San Francisco, CA (Press Release) – New treat­ment com­bi­na­tions and targeted ther­a­pies for lym­phoma and multiple myeloma are improving out­comes for vulnerable patient pop­u­la­tions with hard-to-treat disease, according to studies presented today at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.

Despite ad­vances in lym­phoma treat­ments, improving the prognosis for patients with re­lapsed and treat­ment-resistant disease remains a chal­lenge. The early success of several precision ther­a­pies asso­ci­ated with fewer side effects than conventional ap­proaches offers new hope for conquering aggressive disease. For lym­phoma patients who relapse or do not respond to initial ther­apy, stem cell trans­plan­ta­tion also presents a poten­tially curative option; how­ever, this procedure is not always successful. Two studies presented today detail methods to im­prove out­comes in patients with re­lapsed or hard-to-treat lym­phoma, in­­clud­ing adding a targeted anti­body to standard treat­ment to prevent relapse after trans­plant, and an ap­proach to making stem cell trans­plan­ta­tion the standard of care for patients with HIV-associated lym­phoma.

In three other studies, researchers will describe new ad­vances in the treat­ment of myeloma. These reports are examples of new precision treat­ments, in­­clud­ing a pro­te­a­some inhibitor and two anti-CD28 anti­bodies that dem­onstrate encouraging results when com­bined with standard care for patients with re­lapsed and treat­ment-resistant disease.

“While eradicating aggressive lym­phoma and multiple myeloma remains a major hurdle, the emergence of several promising strategies makes this an exciting time for physician-scientists in this field,” said Brad Kahl, MD, moderator of the press briefing and Associate Professor of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison. “By combining ther­a­pies and studying out­comes in vulnerable subsets of patients, we are learning more about how we can best help those who have not responded to any other treat­ment.”

Brentuximab Vedotin Prolongs Post-Transplant Survival in Hard-to-Treat Lymphoma Patients in Phase III Study
The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma [673]

Roughly half of patients with re­lapsed and hard-to-treat Hodgkin lym­phoma respond to a com­bi­na­tion of high-dose ther­apy and au­tol­o­gous stem cell trans­plant, a procedure in which healthy cells are taken from the patient’s own blood or bone marrow to effectively “replace” damaged cells. Unfortunately, many patients still ex­peri­ence recurrence of disease after undergoing this intense procedure.

This Phase III, ran­dom­ized, multi-center study compared brentuximab vedotin (BV), an anti­body targeting the CD30 protein on Hodgkin lym­phoma cells, with placebo in 327 patients at risk of post-transplant disease pro­gres­sion. All trial par­tic­i­pants had either achieved remission or had stable, non-progressing disease at time of trans­plant. Between 30 and 45 days after trans­plant, patients were ran­dom­ized to receive either BV or placebo for up to one year. After a median of two years of follow up, researchers observed that patients receiving BV had a 20 per­cent im­prove­ment without disease pro­gres­sion compared to patients receiving placebo (progression-free survival rate of 65% vs. 45%) The safety profile was generally con­sis­tent with existing pre­scrib­ing in­for­ma­tion. The most common events asso­ci­ated with BV in­cluded periph­eral sensory neu­rop­athy, upper res­pira­tory tract in­fec­tion, and neu­tro­penia.

“This is the first study in lym­phoma to dem­onstrate that the addi­tion of a main­te­nance drug after trans­plant can markedly im­prove patient out­comes,” said lead study author Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York. “Given these extremely positive results, we predict that brentuximab vedotin will soon become the standard of care for Hodgkin lym­phoma patients who undergo an au­tol­o­gous stem cell trans­plant.”

Stem Cell Transplantation Safe for Patients with HIV-Associated Lymphoma
Autologous Hematopoietic Stem Cell Transplantation (AHCT) in Patients with Chemotherapy-Sensitive, Relapsed/Refractory (CSRR) Human Immunodeficiency Virus (HIV)-Associated Lymphoma (HAL): Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial [674]

Historically, prognoses have been poor for patients diag­nosed with HIV-associated lym­phoma (HAL); how­ever, highly active antiretroviral ther­apy has in­­creased these patients’ ability to tolerate standard of care and has led to sig­nif­i­cantly im­proved out­comes. Within the last decade, HAL patients have received com­parable ther­a­pies to those offered to other lym­phoma patients. However, because HAL patients are immunocompromised, they have been con­sidered to be in­eli­gible for stem cell trans­plan­ta­tion, regarded as the standard of care for re­lapsed or treat­ment-resistant disease. As a result, HAL patients remain at a sig­nif­i­cant treat­ment disadvantage.

