Our previous studies have shown that lowering the dose of pegylated liposomal doxorubicin (PLD) and bortezomib in combination with intravenous dexamethasone on a longer 4-week cycle maintained efficacy and improved tolerability in both previously untreated and relapsed/refractory (R/R) multiple myeloma (MM) patients. Lenalidomide has shown efficacy in combination with bortezomib and dexamethasone but this combination has been poorly tolerated. We conducted this phase 2 study (clinicaltrials.gov identifier: NCT01160484) to evaluate whether a longer 4-week schedule using modified doses and schedules of IV dexamethasone (40 mg), bortezomib (1.0 mg/m2) and PLD (4.0 mg/m2) administered on days 1, 4, 8, and 11 with lenalidomide 10 mg daily on days 1–14 (DVD-R) would be effective and tolerated for patients with R/R MM. A total of 40 heavily pretreated patients were enrolled and 84.6% showed clinical benefit (complete response, 20.5%; very good partial response, 10.3%; partial response, 17.9%; minimal response, 35.9%) to the combination regimen. An additional 10.3% showed stable disease and 5.1% progressed while on study. The regimen was well tolerated, with a low incidence of adverse events such as fatigue (40%), thrombocytopenia (35%), neutropenia (35%), anemia (30%), peripheral neuropathy (25%) and pneumonia (15%). Thus, the DVD-R regimen is well tolerated and produces high response rates for patients with R/R MM.
The use of newer therapeutic agents such as thalidomide, lenalidomide and bortezomib has markedly increased the median overall survival of multiple myeloma (MM) patients during the past decade.1, 2, 3 Improvements in efficacy have been found in combination therapies using these newer agents by showing superior response rates compared to single-agent therapies for MM, likely because of synergistic effects of these newer agents when combined with chemotherapeutic agents such as alkylating agents, anthracyclines or glucocorticosteroids.4, 5, 6, 7, 8 This has led to a proliferation of combination regimens such as combining the proteasome inhibitor bortezomib with doxorubicin,9 melphalan,10 dexamethasone plus cyclophosphamide11 and pegylated liposomal doxorubicin (PLD) plus dexamethasone (DVD).12, 13 As efficacy seems to increase as more active agents are combined, preclinical and clinical studies have also evaluated the addition of a fourth drug to the three-drug regimens in an attempt to further enhance their efficacy.3, 14, 15
The IMiD lenalidomide has shown promising results as a single agent16 as well as in combination with other active agents for the treatment of MM.15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 Preclinical data has shown lenalidomide to have synergistic properties with agents such as melphalan, bortezomib, doxorubicin and dexamethasone,28, 29 and this effect has been validated in clinical trials.15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 This has led to the addition of lenalidomide to already established combination therapies such as bortezomib with PLD and dexamethasone, which was recently evaluated in a phase 1/2 trial involving untreated MM patients, showing a high response rate (96%) and long progression-free survival.15 However, tolerability of this four-drug combination even in this previously untreated population was generally poor and these deleterious effects did not improve with ongoing treatment, with frequent occurrences of hematological toxicities such as neutropenia, thrombocytopenia and anemia, and non-hematological toxicities such as peripheral neuropathy (PN), palmar–plantar erythrodysesthesia (PPE) and fatigue.
This highlights an unfortunate consequence of these increasingly intensive multi-drug anti-myeloma regimens: they are often associated with significant side effects, with toxicity increasing with the addition of each new agent to the regimen. The value of treatment regimens that improve response rates at the expense of increasing toxicity is questionable,30 as increased toxicity often leads to complications that have a detrimental effect on quality of life and result in poor treatment.31 This especially holds true for retreatment regimens where toxicity is theoretically exacerbated by the toxicity experienced from previous treatments, reducing the number of treatment options available for previously treated MM patients.
