The Nobel Prize in Chemistry 2015

The cells’ toolbox for DNA repair

The Nobel Prize in Chemistry 2015 is awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for having mapped, at a molecular level, how cells repair damaged DNA and safeguard the genetic information. Their work has provided fundamental knowledge of how a living cell functions and is, for instance, used for the development of new cancer treatments.

Each day our DNA is damaged by UV radiation, free radicals and other carcinogenic substances, but even without such external attacks, a DNA molecule is inherently unstable. Thousands of spontaneous changes to a cell’s genome occur on a daily basis. Furthermore, defects can also arise when DNA is copied during cell division, a process that occurs several million times every day in the human body.

The reason our genetic material does not disintegrate into complete chemical chaos is that a host of molecular systems continuously monitor and repair DNA. The Nobel Prize in Chemistry 2015 awards three pioneering scientists who have mapped how several of these repair systems function at a detailed molecular level.

In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Tomas Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover a molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA.

Aziz Sancar has mapped nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA. People born with defects in this repair system will develop skin cancer if they are exposed to sunlight. The cell also utilises nucleotide excision repair to correct defects caused by mutagenic substances, among other things.

Paul Modrich has demonstrated how the cell corrects errors that occur when DNA is replicated during cell division. This mechanism, mismatch repair, reduces the error frequency during DNA replication by about a thousandfold. Congenital defects in mismatch repair are known, for example, to cause a hereditary variant of colon cancer.

The Nobel Laureates in Chemistry 2015 have provided fundamental insights into how cells function, knowledge that can be used, for instance, in the development of new cancer treatments.

The Nobel Prize in Chemistry 2015

S1 Biopharma supports FDA's approval of flibanserin for women living with HSDD

Approval of flibanserin by the U.S. Food and Drug Administration (FDA) was a significant advancement for women's health, addressing the important unmet medical need for women living with HSDD. The condition is marked by a lack of sexual thoughts and desire for sexual activity that cannot be accounted for by another medical, physical, psychiatric, or medication-induced condition. An estimated one in 10 women may have HSDD at some point in their life, for which therapies like flibanserin and Lorexys, S1 Biopharma's next-generation first in class drug, are being developed to address.

We are pleased for Dr. Robert Pyke, who before joining S1 Biopharma as Chief Medical Officer in 2012 to develop Lorexys, had fathered flibanserin at Boehringer Ingelheim before it was acquired by Sprout Pharmaceuticals.

S1 Biopharma, Inc. is continuing the development of Lorexys, a unique multi-receptor oral tablet being studied for the treatment of HSDD in pre-menopausal women. Lorexys will provide first-line treatment for women suffering from HSDD as an easy to administer daily pill.

S1 Biopharma supports FDA's approval of flibanserin for women living with HSDD

STA inks license and commercialisation agreement with PharmaMar for APLIDIN (plitidepsin)

Australian biopharmaceutical company Specialised Therapeutics Australia has struck an exclusive license and commercialisation agreement with European pharmaceutical partner company PharmaMar to market and distribute the novel oncology drug APLIDIN® (plitidepsin) in Australia and New Zealand.

Under the terms of the agreement, PharmaMar will receive an upfront payment, royalties and additional remunerations for regulatory and sales milestones achieved by APLIDIN® (plitidepsin).

PharmaMar will retain production rights and will supply the finished product to STA for exclusive commercial use in Australia and New Zealand.

APLIDIN® (plitidepsin) is PharmaMar´s second anticancer drug candidate obtained from a marine organism. This first in class drug is currently in development for the treatment of multiple myeloma and a type of T cell lymphoma. The company announced in June that patient recruitment of the international pivotal Phase III trial (ADMYRE) for APLIDIN® (plitidepsin) in refractory/relapsed multiple myeloma was successfully completed.

