pre-de-

fined subgroups (age, ISS, disease status, prior lines of therapy, prior bortezomib) (8). Renal impairment is a common and early complication in MM that has been linked to an increased risk of early mortality. A recent phase IB trial supports the use of elotuzumab for the treatment of patients with MM and renal impairment without dose adjustment (9).

We have described the clinical history of a young MM patient who relapsed 8 years after diagnosis. In the ELOQUENT-2 trial median age was 66 years (range 37-91), median time from diagnosis to randomization had been 3.5 years. Moreover, 35% of patients in the trial had achieved a VGPR at the 3-years update (10). Thus our patient’s response was similar to that of the EloRd treatment group in the ELOQUENT-2 popu-lation. He had no adverse events of any grade. He rap-idly achieved a VGPR, with a continuous and progres-sive decrease in monoclonal component and treatment is ongoing (7 cycles administered to date). His results are consistent with previous evidence supporting the role of EloRd as a valid treatment option in patients with RRMM.

Summary points

• We present the case of a male MM patient with a history of IgG K MGUS, a premalignant condition that can progress to MM, and occasionally to other plasma cell disorders.

• Eight years after primary diagnosis of MM, the pa-tient initiated second-line treatment with the EloRd regimen.

• EloRd was approved in 2016 by the EMA for treat-ment of relapsed-refractory MM based on evidence from the phase III ELOQUENT-2 trial.

• Extended follow-up of the ELOQUENT-2 trial population confirmed a beneficial effect on PFS in all treated subgroups.

• The good response in this patient is consistent with previous results showing that EloRd is a valid second line treatment in RRMM.

Financial disclosureThe authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials dis-

Rapid and progressive response to elotuzumab in combination with lenalidomide and dexamethasone 17

cussed in the manuscript. This includes employment, consultan-cies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethical conduct of researchWritten informed consent was obtained from the patient for publication of this case report and and any accompanying im-ages.

References

1. Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma: novel agents, an-tibodies, immunotherapies and beyond. Leukemia 2018; 32: 252-62.

2. Nooka AK, Gleason C, Sargeant MO, et al. Managing Infu-sion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab. J Oncol Pract 2018; 14: 414-22.

3. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015; 373: 621-31.

4. Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in pa-tients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2015; 2: e516-27.

5. Richardson PG, Laubach J, Gandolfi S, Facon T, Weisel K, O’Gorman P. Maintenance and continuous therapy for mul-

tiple myeloma. Expert Rev Anticancer Ther 2018; 18: 751-64.

6. Lonial S, Dimopoulos MA, Weisel K, et al. Extended 5-year follow-up (FU) of phase 3 ELOQUENT-2 study of elotu-zumab + lenalidomide/dexamethasone (ELd) vs Ld in re-lapsed/refractory multiple myeloma (RRMM). J Clin On-col 2018; 36 (suppl; abstr 8040).

7. Lancman G, Tremblay D, Barley K, et al. The effect of novel therapies in high-molecular-risk multiple myeloma. Clin Adv Hematol Oncol 2017; 15: 870-9.

8. Offidani M, Corvatta L. A review discussing elotuzumab and its use in the second-line plus treatment of multiple my-eloma. Future Oncol 2018; 14: 319-29.

9. Berdeja J, Jagannath S, Zonder J, et al. Pharmacokinetics and Safety of Elotuzumab Combined With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma and Various Levels of Renal Impairment: Results of a Phase Ib Study. Clin Lymphoma Myeloma Leuk 2016; 16: 129-38.

10. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refrac-tory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol 2017; 178: 896-905.

Corrispondenza: Concetta Conticello*1Division of Hematology, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Catania, ItalyE-mail: [email protected]

Elotuzumab plus lenalidomide and dexamethasone as rescue therapy for multiple myeloma failing bortezomib-based induction therapyGiuseppe Mele, Domenico PastoreDivision of Haematology and BMT Unit, “Antonio Perrino” Hospital, Brindisi - Italy

Summary. We report the case of a 67-year-old man with primary myeloma that was refractory to borte-zomib-based induction therapy and complicated by lung adenocarcinoma. This patient obtained a significant reduction of the serum M-component with EloRd, while avoiding aggressive therapies, suggesting that the combination of elotuzumab, lenalidomide and dexamethasone could be an effective therapeutic option also in critical situations.