Recent studies have shown promise in modifying dosing and scheduling to both improve efficacy and reduce toxicity for therapeutic agents and combination regimens for MM patients. In our preclinical in vivo studies using our severe combined immunodeficiency–hu myeloma models, we showed that administration of low-dose PLD administered on a daily basis produced more marked anti-myeloma effects and was better tolerated compared to administering PLD at a higher dose once weekly.32 Clinical data has shown that increasing the length of each cycle while reducing the dose of bortezomib and the dose and schedule of PLD can result in similar efficacy and improved tolerability for relapsed/refractory (R/R)13 and untreated33 MM patients receiving these two agents with intravenously administered dexamethasone. In both of these studies, the traditional dosing of bortezomib at 1.3 mg/m2 and oral dexamethasone 40 mg both on days 1, 4, 8 and 11 with PLD at 30 mg/m2 on day 4 on a 3-week cycle12, 15 was modified to a longer 4-week cycle in which PLD at 5 mg/m2, bortezomib at a lower dose (1 mg/m2) and dexamethasone administered intravenously (IV) at 40 mg were all given on days 1, 4, 8 and 11. Response rates using this modified ‘metronomic’ dosing and schedule were found to be comparable to the same regimen using the traditional dosing and schedule but with a marked decrease in the frequency and severity of several common adverse events (AEs) including PN and PPE as we recently reported.33
Here, we report the results of a phase 2 trial investigating whether treatment of R/R MM patients with PLD, bortezomib, IV dexamethasone and lenalidomide (DVD-R) using metronomic dosing would result in reduced toxicity and better tolerability while maintaining acceptable efficacy compared to the recent report using these same drugs together in the frontline setting.15 This trial represents the first phase 2 investigation of both DVD-R in the R/R setting and of metronomic dosing of the DVD-R combination.
Patients and methods
Eligible patients had to have a prior confirmed diagnosis of MM based on the Durie criteria.34 All patients had to have been pretreated, showing either relapsed disease at any point in time following stabilization or a response to at least one prior anti-myeloma regimen or refractory disease (progressed while receiving an anti-myeloma treatment). Patients were ineligible for the trial if they had any of the following: POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes), grade⩾2 PN (based on Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 criteria) within 14 days before enrollment, impaired cardiac function/cardiac disease or severe hypercalcemia. Any patient receiving another investigational agent, glucocorticosteroids (>10 mg prednisone per day or equivalent), or any other anti-myeloma treatment within 3 weeks of the study entry was also ineligible.
Study design and treatment
This prospective, open-label, single-arm, phase 2 trial enrolled patients from eight different sites in the United States. The study consisted of a screening period, followed by up to a maximum of eight 28-day open-label treatment cycles and a final assessment was done 28 days after the end of the last treatment cycle, and patients were followed monthly after completion of study treatment for disease status.
During screening, a medical history, complete physical and neurological examinations and 12-lead electrocardiogram were performed. MM disease assessments were performed, including serum β2-microglobulin (B2M), a 24-h urine total protein, serum and urine protein electrophoresis, quantification of serum immunoglobulins, and serum and urine immunofixation. In addition, a MUGA scan or echocardiogram, posteroanterior and lateral chest radiographs, skeletal survey, and BM aspirate and biopsy were performed.
The following three drugs were IV administered on days 1, 4, 8 and 11 of a 28-day cycle: dexamethasone at 40 mg over 30 min, bortezomib administered at a dose of 1.0 mg/m2 over 3–5 s and PLD given at a dose of 4.0 mg/m2 as a 90 min infusion on day 1 of cycle 1 with subsequent doses administered over 30–60 min. Lenalidomide capsules were administered at a dose of 10 mg daily for the first 14 days of each treatment cycle, followed by a 14-day rest period. Patients were required to take prophylactic anticoagulant aspirin (or other anticoagulants such as warfarin or heparin if intolerant to aspirin). Patients were treated to a maximum response (lowest level of paraprotein) plus two additional cycles or a maximum of eight cycles. For those patients who showed stable disease or did not show a maximum reduction in their paraprotein after eight cycles, the treatment regimen was discontinued. Any patient demonstrating disease progression discontinued study treatment.
Safety and dose modification
Subjects were evaluated for severity and frequency of AEs at each visit with the NCI CTCAE (Common Terminology Criteria for Adverse Events) v3.0 used as a guide for the grading of severity. There was no dose escalation allowed in the study. Serious AEs (SAEs) were followed until resolution or until clearly determined to be unrelated to the study treatment. If a patient was determined to have toxicities indicative of clinical deterioration and/or disease progression, then the patient was discontinued from the study.