STA inks license and commercialisation agreement with PharmaMar for APLIDIN (plitidepsin)

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

 

AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced that a Phase 2 trial of its investigational medicine
venetoclax met its primary endpoint of achieving overall response ratesin patients with relapsed/refractory or previously untreated chroniclymphocytic leukemia (CLL) with 17p deletion, according to anindependent review analysis. The open-label study evaluated the efficacy and safety of venetoclax, an inhibitor of the B-cell lymphoma-2 (BCL-2)
protein that is being developed in partnership with Genentech and Roche.

Data from this study will be presented at an upcoming medical conference and will serve as the pivotal registration data forapplications to the FDA, EMA and other health authorities. The safety profile was similar to previous studies and no unexpected safety signals were reported for venetoclax.

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

Envarsus XR granted FDA orphan drug designation for prophylaxis of organ rejection in kidney transplant patients

Veloxis Pharmaceuticals A/S (OMX: VELO), today announced that Envarsus^® XR was     granted Orphan Drug status by the U.S. Food and Drug Administration(FDA) for prophylaxis of organ rejection in patients who convert fromimmediate-release tacrolimus. Envarsus^® XR received marketing authorization from the FDA on July 10, 2015.

"We view Orphan Drug status as the FDA's recognition of thedifferentiated profile and the unique 'switch' indication of Envarsus^® XR compared  to  other               tacrolimus products," said William Polvino, M.D.,
president and chief executive officer of Veloxis. "We now look forwardto making Envarsus^® XR available to conversion patients by the end of 2015."

Orphan drug designation is designed is to encourage the developmentof drugs that may provide significant benefit to patients suffering from rare diseases. The designation is granted by the FDA upon recognition
that the prevalence of the U.S. target patient population is 200,000patients or less. Orphan drug designation entitles Veloxis to a waiver of the FDA prescription drug user fees for Envarsus^® XR aswell as for potential tax incentives. Additionally, U.S. dataexclusivity protection may be extended for up to seven years.

 

Envarsus XR granted FDA orphan drug designation for prophylaxis of organ rejection in kidney transplant patients

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

Venetoclax, also known as ABT-199 or GDC0199, is an orally bioavailable, selective small molecule inhibitor of the anti-apoptotic protein Bcl-2, with potential antineoplastic activity. Venetoclax mimics BH3-only proteins, the native ligands of Bcl-2 and apoptosis activators, by binding to the hydrophobic groove of Bcl-2 proteins thereby repressing Bcl-2 activity and restoring apoptotic processes in tumor cells. Bcl-2 protein is overexpressed in some cancers and plays an important role in the regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival. Compared to the Bcl-2 inhibitor navitoclax, this agent does not inhibit bcl-XL and does not cause bcl-XL-mediated thrombocytopenia....

AbbVie (NYSE: ABBV), a global biopharmaceutical company,  announced that a Phase 2 trial of its investigational medicine venetoclax met its primary endpoint of achieving overall response rates in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) with 17p deletion, according to an independent review analysis. The open-label study evaluated the efficacy and safety of venetoclax, an inhibitor of the B-cell lymphoma-2 (BCL-2) protein that is being developed in partnership with Genentech and Roche.

Data from this study will be presented at an upcoming medical conference and will serve as the pivotal registration data for applications to the FDA, EMA and other health authorities. The safety profile was similar to previous studies and no unexpected safety signals were reported for venetoclax.

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

Vascular side effects prevent first-line ponatinib use in chronic phase CML

 

In continuation of my update on Ponatinib 

Ponatinib is highly active when given to patients within 6 months of developing chronic phase chronic myeloid leukaemia (CML), phase II results show, but its toxicity profile is unacceptable for first-line treatment.

The investigators, from the University of Texas MD Anderson Cancer Center in Houston, USA, report “deep and early responses” to the third-generation tyrosine kinase inhibitor (TKI) in The Lancet Haematology.

“However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting”, recommend Jorge Cortes and co-authors.