Case report


M 67 yrs

March 2017 – diagnosis of primary IgG-kappa MM (stage ISS II, D&S IIIA); simultaneous incidental discovery of lung adenocarcinoma precluded stem cell transplant for MM

2009 FIRST LINE THERAPY – bortezomib, melphalan, prednisone (VMP), nine 6-week cycles, with prophylaxis per guidelines; monthly zoledronic acid and antiviral therapy for hepatitis-C.

- neutropenia, thrombocytopenia and infections led to treatment delays and finally reduction of bortezomib from twice weekly to once weekly.

- Lack of haematological response after 4 cycles: patient refractory to bortezomib-based therapy

January 2018 - salvage treatment was EloRd with lenalidomide dosage adjusted according to clinical situation.

- after 4 courses, significant reduction in the monoclonal component

- normalization of haematological values.

TREATMENT ACTUALLY ONGOING: currently in cycle 10; continued improvement in the haematological response, control of pain and fatigue, improved health-related quality of life, no infusion reactions or adverse events.

Elotuzamab plus lenalidomide and dexamethasone as rescue therapy for multiple myeloma 19

Introduction

Many triple drug combinations are currently available for relapsed/refractory multiple myeloma (R/RMM). The choice depends on the patient’s clini-cal condition, comorbidities and the previous lines of therapy received. Elotuzumab in combination with lenalidomide and low-dose dexamethasone (EloRd) provides significant antimyeloma activity in terms of overall response rate, progression-free survival, over-all survival and time to next treatment (1). EloRd was efficacious in most key subgroups, including those with resistance to previous therapy with bortezomib or thalidomide (1). The addition of elotuzumab to le-nalidomide and dexamethasone is well tolerated with minimal additional toxicity (1).

Case description

We report the case of a 67-year-old man with pri-mary refractory IgG-kappa Multiple Myeloma (stage ISS II, D&S IIIA), and also a lung adenocarcinoma, who was not eligible for stem cell transplant (SCT) because of the pulmonary comorbidity.

In March 2017, at the time of the myeloma di-agnosis, serum protein electrophoresis showed hyper-gammaglobulinaemia with the evidence of a monoclo-nal spike (>3.5 g/dl); bone marrow aspirate and biopsy revealed extensive plasma cell infiltrate; the peripheral blood smear did not reveal circulating plasma cells; whole-body low-dose Computed Tomography (WB low-dose TC) showed lytic lesions of the skull and pelvis, pathologic fractures of several ribs. In addition, WB low-dose CT resulted in the incidental discov-ery of a second, non-hematological cancer involving the right upper lobe of the lung. Unfortunately, data on cytogenetic abnormalities were not available. The patient was underwent successful lobectomy for pT-1bN0M0 lung-adenocarcinoma. One month later, the patient started the first of nine 6-week cycles of VMP regimen comprising bortezomib (1.3 mg/m2 days 1, 4, 8, 11, 22, 25, 29 and 32, cycles 1-4; days 1, 8, 22, 29, cycles 5-9) plus melphalan (9 mg/m2 days 1-4, all cycles) and prednisone (60 mg/m2 days 1-4, all cycles). Zoledronic acid hydrate was also administered once

a month. Acyclovir (400 mg twice daily) and trime-toprim-sulfametassazole (two tabs twice weekly) were added as prophylaxis. Antiviral therapy with lami-vudine was started for hepatitis B virus surface and core antibody (anti-HBs, anti-HBc IgG); HBsAg, HBeAg, anti-HBe, anti-HBc IgM and HBV-DNA were negative. During the 2nd course the patient de-veloped a cough with copious expectoration accom-panied by fever (body temperature >38°C). Chest X-ray documented a single pulmonary infiltrate; mi-crobiological findings were negative. The pneumonia responded to broad-spectrum antibiotics (B-lactam). During the 3rd and 4th cycles, the main adverse events of clinical interest were neutropenia, thrombocyto-penia and fatigue. Adverse events were graded using NCI CTC v.3.0. Grade 4 neutropenia (absolute neu-trophil count <0.5x103/µL) was managed with drug interruptions and the prophylactic use of granulocyte colony-stimulating factor and anti-infective drugs (oral ciprofloxacin 500 mg twice a day; oral flucona-zole 100 mg once a day). The neutropenia did not fa-vour the appearance of infections. The high incidence of discontinuation, grade 4 neutropenia and grade 2 thrombocytopenia caused a delay in the start of the 3rd and 4th cycle and the consequent dosage reduction: the schedule of bortezomib was reduced from twice week-ly to once weekly (bortezomib 1.3 mg/m2 days 1, 8, 15, 22). At the end of the 4th cycle, an intermediate dis-ease evaluation showed the absence of haematological response according to IMWG criteria (3). Therefore, the patient’s MM was considered to be refractory to bortezomib-based therapy.

