Phase II Study of the Combination of Interleukin-2 with Zoledronic Acid As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background:

Multiple myeloma is still today an incurable disease. The many therapeutic techniques and new therapies proposed in recent years have extended survival but did not allow for healing. Further study allowed to demonstrate that a maintenance could be useful to control the progression of disease. However, there is no clear indication for which maintenance has to be used after a first line of induction therapy. The technique of allograft, used in patients at highest risk, demonstrates that the immune response to the residual disease plays a key role in the success of this technique. Among the major players in response to myeloma, in allogeneic stem cell transplantation, gamma delta lymphocytes play a significant action: complete response after allogeneic few months later (also the molecular level) happen in parallel with the presence in the bone marrow of a significant proportion of lymphocytes with gamma delta oligoclonal expression of TCR rearrangements.

Zoledronic acid induces proliferation of these cells by the production of several cytokines, in particular interleukin-2 (IL-2). Furthermore, T lymphocytes Vdelta2 are proved to be crucial antineoplastic mediators and, after expansion in vitro, capable of controlling tumor growth in animal models. These data confirm the hypothesis that gammadelta lymphocytes have a role in controlling the growth of myeloma plasma cells and can be active on the residual disease after autologous stem cell transplant. We planned to evaluate the role of the association of Zoledronate and IL-2 in vivo as post ASCT maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM).

Methods:

This is a single arm phase II multicenter ongoing study of the combination of IL-2 with zoledronic acid as maintenance therapy for NDMM patients post ASCT. The primary objective was to establish safety and efficacy of IL-2 as maintenance therapy. The secondary objective was to evaluate the immunological expansion of gamma delta lymphocytes. Eligible patients had undergone ASCT, with melphalan as a preparative regimen. At July 2016, forty two patients in very good partial remission (VGPR) have been enrolled in the study (total planned enrollment: 43 pts) and started maintenance therapy 90-180 days post ASCT.

Maintenance schedule included IL2 and zoledronic acid. IL2 was administered at a fixed dose of 2 x 10⁶UI from day 1 to day 7 for the first cycle and with the maximum tolerated dose (up to a max of 8 x 10⁶UI) from day 1 to day 7 for subsequent cycles (dose escalation of 25% in each cycle in the absence of toxicity). Zoledronic acid was infused 4 mg iv on day 2. This dosing regimen is repeated every 28 days until disease progression. Adverse events were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria.

Results and toxicity:

42 patients (pts) have been enrolled with a median age of 59 (range 42-72); 50% were male and 50% female. All the 42 pts have received a median of 11 cycles (range 1-23). Of the 42 pts 21 remain on therapy (data at July 2016), 21 pts are off study: 9 due to progressive disease (PD) and 12 due to consent withdrawal. Among the 9 pts with PD, the median PFS post ASCT was 12 months (2-18 months). Of the 42 pts, 33 (79%) not progressed after a median of 13 months (range 1-33) and the median PFS has not been reached. 7/42 patients (17%) reached complete remission. Peripheral and bone marrow analysis of gamma delta lymphocytes expansion to evaluate the level of immune response is still under examination.

Grade 1/2 hematologic adverse events (AEs) included: grade 1 (G1) anemia (3 pts), G1 neutropenia (3). Grade 1/2 drug-related non-hematologic AEs included: G1 fever (25) G2 fever (8); G2 constitutional symptoms (joint pains) (20); G2 constipation (4); G1/2 nausea (10); G1 fatigue (15), G1/2 cutaneous rash (2).

Conclusions:

Long term administration of combination of IL-2/zoledronate as maintenance therapy post ASCT is feasible. The incidence of non hematologic adverse events (in particular fever) were manageable with no dose escalation of IL-2 over 5 x 10⁶UI. This immunological approach, without any chemotherapeutic drug, seems to be able to control the disease and to obtain the complete remission in a subgroup of myeloma patients.