To examine whether trans­plant could be a safe and effective ap­proach for HAL patients, researchers from the National Cancer Institute Bone Marrow Transplant Clinical Trials Network work­ing in col­lab­o­ration with the AIDS Malignancy Consortium, conducted a large, multi-center study among 40 patients with controlled HIV in­fec­tion receiving au­tol­o­gous stem cell trans­plants with a high-dose preparative regi­men. Patients had persistent or recurrent Hodgkin or aggressive non-Hodgkin lym­phoma. At 100 days post-transplant, 36 patients (92.3%) had achieved com­plete response, one (2.6%) reached partial remission, and two (5.1%) had re­lapsed. One patient had died. Within a year after trans­plant, 17 patients (42.5%) developed a total of 42 unique in­fec­tions. Nine of 17 patients developed severe in­fec­tion. After a median two-year follow-up, the one-year survival among the trans­planted patients was 86.6 per­cent. The cumulative incidence of trans­plant-related mortality was 5.2 per­cent.

“These impressive survival data dem­onstrate that au­tol­o­gous stem cell trans­plants can be highly effective, tolerable, and not overly toxic for patients with HIV-associated lym­phoma,” said lead study author Joe Alvarnas, MD, of City of Hope National Medical Center in Duarte, CA. “Ultimately, our results provide a persuasive argument that HIV or AIDS status should not be a barrier to au­tol­o­gous stem cell trans­plant for patients who meet standard eligibility criteria.”

Carfilzomib Represents Potent, Effective Addition to Standard Multiple Myeloma Therapy in Phase III Study
Carfilzomib, Lenalidomide, and Dexamethasone vs. Lenalidomide and Dexamethasone in Patients (Pts) with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase III Study [79]

The recently approved targeted treat­ment car­filz­o­mib has been shown to help slow or halt the spread of cancer by targeting the mech­a­nisms that control excess proteins on which multiple myeloma cells thrive for con­tinued growth. Carfilzomib adds to an in­creas­ing number of precision ap­proaches that are shifting the treat­ment paradigm away from chemo­ther­apy. In fact, the current global standard of care for patients with re­lapsed or treat­ment-resistant multiple myeloma is a com­bi­na­tion of a drug called lena­lido­mide that specifically targets the immune system and the steroid dexa­meth­a­sone.

In order to eval­u­ate whether car­filz­o­mib com­bined with standard ther­apy might im­prove treat­ment responses in patients with re­lapsed or treat­ment-resistant multiple myeloma, researchers enrolled 792 patients from 20 countries in a Phase III clin­i­cal trial, ran­domizing them to receive the standard com­bi­na­tion of lena­lido­mide and dexa­meth­a­sone (Rd) or the com­bi­na­tion along with car­filz­o­mib (KRd). Upon interim analysis, the group treated with KRd dem­onstrated a longer duration of response without disease pro­gres­sion (26.3 months) compared with the Rd-treated group (17.6 months). The dif­fer­ence in over­all response rates in the two treat­ment groups was also sig­nif­i­cant, at 87.4 per­cent in the KRd group compared to 66.9 per­cent in the Rd group. Importantly, despite the addi­tion of a drug to the regi­men, no dramatic in­­crease in toxicity was observed in the KRd group. In addi­tion, patients in the KRd group con­sis­tently reported higher quality of life scores than those receiving Rd.

“By adding car­filz­o­mib to the gold standard in multiple myeloma ther­apy, we are observing an unprece­dented duration of remission without addi­tional toxicity, a promising out­come in re­lapsed and heavily pre-treated patients,” said lead study author A. Keith Stewart, MD, of Mayo Clinic Arizona in Scottsdale. “We hope that the results of this trial will lead to approval of this treat­ment com­bi­na­tion in patients with re­lapsed multiple myeloma world­wide.”

Daratumumab Plus Standard Treatment Improves Outcomes in Relapsed, Hard-to-Treat Multiple Myeloma in Phase I Study
An Open-Label, Multicenter, Phase 1b Study of Dara­tu­mu­mab in Combination with Backbone Regimens in Patients with Multiple Myeloma [176]

A new class of drugs called anti-CD38 anti­bodies target multiple myeloma cells by binding to an an­ti­gen (CD38) expressed on the myeloma cell and then signaling the patient’s immune cells to attack myeloma cells. Dara­tu­mu­mab, one of three anti-CD38 anti­bodies under in­ves­ti­ga­tion for multiple myeloma, has been reported in early trials to be effective and relatively safe as a single agent in patients with re­lapsed or treat­ment-resistant disease. Given these positive results, researchers hypothesized that they could po­ten­tially im­prove response rates for these patients by adding dara­tu­mu­mab to already-proven treat­ment regi­mens.