In January 2018, in view of the inefficacy of in-duction therapy, salvage treatment with EloRd regi-men was administered. EloRd was considered an ideal treatment option due to the patient’s fragility (pul-monary comorbidity, infective adverse events (AEs) during bortezomib-based induction therapy). Elotu-zumab was infused on days 1, 8, 15, 22 at 10 mg/kg of body weight during the first two cycles, and every 15 days during subsequent cycles. Lenalidomide was administered with a reduced dose of 15 mg orally on days 1-21 of repeated 28-day cycles together with oral dexamethasone 40 mg on days 1, 8, 15 and 22 of each 28-day cycle. The dose of lenalidomide was modified according to patient’s clinical features (neutropenia,

G. Mele, D. Pastore20

thrombocytopenia, increased infectious risk, pulmo-nary comorbidity). Low dose-intensity treatments are preferred for frail patients because they reduce the risk of AEs during the initial phase of therapy; the drug discontinuation due to AEs correlates with an increased risk of death within the first 6 months of treatment (4). Thromboembolic prophylaxis with low molecular weight heparin was administered according to international guidelines. The patient received the premedication protocol (diphenhydramine 25 mg, ra-nitidine 50 mg, acetaminophen 1000 mg) 30 minutes before the elotuzumab infusion. The patient tolerated treatment very well, with no drug-related toxicities. During EloRd treatment, there was no evidence of in-fusion reactions including pyrexia and chills; there was no evidence of non-haematological or haematologi-cal toxicities (Fig. 1); the incidence of opportunistic infections did not increase. After the 4th course, the response included a significant reduction in the M-component from > 3.3 g/d to 1 g/dl, normalization of haematological values and a clinical improvement. The patient reported significant control of pain and fatigue and an improvement of health-related qual-ity of life. Continuous treatment improved the quality and depth of the haematological response (Fig. 1). At this writing, the patient is receiving the 10th cycle of therapy, maintaining the same very good response.

Discussion

Reviewing this clinical experience has highlight-ed several important considerations.

First, non-response to induction regimens that include new drug classes is an established negative prognostic factor. According to Majithia et al., median overall survival is significantly shorter for patients with primary refractory myeloma (5). In the era of conven-tional chemotherapy, the only approaches that could overcome drug resistance were high-dose therapy and ASCT, both of which are contraindicated in frail pa-tients. Our patient’s experience suggests that EloRd may represent an active alternative for primary refrac-tory myeloma failing bortezomib-based induction therapy. Our patient achieved a significant reduction of the serum M-component after 4 cycles and she has maintained a good haematological response for 10 months since starting EloRd.

Second, infections are the major cause of morbid-ity and mortality in myeloma patients and the most common sites of infection are the lung and upper respiratory tract. Neutropenia is the most important factor predisposing to infection, although other co-morbidities can play important roles (e.g., diabetes, cardiovascular diseases). The degree and duration of neutropenia play a crucial role in the outcome of clini-

Figure 1. Serum M-protein and neutrophil counts since starting EloRd therapy in January 2018.

Elotuzamab plus lenalidomide and dexamethasone as rescue therapy for multiple myeloma 21

cal infections. Interestingly, during EloRd treatment, our patient had a gradual increase in the neutrophil count that led to complete normalization, indicative of a good haematological response (Fig. 1). This is con-sistent with the preliminary observation in clinical tri-als that neutropenia does not appear to be problematic with elotuzumab (1,6,7). Recovery of a normal neutro-phil count significantly decreases the risk of opportun-istic infections.

Conclusions

This case suggests that EloRd may induce a good haematological response also in forms of primary myeloma that are refractory to bortezomib-based approaches and favour normalization of neutrophil counts with a reduced risk of infections.