If study drug(s) were held and the toxicity did not resolve within 2 weeks, then the agent(s) were discontinued. However, if the toxicity resolved, study drugs were restarted, and the dose was reduced as follows: bortezomib (0.7 mg/m2); PLD (3 mg/m2); dexamethasone (20 mg); lenalidomide (5 mg for the first reduction, dosing schedule change to every other day for the second modification). Further reductions were possible with the consent of the medical monitor if the patient was responding. In general, dose reductions occurred in a specified order per consecutive AE (PLD, lenalidomide, bortezomib and lenalidomide) except for specific AEs felt to result from a particular drug that resulted in a dose reduction of that agent.
For each patient, we recorded age, gender, prior MM treatments and stage at the time of diagnosis according to the International Staging System (ISS) guidelines.35 Disease responses were recorded and assessed according to modified Bladé criteria.36 Patient responses to treatment were assessed during the 4th week of each cycle. AEs were assessed continuously throughout the study. The response status of all patients was determined at the end of the study treatment, and those who did not show signs of progressive disease at the completion of study treatment were evaluated on a monthly basis thereafter in addition to follow-up for survival.
The primary statistical endpoints for this study were the efficacy and safety of this modified dexamethasone, bortezomib, PLD and lenalidomide regimen for R/R MM patients. Efficacy was primarily evaluated via a modified version of the Bladé response criteria (that is, proportion of patients achieving complete response, very good partial response, partial response and those achieving minimal response (MR)) as well as time-to-progression. Secondary efficacy endpoints included time to response, duration of response, progression-free survival and overall survival. Safety was evaluated via the frequency and intensity of AEs.
A total of 40 patients with R/R MM were enrolled in the trial. Data was collected until 25 July 2011. Patient demographics are summarized in Table 1. The median time of follow-up was 11 months (range, 2–22 months). In all, 9 patients remain active and 31 patients discontinued study treatment for the following reasons: 13 for completion of eight cycles or achievement of a maximum response, 9 for progressive disease, 6 for AEs, 2 for withdrawal of consent and 1 for failure to meet inclusion/exclusion criteria. Note that response data are not available for the latter patient as this patient only received 1 week of study drugs before being removed from the study.
Treatment response and efficacy
All 40 patients were evaluated for efficacy of DVD-R. Response rates and other efficacy endpoint data are summarized in Tables 2 and 3, respectively. Among 39 patients evaluable for response, 84.6% showed clinical benefit, defined as either an objective response (48.7%) or MR (35.9%) following study treatment. Four patients (10.3%) showed stable disease and only two patients (5.1%) suffered from progression of their MM. The median time to first response was 1 month (range, 1–5) and to best response was 2 months (range, 1–6).
Patients were heavily pretreated, with a median of three previous treatment regimens. Table 4 shows the clinical benefit rate (⩾MR) achieved among patients on this study according to the agents and regimens that they previously received. Response rates were high regardless of the type of prior treatment including those exposed to bortezomib, PLD, glucocorticosteroids or lenalidomide. Notably, responses occurred frequently even among patients who had progressed from prior treatment with DVD (76.5%), and even in the majority of patients (60%) who had failed both DVD and prior lenalidomide-based therapies.
As of 25 July 2011, the median duration of follow-up was 11 months (range, 2–22 months). The median duration of response and time-to-progression were 12 (range, 1–21 months) and 9 months (range, 1–22 months), respectively, in this heavily pretreated population (Figures 1 and 2). The median overall survival has not been reached. A total of 16 patients suffered progression of their disease; 9 occurred during study treatment and 7 after study treatment was completed. Of the 16 who progressed, 4 responded initially (⩾partial response) before eventually progressing. Nine patients died during or after completion of study treatment, including six patients with progressive disease following discontinuation of study treatment, two that had stopped treatment due to AEs and one that expired after withdrawing consent.
Safety and tolerability
The median number of cycles completed for all patients was five (range, 0–8). AEs are listed in Table 5, including the total number of patients experiencing any grade, grades 3 or 4, and SAEs is shown for each selected AE.
The most commonly reported hematological toxicities were neutropenia and thrombocytopenia, both occurring in 14 (35%) patients. Neutropenic AEs consisted of three (7.5%) grade 1, five (12.5%) grade 2 and six (15%) grade 3, and there were six (15%) grade 1, four (10%) grade 2, two (5%) grade 3 and two (5%) grade 4 thrombocytopenic AEs. Anemia occurred in 12 (30%) patients, with 5 (12.5%) cases consisting grade 3 and the remainder grades 1 or 2.
