Plitidepsin Evaluated for Refractory Multiple Myeloma

MedicalResearch.com Interview with:
PharmaMarDr. Javier Gómez García
Senior Manager. Biostatistics and Data Management
PharmaMar
Madrid Area, Spain

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Multiple myeloma accounts for approximately 1 percent of all cancers and slightly more than 10 percent of all hematologic malignancies. At present, more than 80,000 new cases are reported worldwide each year, and the disease prevalence is increasing.

Plitidepsin is a synthetic cyclic depsipeptide isolated from the marine tunicate Aplidium albicans targeting the proto-oncogene eEF1A2, which is over-expressed in multiple myeloma cells.

In ADMYRE trial 255 relapsed and refractory multiple myeloma patients with at least three but not more than six prior regimens, including at least bortezomib and lenalidomide/thalidomide, were randomized at 2:1 ratio to receive plitidepsin 5 mg/m2 D1 and 15 plus DXM 40 mg D1, 8, 15 and 22 (P+DXM), or DXM 40 mg D1,8,15 and 22 (DXM) every four weeks.

P+DXM met the primary endpoint, progression-free survival (PFS) assessed by an Independent Review Committee, showing a 35% risk reduction in the probability of progression or death. Indeed, a 20% risk reduction in the probability of death was also observed in spite of the fact that 44% of patients from control arm (DXM) switched to P+DXM arm after progression. Therefore, survival in the control arm might have been extended by the effect of plitidepsin, increasing the post progression survival and overestimating the survival observed in the control arm and consequently underestimating the actual difference between treatment arms.

Several methods were used to assess the impact of crossover and the robustness of the results even when penalizations were applied; PharmaMar believes that strong evidence in terms of survival benefit in favour of P+DXM has been established.  Continue reading

Multiple Myeloma Cases and Deaths Increase Worldwide

MedicalResearch.com Interview with:

Andrew J. Cowan, MD Seattle Cancer Care Alliance Division of Medical Oncology University of Washington, Seattle

Dr. Cowan

Andrew J. Cowan, MD
Seattle Cancer Care Alliance
Division of Medical Oncology
University of Washington, Seattle

MedicalResearch.com: What is the background for this study? What are the main findings?

 

Response: Multiple myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality. A comprehensive description of the global burden of multiple myeloma is needed to help direct health policy, resource allocation, research, and patient care.

Myeloma cases and deaths increased from 1990 to 2016, with middle-income countries contributing the most to this increase. Treatment availability is very limited in countries with low socioeconomic development.

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DARZALEX® (daratumumab) Approved for Newly Diagnosed Patients with Multiple Myeloma who are Transplant Ineligible

MedicalResearch.com Interview with:

Andrzej Jakubowiak, MD, PhD Professor of Medicine Director, Myeloma Program University of Chicago

Dr. Jakubowiak


Andrzej Jakubowiak, MD, PhD
Professor of Medicine
Director, Myeloma Program
University of Chicago

MedicalResearch.com: What is the background for this announcement? Would you briefly explain what is meant by multiple myeloma?

 

Response: DARZALEX (daratumumab) in combination with VELCADE (bortezomib), melphalan and prednisone – VMP – received U.S. FDA approval for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). With this most recent approval, DARZALEX is now the first monoclonal antibody approved for newly diagnosed patients with this disease.

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow. Despite the introduction of new medicines over the last decade, which has led to significant improvements in outcomes for patients with multiple myeloma, multiple myeloma remains an incurable disease. In 2018, it is estimated that 30,700 people will be diagnosed and 12,770 will die from the disease in the United States.

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ASPIRE: Combination Therapy With KYPROLIS (carfilzomib) Extended Overall Survival in Relapsed/Refractory Multiple Myeloma

MedicalResearch.com Interview with:

David S. Siegel, MD, PhD Chief, Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ 07601

Dr. Siegel

David S. Siegel, MD, PhD
Chief, Myeloma Division
John Theurer Cancer Center
Hackensack University Medical Center
Hackensack, NJ 07601

MedicalResearch.com: What is the background for this study? What are the main findings?