To study the safety, tolerability, and appro­pri­ate dose regi­men of dara­tu­mu­mab in com­bi­na­tion with standard treat­ment, researchers enrolled patients with newly diag­nosed, re­lapsed, or treat­ment-resistant multiple myeloma in a multi-center trial in which they received dara­tu­mu­mab with one of four standard regi­mens. Standard regi­mens in­cluded bor­tez­o­mib-dexamethasone (VD), bor­tez­o­mib-thalidomide-dexamethasone (VTD), bor­tez­o­mib-melphalan-prednisone (VMP), and poma­lido­mide-dexamethasone (POM-D). After median treat­ment duration of 44 days, tolerability assess­ments for 17 patients in the newly diag­nosed multiple myeloma group receiving a bor­tez­o­mib-based regi­men (VD, VTD, or VMP) indicated that patients ex­peri­enced no addi­tional toxicity. Four patients ex­peri­enced infusion-related reac­tions asso­ci­ated with dara­tu­mu­mab; how­ever, this did not interrupt treat­ment. All other adverse events were con­sis­tent with those accompanying standard regi­mens. Preliminary data dem­onstrate a high patient response rate to this new thera­peutic ap­proach. Efficacy and safety assess­ments in the trial are ongoing and will be presented at the meeting.

“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision ap­proach with the standard of care is leading to more effective treat­ment without in­­creased toxicity,” said lead study author Philippe Moreau, MD, of University Hospital of Nantes in France. “By targeting a simple molecule expressed by the cancer cells, this ther­apy has the poten­tial to become a potent addi­tion to conventional treat­ment.”

Investigational Antibody Demonstrates Efficacy, Safety for Patients with Aggressive Multiple Myeloma in Phase I Study
A Phase Ib Dose Escalation Trial of SAR650984 (Anti-CD-38 mAb) in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma [83]

SAR650984 (SAR) is another anti-CD38 anti­body that has shown single-agent activity in Phase I testing among heavily pre-treated myeloma patients. In this Phase Ib trial, researchers added escalating doses of SAR to a standard regi­men of lena­lido­mide and dexa­meth­a­sone in patients with re­lapsed or treat­ment-resistant multiple myeloma.

The goals of this study were to identify the maximum tolerated dose of SAR in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone, and to assess pre­lim­i­nary efficacy of the regi­men. Thirty-one patients with re­lapsed or treat­ment-resistant disease were enrolled, with 13 patients receiving escalating doses of SAR650984 and 18 patients receiving the highest dose. After a median of nine months of follow-up, 58 per­cent of patients responded to treat­ment. Progression-free survival was 6.2 months. The response rate was slightly higher in patients receiving the highest dose of SAR. Responses were observed in patients who had pre­vi­ously re­lapsed or dem­onstrated resistance to lena­lido­mide or other similar drugs (called immune modulators). While no in­­creased toxicity was observed, the most common adverse events reported in­cluded mild fatigue, nausea, diarrhea, blood count suppression, and upper res­pira­tory tract in­fec­tion. Two patients dis­con­tinued treat­ment due to infusion-associated reac­tions.

“The addi­tion of this anti­body made a sig­nif­i­cant dif­fer­ence in out­comes among these patients, even among those who had pre­vi­ously re­lapsed or did not respond to initial ther­apy with immune modulator drugs,” said lead study author Thomas Martin, MD, of the University of California, San Francisco. “Our next steps are to further eval­u­ate even higher doses of the anti­body and to per­form a ran­dom­ized study in the hopes of showing that treat­ment with the anti­body plus immune modulator drugs is better than treat­ment with immune modulators alone.”

American Society of Hematology 56th Annual Meeting

The study authors and press pro­gram moderator will be avail­able for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on ad­vances in lym­phoma and myeloma treat­ment, immuno­therapy, anemia and novel care ap­proaches, and blood clots. For the com­plete annual meeting pro­gram and abstracts, visit www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH14 on Twitter and like ASH on Facebook for the most up-to-date in­for­ma­tion about the 2014 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the under­stand­ing, diag­nosis, treat­ment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the devel­op­ment of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is avail­able weekly in print and online.

Source: American Society of Hematology.