At 6 months, a complete cytogenetic response (CCyR) was achieved by 94% of 46 assessed patients and a major molecular response (MMR, BCR–ABL1 ≤0.1%) by 83%, with undetectable levels of BCR–ABL1 in 22% of assessed patients and a level of 1% or below in 96%.

The median times to a complete haematological response, CCyR and MMR were 0.6, 2.89 and 2.90 months, respectively, and there was 100% overall and transformation-free survival after 2 years.

But the initial starting dose of 45 mg/day in 43 patients was reduced to 30 mg/day or 15 mg/day for 18 patients after tolerability issues, while six of eight patients started on 30 mg/day had the dose reduced to 15 mg/day. At least one treatment interruption was required by 85% of patients, while 88% had their dose reduced due to adverse events (66%) or US Food and Drug Administration (FDA) advice (24%).

All of these patients finally discontinued ponatinib therapy and switched to an alternative TKI following adverse events or FDA concerns about an increased risk of thromboembolism.

In all, 49% of patients experienced cardiac or vascular events and 22% had more than one such episode. These included worsening or new-onset of hypertension, one case each of acute coronary syndrome and myocardial infarction, and three cases of vaso-occlusive disease. Two patients experienced cerebrovascular events, and one patient developed pulmonary hypertension within a month of discontinuing ponatinib.

Vascular side effects prevent first-line ponatinib use in chronic phase CML

MedDay announces additional positive results from MD1003 Phase III trial in patients with progressive MS

MedDay, a biotechnology company focused on the treatment of nervous system disorders, reports additional positive data from its pivotal Phase III clinical trial, MS-SPI, with MD1003, a highly-concentrated pharmaceutical grade biotin, in patients with Progressive Multiple Sclerosis. The data, to be announced on Saturday 20th June at The 1st Congress of the European Academy of Neurology (EAN), shows an improvement of the Clinical Global Impression of change observed after 12 months of treatment with MD1003 and confirms the positive results presented at the American Academy of Neurology in April 2015.

The Clinical Global Impression of change is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. During the MS-SPI trial, the Clinical Global Impression of change has been assessed by the clinician (clinician global impression, CGI) as well as by the patient (subject global impression, SGI) after 12 months of treatment. Mean CGI and SGI scores assessed at month 12 were statistically significantly better in the intervention group compared with the placebo group (p<0.0001 and p=0.0094, respectively).

These important results confirm the previously reported data of MS-SPI where the primary endpoint was defined as the proportion of patients who improved either on EDSS or on timed 25-foot walk (TW25) at M9, with a confirmation of the improvement at 12 months (M12) was met (p=0.0051). The mean change of EDSS between M0 and M12 decreased in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.014). In the MD1003 arm, only 4% of patients treated with MD1003 exhibited EDSS progression at M9 confirmed at M12 vs 13% in the placebo group (p=0.07), which equates to a 67% decreased risk of progression in the active arm within the studied period.

MedDay announces additional positive results from MD1003 Phase III trial in patients with progressive MS

Scientists identify new agent to combat tuberculosis

(Griselimycin)

Above pic: The protein forms a homodimeric ring (shown as blue cartoon & surface representation). Each polypetide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground).

According to figures of the World Health Organization, some 8.7 million people contracted tuberculosis in 2012 and this disease is fatal for approximately 1.3 million people throughout the world each year. One of the main problems is that the tuberculosis pathogens have become resistant to the antibiotics used to fight them. Scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken, the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the German Center for Infection Research (DZIF) joined forces with scientists from Sanofi, a global health care company, and identified a new agent, which might potentially remedy these problems. The scientists just described this agent and its unique mechanism of action in the highly renowned scientific journal Science.