  •  We reported results from the prospectively planned final analysis of overall survival (OS) from the Phase 3 ASPIRE trial, an international, randomized study evaluating KYPROLIS (carfilzomib) in combination with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma following treatment with one to three prior regimens. Overall survival was a secondary endpoint in the trial.
  • Data published last week in the Journal of Clinical Oncology demonstrated that the addition of KYPROLIS to Rd reduced the risk of death by 21 percent versus Rd alone and extended OS by 7.9 months (median OS 48.3 months for KRd versus 40.4 months for Rd, HR = 0.79, 95 percent CI, 0.67 – 0.95; one-sided p=0.0045).
  • Notably, an OS improvement of 11.4 months was observed for patients at first relapse (47.3 versus 35.9 months [HR = 0.81, 95 percent CI, 0.62 – 1.06]), supporting early use of KRd.
  • The safety data from ASPIRE was consistent with the known safety profile of KYPROLIS. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were diarrhea, anemia, neutropenia, fatigue, upper respiratory tract infection, pyrexia, cough, hypokalemia, thrombocytopenia, muscle spasms, pneumonia, nasopharyngitis, nausea, constipation, insomnia and bronchitis.

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Phase 3 Darzalex Trial Demonstrated Meaningful Improvement in Patients with Newly Diagnosed Multiple Myeloma

MedicalResearch.com Interview with:
janseen-oncologyMaria-Victoria Mateos, MD, PhD

University Hospital of Salamanca/IBSAL
Salamanca, Spain

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Phase 3 ALCYONE study data showed DARZALEX (daratumumab) in combination with bortezomib, melphalan, and prednisone (VMP) significantly improved clinical outcomes, including reducing the risk of disease progression or death by 50 percent, in newly diagnosed patients with multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) at a median follow-up of 16.5 months (Hazard Ratio [HR] = 0.50; 95 percent CI [0.38-0.65], p<0.0001).

The median progression-free survival (PFS) for DARZALEX-VMP had not yet been reached, compared to an estimated median PFS of 18.1 months for patients who received VMP alone. In addition to reducing the risk of disease progression or death, DARZALEX significantly improved the overall response rate (ORR) as compared to VMP alone, including more than doubling rates of stringent complete response, significantly improved rates of very good partial response or better and complete response or better (CR).

The most common (≥10 percent) Grade 3/4 treatment-emergent adverse events (TEAEs) for DARZALEX-VMP vs. VMP were neutropenia (40 percent vs. 39 percent), thrombocytopenia (34 percent vs. 38 percent), anemia (16 percent vs. 20 percent) and pneumonia (11 percent vs. 4 percent). One patient in each arm discontinued treatment due to pneumonia, and 0.9 percent of patients discontinued DARZALEX due to an infection. Twenty-eight percent of patients experienced infusion reactions (IRs) due to DARZALEX.. In the DARZALEX-VMP arm, 42 percent of patients experienced a serious adverse event (SAE), compared to 33 percent in the VMP arm.

The study findings were as a late-breaking abstract (Abstract #LBA-4) at the 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, and simultaneously published in the New England Journal of Medicine (NEJM).

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Daratumumab Monotherapy for Patients with Intermediate or High-Risk Smoldering Multiple Myeloma

MedicalResearch.com Interview with:

Craig C. Hofmeister, MD, MPH The Ohio State University 

Dr. Hofmeister

Craig CHofmeisterMD, MPH
The Ohio State University 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Preliminary data presented from the randomized, open-label, Phase 2 CENTAURUS (SMM2001) study evaluated three dosing schedules for DARZALEX monotherapy in patients with intermediate or high-risk smoldering multiple myeloma. A total of 123 patients were enrolled, with a median time since initial smoldering multiple myeloma diagnosis of 6.83 months (0.4-56). Patients were randomized to one of three treatment arms receiving DARZALEX 16 mg/kg intravenously in 8-week cycles: 1.) a long-intense dosing schedule (LONG) where DARZALEX was administered weekly in Cycle 1, every other week in Cycle 2-3, every 4 weeks in Cycle 4-7, and every 8 weeks up to Cycle 20; 2.) an intermediate dosing schedule (INT), where DARZALEX was given weekly for 1 cycle, and every 8 weeks up to Cycle 20 and; 3.) a short intense dosing schedule (SHORT), where DARZALEX was given weekly for 1 cycle. Results from the study showed DARZALEX monotherapy had a tolerable safety profile in patients with intermediate or high-risk smoldering multiple myeloma, with the most common treatment-emergent adverse events (TEAEs) being fatigue, cough, headache and insomnia. The efficacy endpoints included overall response rate, progression free survival, time to next treatment, and overall survival rate at 4 years. These study results serve as the basis for a Phase 3 study for DARZALEX in smoldering multiple myeloma, which is actively enrolling. These findings demonstrated DARZALEX had a manageable safety profile in patients with intermediate or high-risk smoldering multiple myeloma.

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Marital and Insurance Status Affect Survival in Multiple Myeloma

MedicalResearch.com Interview with:

Luciano J. Costa, MD, PhD Associate Professor Department of Medicine and UAB-CCC Bone Marrow Transplantation and Cell Therapy Program Birmingham, AL 35294

Dr. Luciano Costa

Luciano J. Costa, MD, PhD
Associate Professor
Department of Medicine and UAB-CCC
Bone Marrow Transplantation and Cell Therapy Program
Birmingham, AL 35294

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Even though expected survival for multiple myeloma patients has increased over the last two decades, that improvement has not been much more pronounced among White than among patients of racial/ethnic minorities. It is possible that such discrepancy results from unequal access to care, particularly as treatment becomes more complex and expensive. We used a large dataset of patients with  multiple myeloma to explore how socioeconomic factors, specifically marital status, income and insurance affect outcome and how these factors relate to race/ethnicity.

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Multiple Myeloma: Thalidomide Derivative Lenalidomide Improved Survival After Chemo and Stem Cell Transplant

MedicalResearch.com Interview with:

Philip McCarthy, BA, MD Professor of Oncology Director, Blood and Marrow Transplant Program Roswell Park Cancer Institute Associate Professor of Medicine Jacobs School of Medicine and Biomedical Sciences State University of New York at Buffalo Buffalo, NY 14263

Dr. Philip McCarthy

Philip McCarthy, BA, MD
Professor of Oncology
Director, Blood and Marrow Transplant Program
Roswell Park Cancer Institute
Associate Professor of Medicine
Jacobs School of Medicine and Biomedical Sciences
State University of New York at Buffalo
Buffalo, NY 14263

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. McCarthy: There have been three Phase III studies that examined the role of maintenance lenalidomide after autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma patients. IFM 2005-02 (France), CALGB 100104 (Alliance, USA), GIMEMA-RVMM-PI-209 (Italy). All three studies had progression free survival (PFS) as their primary endpoint and all demonstrated a superior PFS when compared to placebo or no therapy after ASCT. However only the CALGB 100104 study demonstrated a statistically superior overall survival (OS). Thus, a meta-analysis was necessary to assess the effect of post-ASCT lenalidomide maintenance on overall survival. This study utilized a pooled analysis of updated primary-source patient data from all three studies after the primary efficacy analyses had been conducted. The meta-analysis demonstrated that there is a statistically superior OS (P value=0.001, HR=0.74 (0.62-0.89)), Median OS for no maintenance or placebo was 86 months and the median OS for lenalidomide had not been reached. The median OS for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). Thus, there is a 26% reduction in the risk of death which is an estimated 2.5 year increase in median OS. There is an increased incidence of second primary malignancies with lenalidomide maintenance when compared to placebo but this risk is less than the risk of dying when not receiving lenalidomide.

