Abstract

Background: Although with the introduction of novel agents, clinical outcomes have significantly improved in patients of multiple myeloma (MM); however, nearly all relapse, requiring subsequent treatment. Patients who have been heavily treated for relapsed/refractory MM (RRMM) have limited options and poor survival outcomes. Carfilzomib plus daratumumab combination have been evaluated in a phase 1b study in patients of RRMM progressing after 1–3 lines of therapies including bortezomib and an immune-modulatory drug. However, data are lacking evaluating the efficacy of this combination in RRMM patients who have progressed or have suboptimal response on either of these drugs (carfilzomib or daratumumab). Methods: Prospective analysis of data of 19 RRMM patients who progressed after multiple lines of therapy (including bortezomib and lenalidomide/pomalidomide) and had suboptimal response/stable/progressive disease after receiving carfilzomib or daratumumab based combination as last therapy. All patients received combination of carfilzomib plus daratumumab along with dexamethasone (DKd) after prior consent. Daratumumab (16 mg/kg IV) was administered weekly (days 1, 8, 15, and 22) during cycles 1 and 2, every 2 weeks (days 1 and 15) during cycles 3–6, and every 4 weeks thereafter. Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle. Patients received an initial carfilzomib dose of 20 mg/m2 on day 1,2; 27 mg/m2 on day 8, 9, 15, 16 of cycle 1, which increased to 70 mg/m2 on day 1, 8, 15 from cycle 2 onwards if deemed tolerable. Dexamethasone was given as fixed-dose of 40 mg weekly. Results: Eighteen of 19 patients (including 3 high risk cytogenetics) to DKd (CR-4, very good partial response-10, partial response-02). After median follow-up of 16 months, progression-free survival (PFS) was 95%. Median PFS was not reached. Three patients who were transplant eligible received high-dose chemotherapy followed by autologous stem-cell transplantation and achieved minimal residual disease negativity. The most frequent all grade side effects were hematological, which included neutropenia 30%, anemia 70%, and thrombocytopenia 42%. Most frequent non hematological side effects were nausea 40%, vomiting, cough, respiratory tract infections, asthenia, and loss of appetite. Conclusion: Carfilzomib plus daratumumab based combination in RRMM patients has shown promising results in phase Ib study, where patients with prior exposure to either of these drugs were excluded. Our data show similar or better response of this combination in patients who had progressive disease/stable disease/minimal response to either of carfilzomib or daratumumab. This combination can be a better option in heavily treated RRMM (with prior exposure to either of carfilzomib or daratumumab) producing deeper and durable responses. A larger study may be required to prove this benefit.

Introduction

Multiple myeloma (MM) is an incurable disease, accounting for 1% of all cancers and 15% of all hematological malignancies. It is characterized by recrudescing patterns of remissions and relapses warranting subsequent therapy.[1] Though with the introduction of novel therapies, the outcome has dramatically improved in patients of MM, but the widespread use of lenalidomide early in course of disease either as a component of initial therapy or as maintenance emphasizes the need to explore more effective combinations among patients with relapsed/refractory MM (RRMM).[2]

Daratumumab and carfilzomib have got approval in many countries both as monotherapy as well as incorporating them individually with standard of care regimens, based on their rapid and durable responses in patients with RRMM. Both these drugs individually as monotherapy or in combination with other standard therapy has significantly resulted in reduced disease progression or death by inducing rapid, deep, and durable responses in patients of RRMM.[3],[4],[5] However, majority of these trials either excluded lenalidomide refractory patients (POLLUX and ASPIRE) or bortezomib refractory patients (CASTOR), making it difficult to extrapolate results of these studies in patients who are refractory to both bortezomib and lenalidomide.[3],[6],[7] Second, the patients in these trials who had received only one or two prior lines of treatment were significantly higher in number as compared to those who received 3 or more lines of prior therapy (80% vs. 20%). Prognosis of patients who had received multiple lines of treatment remains dismal in view of poor and short-term responses to subsequent therapy and thus demands exploring the more effective combination therapies.

Favorable toxicity profiles and better tolerability of these drugs in triplet- and quadruple-based regimes has led to explore daratumumab and carfilzomib as combination therapy in multiarm phase 1b MMY1001. The combination of these two drugs have resulted in better and durable responses fetching 12 months progression-free survival (PFS) of 75% in patients with RRMM after 1–3 lines of therapy. As it is common practice to add or replace one or more drugs of regimen, to which disease is not responding, but there is lack of data for the outcome of this combination in patients progressing or poor/suboptimal responses to either of these drugs. We present data of nineteen patients who after inadequate (minimal response or stable disease [SD]) response to either carfilzomib or daratumumab based regime and received a combination of these drugs as subsequent therapy.

Methods

Patients diagnosed with MM and either having progressive or SD as per international myeloma working congress (IMWG) to either daratumumab or carfilzomib based regime in addition to at least one prior line of therapy, received combination therapy of daratumumab, carfilzomib, and dexamethasone. Patients received this combination between June 2017 and August 2018. All patients were treated in 28-day cycles until disease progression (cycle 1 was 29 days). Daratumumab (16 mg/kg IV) was administered weekly (days 1, 8, 15, and 22) during cycles 1 and 2, every 2 weeks (days 1 and 15) during cycles 3–6, and every 4 weeks thereafter. Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle as a 30-min infusion (before daratumumab on days when both were administered). Patients received an initial carfilzomib dose of 20 mg/m2 on day 1, 2; 27 mg/m2 on day 8, 9, 15, 16 of cycle 1, which increased to 70 mg/m2 on day 1, 8, 15 from cycle 2 onward if deemed tolerable. Post 16 weeks of daratumumab (08 weekly and 08 fortnightly doses) and 12 cycles of carfilzomib, patients continued receiving maintenance daratumumab monthly (16 mg/kg) and carfilzomib every 2 weeks (56 mg/m2). Dexamethasone was given as fixed-dose of 40 mg weekly, later modified to every 2 weeks as per the maintenance schedule. Premedication included diphenhydramine, acetaminophen, and ranitidine. Patients also received zoledronic acid 4 mg or denosumab 120 mg on day 1 of each cycle.

Response to treatment and disease progression were evaluated according to the IMWG response criteria at the end of each treatment cycle. M protein measurements in serum were assessed by a central laboratory. Serum immunofixation electrophoresis was performed at screening and when complete response (CR) was suspected. Minimal residual disease (MRD) assessment was done at CR in all patients and post 3 months of high dose chemotherapy (HDT) followed by autologous stem cell rescue in patients who were undertaken for the same.

Results

A total of 19 patients received DKd combination therapy. Baseline characteristics, as well as prior therapies, are presented in [Table 1]. The median age of patients was 56 years (39–68), and the median number of prior therapies received was 3 (2–5). Fifteen (80%) patients received 3 or more lines of therapy. The median duration of illness in patients before this study was 38 months. None of the patients had undergone prior autologous stem-cell transplantation (ASCT), and three had high-risk cytogenetics. All patients received bortezomib and lenalidomide as prior therapy. Five (26%) patients had the extramedullary disease. All patients received carfilzomib or daratumumab as last therapy (carfilzomib-11, daratumumab-08) and had progressive disease (PD), minimal response (MR) or SD as best response (PD-02, MR-04, SD-13). All but one patient responded to DKd (CR-4, very good partial response [VGPR-10], partial response-02). After the median follow-up of 16 months, PFS was 95% irrespective of prior therapies. All standard-risk patients and two of 3 high-risk patients achieved VGPR or better. Three patients (including one high-risk cytogenetics) who were transplant eligible received HDT followed by ASCT and achieved MRD negativity.

References

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