EHA 2016: How monoclonal antibodies will change the treatment of multiple myeloma. Professor Antonio Palumbo (Torino, Italy) discuss the results of the CASTOR trial and Professor Meletios-Athanasios Dimopoulos (Athens, Greece) discussing POLLUX.

How monoclonal antibodies will change the treatment of multiple myeloma 

by Maria Dalby

 

Philippe Moreau, University Hospital Hôtel-Dieu, Nantes, France

Meletios Dimopoulos, University of Athens School of Medicine, Greece

Antonio Palumbo, University of Turin, Italy

Monoclonal antibodies have been a tremendous success story in haematological oncology since the introduction of rituximab for the treatment of diffuse large B-cell lymphoma in 2002.^{1, 2} Recent study results obtained with daratumumab in combination with lenalidomide + dexamethasone and bortezomib + dexamethasone for the treatment of relapsed/refractory MM show the best hazard ratios for PFS ever reported in an MM trial. Professor Philippe Moreau, University Hospital Hôtel-Dieu, Nantes, France, outlined how monoclonal antibodies are setting new standards in the treatment of MM and adding to the backbone of therapy.

A large number of monoclonal antibodies are currently in clinical development in MM. Two of these, elotozumab which targets the SLAMf7 surface antigen, and daratumumab which targets the CD38 surface glycoprotein, have both been approved. Other targets for monoclonal antibody therapy include signalling molecules and immune checkpoint inhibitors; anti-RANKL denosumab and anti-PD-1 pembrolizumab are both in phase 3 clinical development.

Elotuzumab, whilst having no single-agent activity, has been shown to significantly improve PFS when administered in combination with lenalidomide and dexamethasone (ERd) to patients with relapsed/refractory MM.³ In the subsequent phase-3 ELOQUENT-2 study median PFS in the ERd group was 19.4 months, versus 14.9 months in the Rd group (HR 0.70; 95% CI 0.57, 0.85; p<0.001) and the overall response rate was 79% versus 66% (p<0.001).⁴ Elotuzumab was very well tolerated with comparable rates of grade 3 and 4 adverse events to the Rd arm and very low rates of infusion-related reactions. A very recent study has shown that ERd triplet therapy can be used in patients with impaired renal function without dose adjustment.⁵ Ongoing studies with elotuzumab include the ELOQUENT-1 study which will compare ERd with Rd in patients with newly-diagnosed MM, and the GMMG-HD6 study which will evaluate elotuzumab in combination with bortezomib, lenalidomide and dexamethasone triplet therapy (VRd) as induction and consolidation therapy followed by lenalidomide maintenance therapy in transplant-eligible patients.

Daratumumab induces tumour cell death in MM through a direct anti-tumour mechanism and through immune-mediated activity on macrophages, natural killer (NK) cells and the complement system.^6-10 In addition, recently published data shows that daratumumab also has an immunomodulatory effect on CD38+ immune suppressive cells, which promotes T-cell expansion and functional response and skews the T-cell repertoire.¹¹ Daratumumab monotherapy has been shown to have a stabilising effect on very heavily pre-treated relapsed/refractory MM, with a favourable safety profile.¹² Two phase 3 trials documenting daratumumab in combination with Rd and Vd in less advanced relapsed/refractory MM have recently been completed. Studies of daratumumab in the non-transplant setting and in younger, transplant-eligible patients are currently in progress.

The first of the two phase 3 studies with daratumumab in relapsed/refractory MM, the CASTOR study, was presented by Professor Antonio Palumbo, University of Turin, Italy. Patients in the CASTOR study were randomised to receive bortezomib and dexamethasone with (DVd; n=251) or without (Vd; n=247) daratumumab. The primary endpoint was PFS. A pre-specified interim analysis after 177 progression events showed a 1-year PFS rate of 60.7% in the DVd arm compared with 26.9% in the Vd arm. Median PFS had not been reached in the DVd arm, compared with 7.2 months in the Vd arm (HR 0.39; 95%CI 0.28, 0.53; p<0.0001). Patients in the DVd arm also had significantly longer median time to progression (not reached versus 7.3 months; HR 0.30; 95%CI 0.21, 0.43; p<0.0001) and a higher overall response rate (ORR; 83% versus 63%, p<0.0001). The treatment benefit was consistent in all selected sub-groups. Daratumumab was well tolerated overall and the safety profile was consistent with that seen in previous studies. The most common adverse events were thrombocytopenia (59% versus 44%), peripheral sensory neuropathy (47% versus 38%), diarrhoea (32% versus 22%) and anaemia (26% versus 31%). The most common grade 3/4 adverse events were thrombocytopenia (45% versus 33%), anaemia (14% versus 16%) and neutropenia (13% versus 4%). Infusion-related reactions occurred in 45% of patients in the DVd arm, mostly during the first infusion and mostly of grade 1/2 severity.

The POLLUX study, presented by Professor Meletios Dimopoulos from Athens, was similar in design to CASTOR except that the comparator regimen was lenalidomide and dexamethasone (Rd). A total of 286 patients with relapsed/refractory MM were randomised to the DRd arm and 283 patients to the Rd arm. Median PFS was significantly prolonged in the DRd arm compared with Rd (not reached versus 18.4 months), the hazard ratio of 0.37 (95%CI 0.27, 0.52; p<0.0001) is the best ever reported in any MM study. DRd was also associated with significantly prolonged median time to progression (not reached versus 18.4 months; HR 0.34; 95%CI, 0.23, 0.48; p<0.0001) and improved overall response rate (93% versus 76%, p<0.0001). In addition, patients in the DRd arm had significantly higher rates of MRD-negativity: at the 10^-4 level, 30% of patients were MRD-negative in the DRv arm compared with 8% in the Rd arm. The corresponding rates at the 10^-6 level were 10% and 2%, respectively. Daratumumab was well tolerated with no significant additional toxicity compared with Rd.

Professors Palumbo and Dimopoulos both concluded their presentations by stating that daratumumab, in combination with Vd and Rd, respectively, should be considered a new standard of care for the treatment of relapsed/refractory MM.

Professor Dimopoulos also presented a poster showing the results of a post-hoc analysis of PFS by time from diagnosis and the number of prior lines of therapy and tumour shrinkage/regrowth in the ELOQUENT-2 study. The results indicated that the treatment benefit of ERd in terms of PFS was evident across all subgroups, including patients with a prolonged time from diagnosis and with multiple prior lines of therapy. The rate of tumour regrowth, as determined by serum M protein dynamic modelling, was reduced in the ERd arm compared with Rd and the investigators hypothesised that this may be the explanation for the survival benefit seen with ERd and that elotuzumab may have an immunostimulatory mechanism of action in MM.

 

References

1. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-42.
2. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010;116:2040-5.
3. Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients 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.
4. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015;373:621-31.
5. 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.
6. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 2011;186:1840-8.
7. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004;121:482-8.
8. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 2015;7:311-21.
9. Santonocito AM, Consoli U, Bagnato S, et al. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res 2004;28:469-77.
10. Krejcik J, Casneuf T, Nijhof I, et al. Immunomodulatory Effects and Adaptive Immune Response to Daratumumab in Multiple Myeloma. American Society of Hematology. Orlando, FL, 2015.
11. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016.
12. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 2016.