References

1. Lonial S, Dimopoulos M, Palumbo A et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. NEJM 2015; 373: 621-631

2. San Miguel J, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM 2008; 359:906-917

3. Kumar S, Paiva B, Anderson KC et al. International Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The Lancet Oncol-ogy 2016; 17: e328-e346

4. Larocca F, Palumbo A. How I treat fragile myeloma patients. Blood 2015; 126: 2179-2185

5. Majithia N, Rajkumar SV, Lacy MQ et al. Outcomes of pri-mary refractory multiple myeloma and the impact of novel therapies. Am J Hematol 2015; 90: 981-985.

6. Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in pa-tients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2015; 2: e516-e527.

7. Bringhen S, De Wit E, Dimopoulos MA. New Agents in Multiple Myeloma: An Examination of Safety Profiles. Clin Lymphoma Myeloma Leuk 2017; 17: 391-407.

Corrispondenza: Giuseppe MeleHaematology and BMT Unit, Antonio Perrino Hospital,SS 7 per Mesagne - 72100 Brindisi, ItalyTel: +39-831-537506Fax: +39-831-537513E-mail: [email protected]

Elotuzumab lenalidomide and dexamethasone efficacy and tolerability in a multiple myeloma patient in initial relapse: a case reportMarino Brunori1, Luciano Mucci2, Francesca Monaco2, Rita Girolimetti2, Pietro Sodani1, Gabriele Frausini2

1Day Hospital Ematologia Fano; 2Medicina Interna Fano

Summary. The patient, a 63-year-old woman, was diagnosed with micromolecular MM kappa with t(4;14) and chromosome 13 monosomy. (Durie and Salomon stage IIIA, International Scoring System (ISS) stage III). She achieved a complete remission (CR) after first line therapy with velcade, thalidomide, dexamethasone (VTD), and a stringent complete remission (sCR) after double autologous stem-cell transplant with melpha-lan 200 mg/sm induction. After relapse, sCR was re-established with with melphalan, prednisone, bortezomib (VMP) with weekly bortezomib administration. A second relapse in July 2017 was treated with EloRd, which re-established remission after 2 cycles and continues to be effective and well-tolerated. Conclusions: Heavily pre-treated patients may benefit from the EloRd regimen, without experiencing important side-effects.


Case report


F 63 yr

DIAGNOSIS micromolecular MM kappa (Durie and Salomon stage IIIA, ISS stage III); t(4;14) and chromosome 13 monosomy.

2008 FIRST LINE THERAPY: velcade, thalidomide, dexamethasone (VTD; 4 courses) - complete remission

Followed by double autologous stem-cell transplant (ASCT) with melphalan 200 mg/m2 induction (1st ASCT on July 2008 and second ASCT on February 2009)

- Stringent complete remission

March 2014 - biochemical relapse: monoclonal component kappa in urine

2015 SECOND LINE THERAPY: melphalan, prednisone, bortezomib (VMP) until April 2016.- Stringent complete remission.

July 2017 – second biochemical relapse.

2014 THIRD LINE THERAPY: elotuzumab, lenalidomide, dexamethasone; following recommended regimen with prophylaxis.

- Complete remission after the 2 cycles, serum free-light chain kappa reduced from 2600 to 31 mg/L; no toxicity > grade 1.

TREATMENT ACTUALLY ONGOING: complete remission; treatment well tolerated.

Elotuzumab lenalidomide and dexamathasone efficacy and tolerability in a multiple myeloma patient in initial relapse 23

Introduction

Multiple myeloma (MM) is a malignancy ef-fecting mature B-cells characterized by the overpro-duction of monoclonal immunoglobulin (Ig) by bone marrow plasma cells leading to marrow failure and osteolysis (1). Research into the pathogenesis of MM has led to the application of therapies, such as protease inhibitors and immune modulators, which have sig-nificantly prolonged the survival of patients with MM (2). Relapsed/refractory MM (R/RMM) presents a particularly challenging condition that is the focus of therapeutic approaches targeting cellular signalling pathways, DNA methlyation, the cell cycle and others (3). However, MM remains essentially incurable and is often associated with frequent relapses.