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New Immunotherapy For Resistant Multiple Myeloma Receives FDA Approval

Mark Wildgust Global Medical Affairs Head for Hematology The Janssen Pharmaceutical Companies of Johnson & Johnson

Mr. Wildgust

MedicalResearch.com Interview with:
Mark Wildgust
Global Medical Affairs Head for Hematology
The Janssen Pharmaceutical Companies of Johnson & Johnson

This week, the U.S. Food and Drug Administration (FDA) approved first-in-class immunotherapy DARZALEX™ (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma (MM) who have received at least three prior lines of therapy.

You can find the FDA news release here.

MedicalResearch: What is the background for this announcement? What is Multiple Myeloma?

Response: DARZALEX gives people who have limited or no remaining treatment options and are facing a difficult situation a new chance. We are excited about how DARZALEX may help these patients.

Multiple myeloma is a highly complex disease and remains incurable, with almost all patients relapsing or becoming resistant to therapy. Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow. Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.

MedicalResearch: What is DARZALEX (daratumumab) and how does it differ from traditional chemotherapy?

Response: DARZALEX is a first-in-class immunotherapy for certain multiple myeloma patients who have failed current standards of care and have limited treatment options. It is the first human anti-CD38 monoclonal antibody approved anywhere in the world and the first immunotherapy approved for multiple myeloma.

MedicalResearch: Can you tell us a little about the FDA’s accelerated approval program and why DARZALEX was approved under this track?

Why do patients have to fail three prior treatments before being prescribed this medication?

Response: DARZALEX received Breakthrough Therapy Designation from the U.S. FDA based on its potential for use in patients with a very high unmet medical need. The approval of DARZALEX comes just two months after the Biologics License Application was accepted for Priority Review by the FDA in September 2015 and almost four months ahead of its March 9, 2016 PDUFA (Prescription Drug User Fee Act) date. The FDA grants Priority Review to investigational therapies that if approved, may offer significant improvements in the treatment, prevention or diagnosis of a serious condition.

The approval for patients who have received at least three prior lines of therapy was based on the Phase 2 MMY2002 study, which showed treatment with single-agent DARZALEX resulted in an overall response rate of 29.2 percent in patients who received a median of five prior lines of therapy, including a PI and an immunomodulatory agent. We are continuing to evaluate DARZALEX for additional future indications and at this time five Phase 3 registration studies with daratumumab in relapsed and frontline settings are currently ongoing.

MedicalResearch: What are the main side effects?

Response: Overall, DARZALEX has an acceptable adverse event profile. The warnings and precautions for DARZALEX include infusion reactions, interference with serological testing and interference with determination of complete response. The most frequently reported adverse reactions (incidence ≥20 percent) were: fatigue, nausea, back pain, pyrexia, cough and upper respiratory tract infection.

MedicalResearch: Is DARZALEX potentially beneficial for any other hematologic malignancies?

Response: DARZALEX is a remarkable medicine. We have a comprehensive clinical trial program with five Phase 3 studies across a range of treatment settings in multiple myeloma. Additional studies are ongoing or planned to assess its potential in other malignant diseases on which CD38 is expressed, such as non-Hodgkin lymphoma among other hematologic malignancies.

MedicalResearch: What other therapeutics in this category are in the Janssen pipeline?

Response: Janssen is exploring therapeutics across a wide array of oncologic conditions, including  hematologic malignancies, prostate, colorectal and lung cancer. In hematologic malignancies, our approved products include IMBRUVICA, SYLVANT, DACOGEN (and VELCADE, for which we have commercial rights outside the US).  In addition, our marketed oncology products also include ZYTIGA, YONDELIS, DOXIL (sold as CAELYX outside the US) and PROCRIT (sold as EPREX outside the US).  Our pipeline includes a number of compounds in all stages of development, including a number of immuno-oncology agents; in addition, we have a large, active discovery program and a number of research collaborations.  Some of our pipeline compounds are ARN-509, which is being investigated in prostate cancer; imetelstat, CSL-362 and MGD-011, which are being investigated in hematologic malignancies; JNJ-809, which is being investigated as a prostate cancer vaccine; JNJ-757, which is being investigated as a lung cancer vaccine; and JNJ-493, which is being studied for urothelial cancer and lung cancer. A good source for information on our pipeline is the investor relations section of JNJ.com.

Citation:

FDA approves Darzalex for patients with previously treated multiple myeloma

Mark Wildgust (2015). New Immunotherapy For Resistant Multiple Myeloma Receives FDA Approval 

Study Suggests Need For Long Term Follow Up Of Monoclonal Gammopathy

Prof. Sigurdur Y Kristinsson Professor of Hematology University of IcelandMedicalResearch.com Interview with:
Prof. Sigurdur Y Kristinsson
Professor of Hematology
University of Iceland

MedicalResearch: What is the background for this study? What are the main findings?

Prof. Kristinsson: Multiple myeloma is always preceded by a precursor condition called monoclonal gammopathy of undetermined significance (MGUS). MGUS is characterized by a detectable monoclonal protein in persons without evidence for end-organ damage or other related plasma cell or lymphoproliferative disorders. MGUS is very common and is detected in approximately 5 percent of persons 70 years or older. However, only a small proportion of MGUS progresses to a malignant disorder, in fact the annual risk of progression to multiple myeloma or other related disorders is on average 1 percent, with varying risks according to risk groups. Current guidelines suggest, depending on the individual patient’s clinical risk score, life-long monitoring of MGUS individuals to detect progression to multiple myeloma or related disorders. At this time, the impact of annual monitoring on the outcome of patients who eventually develop multiple myeloma is unclear.

Using high-quality population-based data from Sweden, we estimated the impact of prior knowledge of MGUS diagnosis and comorbidities on multiple myeloma survival, by performing a large population-based study using data on more than 14,000 multiple myeloma patients diagnosed in Sweden 1976-2005, with follow-up through 2007. The hypothesis that detection and follow-up of MGUS may influence survival in multiple myeloma is unlikely to ever be tested in a prospective clinical study due to the large sample size required with long follow-up time, and consequent extreme costs.

We found that multiple myeloma patients with prior knowledge of MGUS had significantly 15% better survival, despite having significantly more comorbidities. Interestingly, low-risk MGUS (with very low M-protein) had highest risk of death. The observation that low M-protein concentration at MGUS diagnosis was associated with poorer multiple myeloma survival may reflect less frequent clinical follow-up. Our observations stress the importance of clinical follow-up in MGUS, regardless of risk stratification.

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Phase 3 Study of Oral Proteasome Inhibitor For Relapsed or Refractory Multiple Myeloma

MedicalResearch.com Interview with:
Dr. Dixie-Lee Esseltine MD, FRCPC
Vice President, Oncology Clinical Research
Takeda.

MedicalResearch: What is Ixazomib?

Dr. Dixie-Lee Esseltine: Ixazomib is an investigational, oral, once-weekly proteasome inhibitor (PI) that is being investigated in multiple Phase 3 trials in multiple myeloma (MM) and systemic light-chain (AL) amyloidosis. It is the first oral  proteasome inhibitor to enter Phase 3 clinical trials.

Proteasome inhibition is a mechanism underpinning an established standard of care in the treatment of multiple myeloma. However, the current biweekly parenteral administration of proteasome inhibitors may pose challenges to patients. The ability to demonstrate that an oral, once-weekly PI can extend PFS would be a remarkably important finding in the effort to address these challenges. Early studies suggest ixazomib, has activity in MM patients, both as a single agent in relapsed patients and in combination in frontline patients.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012. It was granted Breakthrough Therapy Designation for AL amyloidosis in the U.S. in 2014.

MedicalResearch: What is the design for this study?

Dr. Dixie-Lee Esseltine: The TOURMALINE MM-1 study (C16010) is a phase 3, randomized, double-blind study comparing ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Patients were randomized to receive ixazomib 4.0mg days 1,8 and 15 or placebo with  lenalidomide 25mg days 1-21 and dexamethasone 40mg days 1,8,15 and 22. Treatment was given every 28 days until disease progression or unacceptable toxicity. Evaluation was based on the International Myeloma Working Group (IMWG) Uniform Response Criteria.

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