Perspective

Addition of daratumumab to chemotherapy doubles PFS in transplant-ineligible newly diagnosed myeloma

ATLANTA — The addition of daratumumab to standard chemotherapy doubled PFS among patients with transplant-ineligible newly diagnosed multiple myeloma, according to late-breaking study results presented at ASH Annual Meeting and Exposition.

Patients who received daratumumab (Darzalex, Janssen) appeared significantly more likely to achieve complete response, and they were more than three times as likely to reach minimal residual disease-negative status.

“The results of this study strongly support [daratumumab plus VMP chemotherapy] as a standard of care in transplant-ineligible newly diagnosed multiple myeloma,” Maria-Victoria Mateos, MD, PhD, consultant physician in the hematology department at University Hospital of Salamanca in Spain, said during her presentation.

Patients aged 65 years or older with newly diagnosed multiple myeloma, as well as those who have comorbidities, are ineligible for autologous stem cell transplantation.

Outside of the United States, VMP chemotherapy — which consists of bortezomib (Velcade, Takeda), melphalan and prednisone — is a standard of care for these patients.

Daratumumab, a humanized IgG-kappa anti-CD38 monoclonal antibody, has been shown to significantly prolong PFS and improve depth of response when combined with standard treatment for relapsed multiple myeloma. A phase 1 study showed the agent in combination with VMP was well tolerated by transplant-ineligible patients with newly diagnosed disease.

In the randomized phase 3 ALCYONE study, Mateos and colleagues assessed the addition of daratumumab to VMP for transplant-ineligible patients with newly diagnosed myeloma.

The analysis included 706 patients aged 65 years or older (median age, 71 years; range, 40-93; 29.9% aged 75 years or older) from 25 countries.

The majority of patients were female (53.7%) and had ECOG performance status of 1 or higher (74.9%).

Researchers randomly assigned 350 patients to VMP alone, administered for a maximum of nine 6-week cycles. The regimen consisted of subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32 of cycle 1, and days 1, 8, 22 and 29 of cycles two through nine; melphalan 9 mg/m2 orally; and prednisone 60 mg/m2 orally on days 1 through 4 of all cycles.

The other 356 patients received daratumumab administered at 16 mg/kg via IV once weekly in cycle 1, followed by every 3 weeks for cycles 2 through 9. Patients assigned the experimental regimen continued to receive daratumumab every 4 weeks as part of a post-VMP treatment phase, and their treatment continued until disease progression.

PFS served as the primary endpoint. Key secondary endpoints included overall response rate, rate of very good partial response or better, rate of complete response or better, rate of minimal residual disease negativity (threshold of 1 x 10-5), OS and safety.

Researchers stratified results by International Staging System stage (stage I, 19.3%; stage II, 42.4%; stage III, 38.4%), age (less than 75 years vs. 75 years or older) and region (Europe vs. other).

Of the 616 patients evaluable for cytogenetic analysis, 15.9% were classified has high risk due to positivity for deletion 17p, translocation t[14;16] or translocation t[4;14].

At data cutoff, patients assigned the daratumumab regimen had received a median 12 (range, 1-24) treatment cycles and patients assigned VMP alone had received a median nine treatment cycles (range, 1-9).

Patient characteristics — including age, sex, race, ECOG status and presence of cytogenetic abnormalities — were well balanced between treatment groups.

A higher percentage of patients assigned daratumumab completed nine treatment cycles of VMP (80% vs. 62%). They also received a higher median cumulative bortezomib dose than those assigned VMP alone (46.9 mg/m2 vs. 42.2 mg/m2).

Median follow-up was 16.5 months. At that time, 71% of patients assigned daratumumab plus VMP remained on treatment, compared with 5% of patients assigned VMP alone.

Patients assigned daratumumab exhibited a 50% reduced risk for progression or death (median PFS, not reached vs. 18.1 months; HR = 0.5; 95% CI, 0.38-0.65).

“The benefit of daratumumab was observed since the beginning of treatment, and just after the first cycle, it was possible to see a significant benefit,” Mateos said. “After discontinuation of treatment in the control arm, the continuation of daratumumab in the experimental arm continued to result in a significant benefit.”