Several immunotherapeutic approaches to treat-ing MM using immunomodulatory biologics and small molecules or adoptive cellular therapies are under investigation or in the clinic (4). One of these strategies targets SLAMF7, a member of the Signal-ling Lymphocytic Activation Molecule (SLAM) fam-ily of receptors, which play important roles in regu-lating immune functions in hematopoietic cells (5). SLAMF7 (also known as CCND3 subset 1, CRACC or CS1) is expressed on both normal plasma cells and myeloma cells (6), and appears to be highly expressed in myeloma cells independently of known indicators of high-risk prognosis, however its role in myeloma is not clear (7,8). SLAMF7 is also expressed at a lower level in activated monocytes, CD8+ T cells, dendrit-ic cells, natural killer (NK) cells and NK-like T cells (7). SLAMF7 may be involved in triggering NK cell-mediated cytotoxicity and may play a role in regulat-ing the proliferation of B lymphocyte during immune responses (6). The extracellular domain of SLAMF7 is targeted by the monoclonal antibody (mAb) elotu-zumab.

Elotuzumab is an immunostimulatory humanized mAb that that binds to SLAMF7, but not to other SLAM family members (5). It induces MM cell ly-sis through direct activation of NK cells and through antibody-dependent cell-mediated cytotoxicity, also in MM cells that are resistant to standard therapies (9). The efficacy and safety of elotuzumab with lenalido-mide and dexamethasone for patients with R/RMM

was evaluated in the randomized ELOQUENT-2 trial, in which patients receiving elotuzumab, lenalido-mide, and dexamethasone (EloRd) had a 30% rela-tive reduction in the risk of disease progression/death compared to patients receiving only lenalidomide, and dexamethasone Rd (10).

Case Report

A 63 year old woman presented with a history of MM with micromolecular kappa since 2008.

Laboratory examination (Table 1)

Serum protein electrophoresis revealed monoclo-nal gammopathy with hypogammaglobulinemia gam-ma: 11.7% (11 - 18%), serum Ig A: 7.04 g/L (0.7-4 g/L), serum Ig G: 23.5 g/L (7-16 g/L), serum Ig M: 1.09 g/L (0.4-2.3), serum free-light chain kappa: 7.3 g/L (3.3-19.4 g/L), serum Ig-light chain lambda: 3.8 g/L (5.7- 26.3).

There were osteolytic lesions in the skull and hu-merus (bilateral) on cranial and lumbosacral plain ra-diographies. The bone marrow plasma cell ratio was 85 %.

Initial diagnostic work-up included both con-ventional karyotyping as well as fluorescence in situ hybridization (FISH) of plasma cells obtained from a bone marrow aspiration. FISH showed presence of

Table 1. Laboratory examination

White blood cells 8900/mm3

Hemoglobin 7.8 g/dLPlatelets 235,000/mm3

Erythrocyte sedimentation rate 53 mm/hSerum albumin 3 g/dLCreatinine 0.7 mg/dLCalcium 7.53 mg/dLAST 40 IU/LALT 25 IU/LALP 360 IU/LGGT 40 IU/LLDH 682 IU/LSerum beta-2 microglobulin 4.9 mg/dLUrinary protein (spot) +++24-h urine protein 3120 mg/dayUrinary Bence Jones protein Positive, kappa

M. Brunori, L. Mucci, R. Monaco, et al.24

high-risk translocations, including t(4;14) and mono-allelic loss of chromosome 13; there was no deletion of 17p (i.e., no loss of p53).

The definitive diagnosis was micromolecular MM kappa with t(4;14) and chromosome 13 monosomy. The patient was considered stage IIIA MM, according to Durie and Salomon criteria and stage III, according to International Scoring System (ISS).

She started first line therapy with velcade, tha-lidomide, dexamethasone (VTD) from January 2008 to April 2008 (4 courses), obtaining a complete remis-sion (CR).

Subsequently double autologous stem-cell trans-plant (ASCT) with melphalan 200 mg/sm induction was well tolerated, and provided a stringent complete remission (sCR), which was maintained for some years. (1st ASCT on July 2008 and second ASCT on February 2009).

In March 2014, a monoclonal component kappa in urine was detected and conclusion was a biochemi-cal relapse.

In 2015, a high level of kappa free light chains was detected (kappa/lambda ratio 42). A bone mar-row biopsy showed 30% plasma cells infiltration while PET CT SCAN showing no active lesions.