Mycobacterium tuberculosis is the main cause of tuberculosis. The treatment for drug-susceptible tuberculosis consists of the daily administration of multiple drugs for a minimum of six months. Lack of adherence to this regimen can result in treatment failure and the emergence of drug resistance. "Complexity and duration of the treatment are true issues and the main reasons for the development of resistant pathogens," says Prof Rolf Müller, who is the Executive Director and head of the Microbial Natural Substances department of the HIPS, an institution jointly sponsored by the HZI and Saarland University.

Consequently, there is an urgent need for new medications and therapeutic approaches to both fight the resistant pathogens, as well as to shorten the duration for the treatment of drug-susceptible organisms. Based on earlier reports, Müller, in collaboration with Prof Jacques Grosset from the Johns Hopkins University School of Medicine in Baltimore, and his colleagues from the HZI and Sanofi scientists, initially focused on the natural substance called griselimycin. The potential of this natural substance, was discovered in the 1960s. However, due to the success of other tuberculosis medications and its low efficacy in an infection model, the substance was not developed any further at the time.

"We resumed the work on this agent and optimised it such that it shows excellent activity in the infection model - even against multi-resistant tuberculosis pathogens," says Müller. In the course of their work, the scientists discovered that cyclohexylgriselimycin, a variant of griselimycin, is particularly effective against Mycobacterium tuberculosis, both in cells and in the animal model. Importantly, cyclohexylgriselimycin was effective when administered orally, which is key in tuberculosis treatment, non-orally available drugs are extremely burdensome to administer daily during the many months of treatment. Moreover, combining this substance with current TB antibiotics increases the efficacy compared to the antibiotic cocktail that is usually administered.

Scientists identify new agent to combat tuberculosis

Once-weekly Trulicity 0.75 mg shows promising results in Japanese patients with type 2 diabetes

In continuation of my update on dapagliflozin

Results from a new study of Japanese patients with type 2 diabetes showed once-weekly Trulicity™ 0.75 mg provided greater hemoglobin A1c (A1C) reduction compared to once-daily Victoza® 0.9 mg after 52 weeks of treatment. Eli Lilly and Company (NYSE: LLY) will present these data at the 75th American Diabetes Association (ADA) Scientific Sessions in Boston.

"These data not only reinforce once-weekly Trulicity as a safe and efficacious GLP-1 receptor agonist, but further support the value for Japanese patients, with greater A1C reductions compared to once-daily Victoza," said Jessie Fahrbach, M.D., medical director, Lilly Diabetes. "We are pleased to present these study findings, which capture important information about a key region where type 2 diabetes is on the rise."

The study's primary objective was met, with Trulicity 0.75 mg demonstrating a greater A1C reduction from baseline compared to placebo at 26 weeks. At the final endpoint of 52 weeks, which is the focus of the data presentation at the meeting, Trulicity 0.75 mg demonstrated statistically greater A1C reductions compared to Victoza 0.9 mg, the highest approved dose in Japan (-1.39 percent vs. -1.19 percent). Additional results showed:

Trulicity 0.75 mg provided statistically greater reductions in the average self-monitored blood glucose levels compared to Victoza 0.9 mg (-53.1 mg/dL vs. -46.8 mg/dL); and

Trulicity 0.75 mg significantly lowered average post-meal blood glucose levels from baseline compared to Victoza 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL).

Results from a new study of Japanese patients with type 2 diabetes showed once-weekly Trulicity™ 0.75 mg provided greater hemoglobin A1c (A1C) reduction compared to once-daily Victoza® 0.9 mg after 52 weeks of treatment. Eli Lilly and Company (NYSE: LLY) will present these data at the 75th American Diabetes Association (ADA) Scientific Sessions in Boston.

"These data not only reinforce once-weekly Trulicity as a safe and efficacious GLP-1 receptor agonist, but further support the value for Japanese patients, with greater A1C reductions compared to once-daily Victoza," said Jessie Fahrbach, M.D., medical director, Lilly Diabetes. "We are pleased to present these study findings, which capture important information about a key region where type 2 diabetes is on the rise."