Researchers reported higher rates of 12-month PFS (87% vs. 76%) and 18-month PFS (72% vs. 50%) in the daratumumab group.

Researchers observed a consistent PFS benefit across all prespecified subgroups, including patients aged 75 years or older, those with International Staging System stage III disease and patients with high-risk cytogenetics.

The daratumumab regimen also appeared associated with significantly higher rates of ORR (90.9% vs. 73.9%), very good partial response or better (71.1% vs. 49.7%), complete response or better (42.6% vs. 24.4%) and minimal residual disease negativity (22.3% vs. 6.2%; P < .0001 for all).

OS data were not yet mature. At data cutoff, 93 patients — 45 assigned daratumumab plus VMP and 48 assigned VMP alone — had died.

The most common all-grade treatment-emergent adverse events included neutropenia (49.7% for daratumumab plus VMP vs. 52.5% for VMP alone), thrombocytopenia (48.8% vs. 53.7%), anemia (28% vs. 37.6%), peripheral sensory neuropathy (28.3% vs. 34.2%), upper respiratory tract infection (26.3% vs. 13.8%), diarrhea (23.7%) vs. 24.6%), pyrexia (23.1% vs. 20.9%) and nausea (20.8% vs. 21.5%).

The most common grade 3 or grade 4 treatment-emergent adverse events included neutropenia (39.9% vs. 38.7%), thrombocytopenia (34.4% vs. 37.6%), anemia (15.9% vs. 19.8%) and anemia (11.3% vs. 4%).

Thirty-three percent of patients assigned VMP alone and 32% of those assigned daratumumab plus VMP discontinued treatment. The most common reasons for treatment discontinuation were progressive disease (13% vs. 19%) or adverse events (9% vs. 5%). One patient in each group discontinued treatment due to pneumonia.

A higher percentage of patients assigned daratumumab developed grade 3 or grade 4 infections (23.1% vs. 14.7%), but the percentage of patients who discontinued treatment due to infections was similar between those who received daratumumab-VMP and those who received VMP alone (0.9% vs. 1.4%).

More than one-quarter (27.7%) of patients assigned daratumumab experienced infusion-related reactions. Most (92.7%) occurred during the first infusion, and the majority (95.1%) were grade 1 or grade 2.

Less than 1% of patients in each treatment group developed tumor lysis syndrome. A similar rate of patients assigned daratumumab-VMP vs. VMP alone developed second primary malignancy (2.3% vs. 2.5%).

Several other studies are ongoing to evaluate daratumumab in the frontline setting. They include the phase 3 MAIA and CASSIOPEIA trials, as well as the phase 2 GRIFFIN and LYRA trials. – by Mark Leiser

Reference:

Mateos M-V, et al. Abstract LBA-4. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

Disclosure: Mateos reports honoraria from, consultant roles with, and advisory/board of directors roles with Amgen, Celgene, Janssen and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.

ATLANTA — The addition of daratumumab to standard chemotherapy doubled PFS among patients with transplant-ineligible newly diagnosed multiple myeloma, according to late-breaking study results presented at ASH Annual Meeting and Exposition.

Patients who received daratumumab (Darzalex, Janssen) appeared significantly more likely to achieve complete response, and they were more than three times as likely to reach minimal residual disease-negative status.

“The results of this study strongly support [daratumumab plus VMP chemotherapy] as a standard of care in transplant-ineligible newly diagnosed multiple myeloma,” Maria-Victoria Mateos, MD, PhD, consultant physician in the hematology department at University Hospital of Salamanca in Spain, said during her presentation.

Patients aged 65 years or older with newly diagnosed multiple myeloma, as well as those who have comorbidities, are ineligible for autologous stem cell transplantation.

Outside of the United States, VMP chemotherapy — which consists of bortezomib (Velcade, Takeda), melphalan and prednisone — is a standard of care for these patients.

Daratumumab, a humanized IgG-kappa anti-CD38 monoclonal antibody, has been shown to significantly prolong PFS and improve depth of response when combined with standard treatment for relapsed multiple myeloma. A phase 1 study showed the agent in combination with VMP was well tolerated by transplant-ineligible patients with newly diagnosed disease.

In the randomized phase 3 ALCYONE study, Mateos and colleagues assessed the addition of daratumumab to VMP for transplant-ineligible patients with newly diagnosed myeloma.

The analysis included 706 patients aged 65 years or older (median age, 71 years; range, 40-93; 29.9% aged 75 years or older) from 25 countries.

The majority of patients were female (53.7%) and had ECOG performance status of 1 or higher (74.9%).

Researchers randomly assigned 350 patients to VMP alone, administered for a maximum of nine 6-week cycles. The regimen consisted of subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32 of cycle 1, and days 1, 8, 22 and 29 of cycles two through nine; melphalan 9 mg/m2 orally; and prednisone 60 mg/m2 orally on days 1 through 4 of all cycles.

The other 356 patients received daratumumab administered at 16 mg/kg via IV once weekly in cycle 1, followed by every 3 weeks for cycles 2 through 9. Patients assigned the experimental regimen continued to receive daratumumab every 4 weeks as part of a post-VMP treatment phase, and their treatment continued until disease progression.

PFS served as the primary endpoint. Key secondary endpoints included overall response rate, rate of very good partial response or better, rate of complete response or better, rate of minimal residual disease negativity (threshold of 1 x 10-5), OS and safety.

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Researchers stratified results by International Staging System stage (stage I, 19.3%; stage II, 42.4%; stage III, 38.4%), age (less than 75 years vs. 75 years or older) and region (Europe vs. other).

Of the 616 patients evaluable for cytogenetic analysis, 15.9% were classified has high risk due to positivity for deletion 17p, translocation t[14;16] or translocation t[4;14].

At data cutoff, patients assigned the daratumumab regimen had received a median 12 (range, 1-24) treatment cycles and patients assigned VMP alone had received a median nine treatment cycles (range, 1-9).

Patient characteristics — including age, sex, race, ECOG status and presence of cytogenetic abnormalities — were well balanced between treatment groups.

A higher percentage of patients assigned daratumumab completed nine treatment cycles of VMP (80% vs. 62%). They also received a higher median cumulative bortezomib dose than those assigned VMP alone (46.9 mg/m2 vs. 42.2 mg/m2).

Median follow-up was 16.5 months. At that time, 71% of patients assigned daratumumab plus VMP remained on treatment, compared with 5% of patients assigned VMP alone.

Patients assigned daratumumab exhibited a 50% reduced risk for progression or death (median PFS, not reached vs. 18.1 months; HR = 0.5; 95% CI, 0.38-0.65).

“The benefit of daratumumab was observed since the beginning of treatment, and just after the first cycle, it was possible to see a significant benefit,” Mateos said. “After discontinuation of treatment in the control arm, the continuation of daratumumab in the experimental arm continued to result in a significant benefit.”

Researchers reported higher rates of 12-month PFS (87% vs. 76%) and 18-month PFS (72% vs. 50%) in the daratumumab group.

Researchers observed a consistent PFS benefit across all prespecified subgroups, including patients aged 75 years or older, those with International Staging System stage III disease and patients with high-risk cytogenetics.

The daratumumab regimen also appeared associated with significantly higher rates of ORR (90.9% vs. 73.9%), very good partial response or better (71.1% vs. 49.7%), complete response or better (42.6% vs. 24.4%) and minimal residual disease negativity (22.3% vs. 6.2%; P < .0001 for all).

OS data were not yet mature. At data cutoff, 93 patients — 45 assigned daratumumab plus VMP and 48 assigned VMP alone — had died.

The most common all-grade treatment-emergent adverse events included neutropenia (49.7% for daratumumab plus VMP vs. 52.5% for VMP alone), thrombocytopenia (48.8% vs. 53.7%), anemia (28% vs. 37.6%), peripheral sensory neuropathy (28.3% vs. 34.2%), upper respiratory tract infection (26.3% vs. 13.8%), diarrhea (23.7%) vs. 24.6%), pyrexia (23.1% vs. 20.9%) and nausea (20.8% vs. 21.5%).