FISH analysis of plasma cells obtained from bone marrow aspiration revealed no evidence of high-risk translocations. Due to the efficacy of first line therapy with bordezomib and lack of therapeutic options at that time, she started a second line with melphalan, prednisone, bortezomib (VMP) with weekly bort-ezomib administration until April 2016. Laboratory findings showed disappearance of the monoclonal component (CR) with a bone marrow biopsy confirm-ing a sCR.

In July 2017 during a follow-up, a monoclonal component kappa was detected in urine and conclu-sion was a second biochemical relapse.

Laboratory examination showed normal white blood cell count, hemoglobin: 10.3 g/dL, platelets: 250,000/mm3, serum albumin: 3.5 g/dL, creatinin: 0.83 mg/dL, calcium: 9.4 mg/dL, 24-h urine protein: 940 mg/day. Serum protein electrophoresis revealed monoclonal gammopathy with hypogammaglobuline-mia gamma: 10.3% (11.1-18.0%), serum free-light chain kappa: 2.6 g/L (3.3-19.4 g/L), serum immuno-

globulin-light chain lambda: 6.3 g/L (5.7-26.3), uri-nary Bence Jones protein: positive kappa.

The patient refused PET or CT scans, but a bone marrow biopsy showed 30% plasma cell infiltration. There was no FISH evidence of high-risk transloca-tions.

We started therapy with elotuzumab 20 mg/kg, lenalidomide 25 mg, dexamethasone 40 mg (EloRd) in 28-day cycles (elotuzumab on days 1, 8, 15, and 22 for cycles 1 to 2 and days 1 and 15 for subsequent cycles; lenalidomide on days 1–21 and dexamethasone once per week), with the intention of continuing this regi-men until disease progression or unacceptable toxic ef-fects occurred. The evaluation after 2 months showed a decrease in serum free-light chain kappa from 2600 to 31 mg/L) with no toxicity higher than grade 1.

In July 2018 laboratory findings showed a normal serum free-light chain kappa level with positive urine immunofixation and a 24-h urine protein of 340 mg/day.

Conclusions

Our experience with this patient suggests that some heavily pre-treated patients may benefit from the EloRd regimen, without experiencing important side-effects. In particular patients with initial relapse may better benefit from this therapeutic approach.

References

1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009; 374: 324-339.

2. Mateos MV, Ocio EM, San Miguel JF. Novel generation of agents with proven clinical activity in multiple myeloma. Semin Oncol 2013; 40: 618-633

3. Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia 2014; 28: 525-542.

4. Kumar SK, Anderson KC. Immune Therapies in Multiple Myeloma. Clin Cancer Res 2016; 22: 5453-5460.

5. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple my-eloma. Crit Rev Oncol Hematol 2013; 88: 168-177.

6. Lee JK, Mathew SO, Vaidya SV, Kumaresan PR, Mathew PA. CS1 (CRACC, CD319) induces proliferation and au-

Elotuzumab lenalidomide and dexamathasone efficacy and tolerability in a multiple myeloma patient in initial relapse 25

tocrine cytokine expression on human B lymphocytes. J Im-munol 2007; 179: 4672-4678.

7. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple my-eloma. Clin Cancer Res 2008; 14: 2775-2784.

8. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized mon-oclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008; 112: 1329-1337.

9. Liu YC, Szmania S, van Rhee F. Profile of elotuzumab and its potential in the treatment of multiple myeloma. Blood Lymphat Cancer. 2014 Jun2014: 15-27.

10. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373: 621-631.

Corrispondence: Marino BrunoriDay Hospital Hematologia FanoE-mail: [email protected]

Elotuzumab in combination with lenalidomide induces rapid response in a patient with relapsed multiple myeloma Angela Bonalumi1, Vittorio Meneghini1, Mauro Krampera1

1Department of Medicine, Section of Hematology, University of Verona, Italy

Summary. We report the case of a 67-year-old man with IgG k multiple myeloma (MM), treated with bort-ezomib, melphalan and prednsione frontline. His clinical picture included significant comorbidities including chronic obstructive pulmonary disease, cardiovascular disease and stroke history. He only tolerated melphalan for the first two cycles. He progressed a few months after completing reduced intensity treatment. We admin-istered EloRd as second-line therapy. After two cycles he obtained a very good partial remission and after 13 cycles he is currently still in stringent complete remission.

EUR. J. ONCOL.; Vol. 23, Suppl. 1, pp. 26-28, 2018 - Reprint © Mattioli 1885

Case report


M 67 yrs

Diagnosis July 2016- IgG Kappa 32 g/L- Serum k/λ Free Light Chain ratio 260- Bence-Jones proteinuria 500 mg/L- BM plasmacytosis 70%

FIRST LINE THERAPY: August 2016 - bortezomib, melphalan, prednisone (VMP) - Melphalan was stopped after 2 cycles because of bone marrow toxicity - partial response after the planned 9 cycles (M-component 8 g/L; Bence-Jones proteinuria

50 mg/L)

RELAPSE September 2017 - Kappa FLC 240 mg/L, serum FLC ratio 90

SECOND LINE THERAPY: November 2017 - elotuzumab, lenalidomide, dexamethasone; recommended premedication

- very good partial response after 2 cycles.

TREATMENT ACTUALLY ONGOING: currently in cycle 13, maintaining stringent complete remission: absence of M component and Bence-Jones proteinuria; FLC ratio 1.43.

Elotuzumab in combination with lenalidomide induces rapid response in a patient with relapse multiple myeloma 27

Introduction

Elotuzumab is a humanized immunostimula-tory monoclonal antibody that targets the extracellular domain of signaling lymphocytic activation molecule F7 (SLAMF7), which is highly expressed on multiple myeloma (MM) and natural killer cells. Upon bind-ing, elotuzumab induces antibody-dependent cellular cytotoxicity, i.e. the antibody-induced selective lysis of tumor cells by activated natural killer (NK) cells (1, 2).

Recently, it has been shown that elotuzumab in combination with lenalidomide and dexamethasone (EloRd) may significantly improve progression-free survival in patients with relapsed or refractory MM, compared to lenalidomide dexamethasone (Rd), re-gardless of previous exposure and resistance to bort-ezomib (3). We report our clinical experience with a patient with treated with EloRd after relapsing from first-line combination therapy with bortezomib, mel-phalan and prednisone.

Case presentation

In July 2016 a 67-year-old man was admitted to hospital for lumbar spine and rib pain. The X-ray re-vealed multiple fractures. He had moderate renal im-pairment (serum creatinine 1.32 mg/dL), and normal hemoglobin and calcium values. An IgG kappa mono-clonal component (MC) of 32 g/L was detected, with urinary kappa MC (kappa Bence-Jones proteinuria) of 500 mg/L. Serum k/λ Free Light Chain (FLC) ratio was 260.

Both the bone marrow biopsy and aspirate re-vealed a plasma cells infiltration of 70%. Fluorescence in situ hybridization analysis (FISH) could not be per-formed. Active MM was diagnosed according to the International Myeloma Working Group (IMWG) criteria (4), based on the presence of bone lesions and two biomarkers of malignancy (BM plasmacytosis above 60% and the FLC ratio >100). According to the International Scoring System (ISS), the case was clas-sified as intermediate-grade (II). The patient was not transplant-eligible because of comorbidities (chronic obstructive pulmonary disease, hypertensive heart dis-ease, previous ischemic stroke).

In August 2016 the patient started first-line ther-apy with bortezomib, melphalan, prednisone (VMP) according to the schedule of the VISTA trial (5). Melphalan was stopped after 2 cycles because of bone marrow toxicity (neutrophil count < 0.5x10e9/L); bortezomib and dexamethasone were continued. The patient experienced two episodes of pneumonia on treatment, both requiring hospitalization.

After 9 cycles, the patient had a partial response (PR) according to IMWG response criteria (6) with an M-component of 8 g/L and Bence-Jones proteinu-ria of 50 mg/L.

In September 2017, an unexplained decrease in hemoglobin was observed (Hb 9 g/dL), as well as a progressive increase in M-component (20 vs 8 g/L). Kappa FLC and serum FLC ratios were 240 mg/L and 90, respectively. Bence-Jones proteinuria was absent. A new bone marrow biopsy revealed a plasma cell infil-tration of about 40%. The patient also reported reap-pearance of spinal pain.

In November 2017 the patient underwent sec-ond-line treatment for progressive disease: elotu-zumab, lenalidomide and dexamethasone combination (EloRd) was administered with premedication as per the technical data sheet. There were no infusion reac-tions during administration and no significant toxicity was observed.

After two cycles the patient obtained a very good partial response (VGPR) according to IMWG crite-ria, with an M-component of 2 g/L (versus 20 g/L). In line with the achievement of a good hematological response, a sustained improvement in hemoglobin and disappearance of bone pain were also obtained.

The patient is currently receiving the 13th cycle of therapy, with good tolerability and achievement of stringent complete remission (sCR), absence of M component and Bence-Jones proteinuria, and an FLC ratio of 1.43.

Discussion

Despite the improved treatment outcomes achieved with proteasome inhibitors and immu-nomodulatory drugs, most MM patients relapse, thus requiring new treatment approaches. Combination

A. Bonalumi, V. Meneghini, M. Krampera28

therapy is crucial for overcoming drug resistance and improving long-term treatment outcomes (7). The combination of immunomodulatory drugs, such as le-nalidomide, with dexamethasone represents a standard regimen in patients with relapsed or refractory disease (8,9). Three-drug combinations are suggested for pa-tients with previously treated MM (9), but their use can be limited by toxic effects. Therefore, new agents with different mechanisms of action are needed, that can be employed in combination with existing thera-pies without increasing side effects.

The randomized, phase 3, ELOQUENT-2 trial showed that patients receiving the triple combination EloRd had a 30% relative reduction in the risk of dis-ease progression or death, as compared to the control group receiving only Rd. Post-hoc analysis of the ef-fects on progression-free suvival (PFS) of either time from diagnosis or number of prior lines of therapy showed that PFS was particularly favorable for EloRd in patients with longer median time from diagnosis and one prior therapy, while benefit favored the EloRd arm, compared to the lenalidomide and dexametha-sone arm across subgroups (10).

Initially, our patient obtained only a partial re-sponse with first-line therapy (VMP), when side ef-fects during treatment forced us to remove one of the active agents (melphalan) from the regimen after only two cycles. In spite of the reduction in treatment intensity, he was hospitalized twice for pneumonia. The occurrence of neutropenia and this patient’s co-morbidities and in particular, his chronic obstructive pulmonary disease, prompted a careful evaluation of options for second-line therapy. Data from the clinical development of elotuzumab indicate that it is well tol-erated and does not appear to exacerbate neutropenia when added to combination therapy (11). In our expe-rience with this patient, treatment with elotuzumab, lenalidomide and dexamethasone resulted in the rapid reduction of the M-component and a clinical improve-ment, without significant toxicity.

Therefore, our experience in this complicated pa-tient with relapsed MM suggests that EloRd may be an option in selected cohorts of patients with signifi-cant comorbidities.

References

1. Einsele H, Schreder M, Treatment of multiple myeloma with the immunostimulatory SLAMF7 antibody elotuzum-ab. Ther Adv Hematol 2016; 7: 288-301.

2. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 2008; 14: 2775-2784

3. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015; 373: 621-631.

4. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. Inter-national Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology 2014; 15: e538-e548.

5. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of mul-tiple myeloma. N Engl J Med 2008; 359: 906-917.

6. Kumar S, Paiva B, Anderson KC, et al. International My-eloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The Lancet Oncology 2016; 17: e328-e346.

7. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myelo-ma: ESMO Clinical Practice Guidelines for diagnosis, treat-ment and follow-up. Ann Oncol 2017; 28(suppl_4):iv52-iv61.

8. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leu-kemia 2009; 23: 2147-2152.

9. Kumar SK, Callander NS, Alsina M, et al. Multiple My-eloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017; 15: 230-269.

10. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refrac-tory multiple myeloma: Eloquent-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. BrJ Haematol 2017; 178: 896-905.

11. Bringhen S, De Wit E, Dimopoulos MA. New Agents in Multiple Myeloma: An Examination of Safety Profiles. Clin Lymphoma Myeloma Leuk 2017; 17: 391-407.

Corrispondence: Mauro Krampera, MD,PhDSection of Hematology, Department of Medicine, University of Verona, ItalyPoliclinico G.B. RossiPiazzale LA Scuro 10 - 37134 Verona, ItalyTel. +390458124420E-mail: [email protected]

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