The study's primary objective was met, with Trulicity 0.75 mg demonstrating a greater A1C reduction from baseline compared to placebo at 26 weeks. At the final endpoint of 52 weeks, which is the focus of the data presentation at the meeting, Trulicity 0.75 mg demonstrated statistically greater A1C reductions compared to Victoza 0.9 mg, the highest approved dose in Japan (-1.39 percent vs. -1.19 percent). Additional results showed:

Trulicity 0.75 mg provided statistically greater reductions in the average self-monitored blood glucose levels compared to Victoza 0.9 mg (-53.1 mg/dL vs. -46.8 mg/dL); and Trulicity 0.75 mg significantly lowered average post-meal blood glucose levels from baseline compared to Victoza 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL).

Once-weekly Trulicity 0.75 mg shows promising results in Japanese patients with type 2 diabetes

Ibrutinib (IMBRUVICA) improves survival in treatment-naïve patients with chronic lymphocytic leukemia

In continuation of my update on Ibrutinib

Pharmacyclics LLC, an AbbVie company, announced that ibrutinib (IMBRUVICA®) improved progression-free survival (PFS; primary endpoint) and multiple secondary endpoints including overall survival (OS) and overall response rate (ORR) in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL, respectively) in the final analysis of the Phase III RESONATE™-2 (PCYC-1115) trial. RESONATE-2 is a randomized, multi-center, open-label study assessing the use of ibrutinib versus chlorambucil in treatment-naïve CLL/SLL patients aged 65 years or older. This is the first head-to-head trial in the clinical program that evaluates the safety and efficacy of ibrutinib versus traditional chemotherapy. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

"In collaboration with our partner Janssen, we are very excited by the findings from RESONATE-2 and look forward to sharing the results from what we see as a potentially transformative study for CLL patients," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "These results from the first IMBRUVICA study for front-line CLL patients may support future treatment paradigms where some CLL patients requiring therapy may not need to be exposed to traditional cytotoxic chemotherapy."

"Over the past several years we've made tremendous progress in treating CLL, thanks in part to therapies such as IMBRUVICA," said Richard A. Gonzalez, Chairman of the Board and Chief Executive Officer at AbbVie. "Based on the results from RESONATE-2, IMBRUVICA continues to demonstrate its strong value and we are very optimistic that it will eventually move into the front-line treatment setting, becoming an alternative option to chemotherapy for previously untreated CLL patients."

Ibrutinib (IMBRUVICA) improves survival in treatment-naïve patients with chronic lymphocytic leukemia

Tentative FDA approval of lopinavir/ritonavir oral pellet formulation closes treatment gap for children with HIV

The Paediatric HIV Treatment Initiative welcomes this important step towards closing the treatment gap for children with HIV

Infants and young children living with HIV will finally have access to an improved formulation of an antiretroviral (ARV) treatment, following the U.S. Food and Drug Administration's (FDA) tentative approval last week of lopinavir/ritonavir (LPV/r) oral pellets developed by the Indian generic company Cipla.

(lopinavir)  (ritonavir)

"The announcement of tentative FDA approval of the lopinavir/ritonavir oral pellet formulation is an important step forward in increasing access to World Health Organization-recommended antiretroviral treatment for children under three years of age," said Ambassador Deborah L. Birx, M.D., U.S. Global AIDS Coordinator and U.S. Special Representative for Global Health Diplomacy. "This supports the goals of key PEPFAR initiatives to improve paediatric HIV/AIDS services, including the Accelerating Children's HIV/AIDS Treatment Initiative and the Global Pediatric ARV Commitment to Action".

Until now, the only available version of this combination treatment was a harsh-tasting syrup that required refrigeration and contained 40% alcohol. Only a quarter of children with HIV are currently on treatment and the lack of child-adapted formulations contributes to this unacceptable situation.