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The most common grade 3 or grade 4 treatment-emergent adverse events included neutropenia (39.9% vs. 38.7%), thrombocytopenia (34.4% vs. 37.6%), anemia (15.9% vs. 19.8%) and anemia (11.3% vs. 4%).

Thirty-three percent of patients assigned VMP alone and 32% of those assigned daratumumab plus VMP discontinued treatment. The most common reasons for treatment discontinuation were progressive disease (13% vs. 19%) or adverse events (9% vs. 5%). One patient in each group discontinued treatment due to pneumonia.

A higher percentage of patients assigned daratumumab developed grade 3 or grade 4 infections (23.1% vs. 14.7%), but the percentage of patients who discontinued treatment due to infections was similar between those who received daratumumab-VMP and those who received VMP alone (0.9% vs. 1.4%).

More than one-quarter (27.7%) of patients assigned daratumumab experienced infusion-related reactions. Most (92.7%) occurred during the first infusion, and the majority (95.1%) were grade 1 or grade 2.

Less than 1% of patients in each treatment group developed tumor lysis syndrome. A similar rate of patients assigned daratumumab-VMP vs. VMP alone developed second primary malignancy (2.3% vs. 2.5%).

Several other studies are ongoing to evaluate daratumumab in the frontline setting. They include the phase 3 MAIA and CASSIOPEIA trials, as well as the phase 2 GRIFFIN and LYRA trials. – by Mark Leiser

Reference:

Mateos M-V, et al. Abstract LBA-4. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

Disclosure: Mateos reports honoraria from, consultant roles with, and advisory/board of directors roles with Amgen, Celgene, Janssen and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Photo of David Siegel

    David Siegel

    Worldwide, this is going to be very important. Melphalan and prednisone has been a backbone of therapy throughout the world for decades. In the United States, this kind of backbone isn’t used. Although it is important conceptionally, it probably will not have a lot of impact on how myeloma is treated here.

    For myeloma doctors, the understanding of what daratumumab does had already started to be well formed. But outside of the United States, and certainly in Europe, regulators need very specific data. This will allow newly diagnosed patients in Europe to start to be considered for daratumumab-containing therapies.

    Daratumumab is an extremely expensive drug. How these data are going to be handled is not known. But, it is very exciting because it shows the kind of impact that daratumumab can have in this newly diagnosed setting. This is a population of patients who do not get treated terribly aggressively outside of the United States. The idea that we can get this kind of depth of response in patients who aren’t considered eligible for transplant is very exciting.

    • David Siegel, MD
    • John Theurer Cancer Center
      Hackensack University Medical Center

    Disclosures: Siegel reports consultant roles with Amgen, Bristol-Myers Squibb, Celgene, Merck, Novartis and Takeda.

    Perspective
    Robert M. Rifkin, MD, FACP

    Robert M. Rifkin

    This late-breaking study likely will be practice transformative in Europe. The study is significant in that the addition of daratumumab to VMP results in a doubling of PFS in newly diagnosed patients not eligible for stem cell transplantation.  Importantly, no safety signals were observed.

    In addition, the study confirms the importance of the depth of the response, and achieving minimal residual disease negativity, to realize the full benefit of the combination. This study further reinforces the results previously reported with the phase 3 POLLUX and CASTOR trials, in which daratumumab was successfully used in combination with standard myeloma chemotherapy and conferred significant improvement in PFS.

    This landmark study will certainly impact the ongoing treatment of multiple myeloma — especially in Europe, where melphalan-based combinations remain in widespread use. Within the United States, daratumumab will continue to take on an increasingly important role early in myeloma patients’ journeys, but the increasing use of the daratumumab-VMP combination largely will be confined to countries outside of the United States.

    • Robert M. Rifkin, MD, FACP
    • McKesson Specialty Health
      The US Oncology Network

    Disclosures: Rifkin reports no relevant financial disclosures.

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