The most commonly reported non-hematological AE was fatigue, which occurred in 16 (40%) patients, and was only grade 1 or 2. The second most common non-hematological AE was edema, occurring in 13 (32.5%) patients, with 12 (30%) grade 1 or 2 and only 1 (2.5%) grade 3 events. The next most common non-hematological AE was upper respiratory infection, occurring in 12 (30%) patients and were grades 1 or 2 with one SAE. Treatment-emergent PN occurred in only 10 (25%) patients, including 8 (20%) grade 1, 1 (2.5%) grade 2 and 1 (2.5%) grade 3 events. Notably, there were no reported instances of PPE or stomatitis.
The results from this phase 2, open-label, prospective trial for previously treated MM patients with modified metronomic dosing of lower doses of PLD, reduced dosing of bortezomib, dexamethasone administered IV and lenalidomide using a longer 4-week cycle demonstrate a very high response rate and favorable toxicity. This study is the first to demonstrate that this modified four-drug regimen is both safe and effective for patients with R/R MM. Response and tolerability compares favorably to a recent report using a shorter 3-week schedule with these same drugs at higher doses and scheduled differently in the frontline setting,15 as well as to other similar three-drug regimens.12, 13 In our study involving this heavily pretreated patient population, 84.6% achieved clinical benefit (⩾MR) with many (48.7%) achieving ⩾partial response. Follow-up on this trial has been relatively short (median 11 months). Notably, nine patients remain on study treatment and may thus show further reduction in their M-protein levels or demonstrate possible additional side effects.
The efficacy of the DVD-R regimen compares favorably with other regimens using similar or identical agents, showing similar improvements in response rates when compared to single-agent lenalidomide in a similar patient population.16 The combination of lenalidomide, bortezomib and dexamethasone has been shown to be very effective in the frontline setting, with ⩾partial response found in 100% in a phase 2 trial,19 but also resulting in a high incidence of AEs including PN (80%), fatigue (64%), diarrhea (35%) and nausea (32%) even in previously untreated MM patients. Our DVD-R regimen also compares favorably with early data for the combination of lenalidomide, bortezomib and dexamethasone in the R/R patient population37 showing a higher rate of patients with ⩾MR and importantly with a lower incidence of many common AEs especially PN (25 vs 64%) and diarrhea (25 vs 39%) with our four-drug combination treatment.
Our results with DVD-R also appear to be superior to other regimens including these three drugs without lenalidomide. Compared to a recently reported retrospective study from our group13 assessing R/R MM patients treated with PLD, bortezomib and IV dexamethasone using the same modified metronomic schedule as administered in this trial shows that the addition of lenalidomide to the regimen in the present study improved the rate of those with ⩾MR (from 61 to 85%) without significantly increasing the low level of toxicity reported with the three-drug combination in a similar patient population. A prospective randomized study will need to be conducted in R/R patients comparing the recently published regimen using these four drugs at higher doses and with a shorter schedule in the frontline setting15 to our treatment with its longer cycle, lower doses and modified schedule of these same agents in the R/R MM patient population in order to more accurately determine both the efficacy and tolerability of these different regimens.
Prospective studies investigating combinations using these agents in the R/R MM population are limited but a comparison of DVD-R in this setting with frontline treatment using the same agents and schedule (DVD) without lenalidomide by our group33 provides an upper limit for the expected response rate and some basis for comparison with regards to its tolerability among patients with R/R disease. Compared to this three-drug regimen without lenalidomide in the frontline setting, our DVD-R regimen showed the expected higher incidence of certain hematological AEs such as thrombocytopenia (8.6% (DVD) vs 35% (DVD-R)), neutropenia (8.6% vs 35%) and anemia (11.5% vs 30%) but very few were ⩾grade 3 (10–15%) and we found no differences in common non-hematological AEs such as fatigue (45.75 (DVD) vs 40% (DVD-R), PN (34.3% vs 25%) and PPE (5.7% vs 0%)). These results are reassuring in that aside from some low grade hematological AEs the addition of a fourth drug did not increase toxicity and yet still increased efficacy compared to the three-drug combination.
Importantly, we have observed a similar reduction in toxicity when comparing our modified DVD-R regimen using a longer 4-week cycle in the R/R setting to the traditional dosing and schedule of these same agents in the frontline setting as recently reported by Jakubowiak et al.15 They investigated the use of these same agents in the frontline setting in a phase 1/2 trial, with the phase 2 portion of their study utilizing eight standard 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 and PLD 30 mg/m2 on day 4 combined with oral dexamethasone (20 mg per d on days 1, 2, 4, 5, 8, 9, 11 and 12 during cycles 1–4 and then reduced to 10 mg per d on the same days for cycles 5–8) and lenalidomide at 25 mg per d daily for days 1–14. AEs that commonly occurred in their study, including fatigue, PN, thrombocytopenia, PPE and pneumonia, occurred much less frequently and were of lower grade in the heavily pretreated MM patients treated with DVD-R in our current study. This highlights the advantages of our metronomic dosing regimen and schedule of PLD and modified dosing and schedule of bortezomib as well as lower dose of lenalidomide in reducing the toxicity of these drugs when combined with intravenously administered glucocorticoids to treat patients with MM. Such dosing and schedule modifications are increasingly important to explore in MM as multi-agent combinations become more commonly used in order to maximize efficacy while at the same time minimizing the side effects of the increasing number of active drugs for treating patients with this B-cell malignancy.
It is also important that regardless of prior drug exposure, most patients responded to DVD-R including the majority of patients who had even failed both DVD- and lenalidomide-based treatments. The demonstration in this study that these four agents are not only able to be effectively combined but also that the combination can result in good tolerability in a heavily pretreated MM patient population when using lower doses, modified schedules and longer cycles has important implications for use of anti-MM agents in general. Effective regimens involving dexamethasone, bortezomib, PLD and lenalidomide that may have previously been considered intolerable or ineffective for patients in the R/R setting due to their past treatment history may, in fact, be both quite effective and well tolerated. For example, patients who previously progressed and/or did not tolerate dexamethasone, bortezomib and PLD may have lenalidomide added to these agents using our modified doses and schedule with a high likelihood of achieving a response and tolerating this four-drug combination well regardless of whether they have had previous exposure to lenalidomide. Notably, even the majority of patients who failed both the PLD, bortezomib and dexamethasone combination treatment and lenalidomide-based therapies responded to DVD-R.
Increasing the number of effective retreatment options, particularly ones that are well tolerated, is an important cornerstone of advancing MM treatment as despite progress and improvements in survival, MM still remains largely incurable. DVD-R should add an effective and well-tolerated option to the growing list of effective therapies for patients in this clinical setting. Future trials will need to further investigate the number and specific types of previous treatment regimens that DVD-R most effectively suits as a retreatment option.
This phase 2 trial demonstrates the efficacy and safety with good tolerability of DVD-R, a modified dosing and schedule of the combination of PLD, bortezomib, dexamethasone and lenalidomide for MM patients with R/R disease. The response rates with this regimen are among the highest reported to date in this patient population and importantly were achieved with very few significant AEs compared to the use of these agents at conventional doses and schedules as reported in other studies. Our results provide further evidence that the tolerability of multi-drug combinations for these previously treated patients can be improved without compromising the high level of efficacy of these newer treatments by utilizing reduced dosing and modifying the schedules of these drugs. Future studies need to investigate the efficacy of other lenalidomide and bortezomib-containing, multi-agent treatments as options for R/R MM patients as well as whether modifications to standard dosing and schedules of these drugs can help alleviate the toxicity frequently experienced by these patients who are exposed to an ever increasing panoply of combination therapies.
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This work was supported by funding provided by the Celgene Corporation.
JRB is on the speakers’ bureau, and receives research grants and is a consultant for Celgene, Takeda and Janssen. RAS is on the speakers’ bureau for Takeda. All the other authors declare no conflict of interest.
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Berenson, J., Yellin, O., Kazamel, T. et al. A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma. Leukemia 26, 1675–1680 (2012) doi:10.1038/leu.2012.51
- multiple myeloma
- clinical trial
- phase 2
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Safety and efficacy of pomalidomide, dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma
British Journal of Haematology (2018)
Incidence of interstitial pneumonitis in non-Hodgkin’s lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab
Annals of Hematology (2018)