"UNITAID and its partners in the Paediatric HIV Treatment Initiative (PHTI)* also welcome the approval of these oral pellets, which brings us a step nearer to closing the shameful treatment gap for the 3.2 million children living with HIV around the world," said Lelio Marmora, Executive Director of UNITAID which is funding the development of paediatric formulations for HIV.

Importantly, intellectual property issues around access to future LPV/r combinations will be reduced, thanks to a licensing agreement the Medicine Patent Pool (MPP) signed in in December 2014 with AbbVie, the patent holder for LPV/r. "This is a crucial licence for paediatric programmes as it benefits low- and middle-income countries where 99% of children with HIV in the developing world live," said Greg Perry, Executive Director of the MPP.

Tentative FDA approval of lopinavir/ritonavir oral pellet formulation closes treatment gap for children with HIV

AWMSG recommends Daklinza (daclatasvir) for treatment of adult patients with chronic HCV infection

In continuation of my update on daclatasvir 

The All Wales Medicines Strategy Group (AWMSG) has recommended Daklinza®(daclatasvir) for the treatment of adult patients with chronic hepatitis C virus (HCV) infection. The recommendation is specifically for patients with advanced liver disease, for whom treatment options can be limited. Daclatasvir is used in combination with other agents to treat adult patients with chronic HCV genotypes 1, 3 and 4 (which include most of the cases seen in Wales). This decision could enable some of the most ‘at-risk’ patients in Wales with chronic HCV to access a new, first-in-class treatment which has been shown, when used with other agents, to clear the viral infection in most of these patients after 12 or 24 weeks of therapy.

AWMSG recommends Daklinza (daclatasvir) for treatment of adult patients with chronic HCV infection

PALOMA3 supports palbociclib use in advanced breast cancer

In continuation of my update on palbociclib... 

Advanced breast cancer patients who have failed prior endocrine treatment may receive a progression-free survival (PFS) benefit if palbociclib is added to fulvestrant, a phase III trial indicates.

The advantage accorded by the small-molecule inhibitor of CDK4 and CDK6 was irrespective of the menopausal status of the women, the team reports in The New England Journal of Medicine.

The research was concurrently presented at the annual meeting of the American Society of Clinical Oncology, held in Chicago, Illinois, USA.

The double-blind PALOMA3 trial comprised women with advanced breast cancer positive for oestrogen and/or progesterone hormone receptors but negative for epidermal growth factor receptor 2 who had progressed or relapsed during endocrine therapy.

PALOMA3 supports palbociclib use in advanced breast cancer

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Amgen announced the initiation of the ARROW trial, a global Phase 3 study evaluating the benefit of Kyprolis®(carfilzomib) for Injection administered once-weekly with dexamethasone versus the current U.S. Food and Drug Administration (FDA) approved twice-weekly administration schedule in patients with relapsed and refractory multiple myeloma who have received prior treatment with bortezomib and an immunomodulatory agent (IMiD). The trial was initiated based on results from the Phase 1/2 CHAMPION study, which were presented (abstract no. 8527) at the 51stAnnual Meeting of the American Society of Clinical Oncology (ASCO) on Sunday, May 31 at 8:00 a.m. CT.

Results from the Phase 1 and 2 portions of CHAMPION were presented for 104 patients (Phase 1, n=15; Phase 2, n=89) with relapsed or refractory multiple myeloma who had received one to three prior treatment regimens at the determined maximum tolerated dose (MTD) of 20/70 mg/m2. In the Phase 2 portion of the study, the overall response rate (ORR; defined as the percentage of patients achieving a partial response or better) was 77 percent. The clinical benefit rate (CBR; defined as the percentage of patients with minimal response or better) was 84 percent; the median time to response for patients who achieved a partial response or better was 1.6 months (range, 0.7-7.2); Kaplan-Meier median duration of response (DOR) was 15 months (95 percent CI 9-not estimable); and the Kaplan-Meier median progression-free survival (PFS) was 10.6 months (95 percent CI 9.0-16.1).

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients